\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"510",leadTitle:null,fullTitle:"Anxiety Disorders",title:"Anxiety Disorders",subtitle:null,reviewType:"peer-reviewed",abstract:"During the last 2-3 decades drastic research progress in anxiety issues has been achieved. It concerns mostly the study of different subtypes of anxiety and their treatment. Nevertheless, the data on anxiety pathogenesis is less elaborated, although here a multidimensional approach exists. It includes neurochemistry, pathophysiology, endocrinology and psychopharmacology. Again, we are able to recognize the multifarious sense of anxiety, and the present collective monograph composed of 16 separate chapters depicting the different aspects of anxiety. Moreover, a great part of book includes chapters on neurochemistry, physiology and pharmacology of anxiety. The novel data on psychopathology and clinical signs of anxiety and its relationship with other psychopathological phenomena is also presented. The current monograph may represent an interest and be of practical use not only for clinicians but for a broad range of specialists, including biochemists, physiologists, pharmacologists and specialists in veterinary.",isbn:null,printIsbn:"978-953-307-592-1",pdfIsbn:"978-953-51-6442-5",doi:"10.5772/1021",price:139,priceEur:155,priceUsd:179,slug:"anxiety-disorders",numberOfPages:338,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"183445801a9be3bfbce31fe9752ad3db",bookSignature:"Vladimir Kalinin",publishedDate:"August 1st 2011",coverURL:"https://cdn.intechopen.com/books/images_new/510.jpg",numberOfDownloads:58425,numberOfWosCitations:70,numberOfCrossrefCitations:25,numberOfCrossrefCitationsByBook:2,numberOfDimensionsCitations:79,numberOfDimensionsCitationsByBook:3,hasAltmetrics:1,numberOfTotalCitations:174,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 25th 2010",dateEndSecondStepPublish:"November 22nd 2010",dateEndThirdStepPublish:"March 29th 2011",dateEndFourthStepPublish:"April 28th 2011",dateEndFifthStepPublish:"June 27th 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"31572",title:null,name:"Vladimir V.",middleName:null,surname:"Kalinin",slug:"vladimir-v.-kalinin",fullName:"Vladimir V. Kalinin",profilePictureURL:"https://mts.intechopen.com/storage/users/31572/images/system/31572.png",biography:"Vladimir V. Kalinin was born in1952 into a family of physicians in Orenburg (Russian Federation). He obtained an MD from Moscow State Medical Stomatological University in 1976. In 1976-1977 he completed an internship in Psychiatry. In 1978 he became a scientific researcher at Moscow Research Institute of Psychiatry of Ministry of Health and Social Development where he is currently the department head. His scientific interests concern a broad range of psychiatry problems. The topic of his doctoral thesis in 1996 was the psychopathology and therapy of anxiety disorders with an emphasis on panic disorder. Prof. Kalinin has authored 228 publications, including research articles in professional journals (in Russian and English), three monographs in Russian, and four monographs in English.",institutionString:"Moscow Research Institute of Psychiatry – The Branch of Serbsky's National Center of Psychiatry and Narcology of Ministry of Health",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"4",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1061",title:"Psychiatry",slug:"mental-and-behavioural-disorders-and-diseases-of-the-nervous-system-psychiatry"}],chapters:[{id:"17567",title:"A Probable Etiology and Pathomechanism of Arousal and Anxiety on Cellular Level - Is It the Key for Recovering from Exaggerated Anxiety?",doi:"10.5772/22581",slug:"a-probable-etiology-and-pathomechanism-of-arousal-and-anxiety-on-cellular-level-is-it-the-key-for-r1",totalDownloads:2494,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:null,signatures:"András Sikter and Roberto De Guevara",downloadPdfUrl:"/chapter/pdf-download/17567",previewPdfUrl:"/chapter/pdf-preview/17567",authors:[{id:"35166",title:"Dr",name:"András",surname:"Sikter",slug:"andras-sikter",fullName:"András Sikter"},{id:"47828",title:"Mr.",name:"Roberto",surname:"De Guevara",slug:"roberto-de-guevara",fullName:"Roberto De Guevara"}],corrections:null},{id:"17568",title:"Relationship Between Oxidative Stress and Anxiety: Emerging Role of Antioxidants Within Therapeutic or Preventive Approaches",doi:"10.5772/19214",slug:"relationship-between-oxidative-stress-and-anxiety-emerging-role-of-antioxidants-within-therapeutic-1",totalDownloads:3535,totalCrossrefCites:3,totalDimensionsCites:11,hasAltmetrics:0,abstract:null,signatures:"Jaouad Bouayed",downloadPdfUrl:"/chapter/pdf-download/17568",previewPdfUrl:"/chapter/pdf-preview/17568",authors:[{id:"34084",title:"Dr.",name:"Jaouad",surname:"Bouayed",slug:"jaouad-bouayed",fullName:"Jaouad Bouayed"}],corrections:null},{id:"17569",title:"Pharmacology of 5-HT2 Modulation of Amygdala & Hypothalamus in Anxiety Disorders",doi:"10.5772/22837",slug:"pharmacology-of-5-ht2-modulation-of-amygdala-hypothalamus-in-anxiety-disorders1",totalDownloads:2926,totalCrossrefCites:0,totalDimensionsCites:4,hasAltmetrics:0,abstract:null,signatures:"Xiaolong Jiang, Aiqin Chen, Stanley Smerin, Lei Zhang and He Li",downloadPdfUrl:"/chapter/pdf-download/17569",previewPdfUrl:"/chapter/pdf-preview/17569",authors:[{id:"30247",title:"Dr.",name:"Lei",surname:"Zhang",slug:"lei-zhang",fullName:"Lei Zhang"},{id:"40664",title:"Prof.",name:"He",surname:"Li",slug:"he-li",fullName:"He Li"},{id:"49431",title:"Dr.",name:"Xiaolong",surname:"Jiang",slug:"xiaolong-jiang",fullName:"Xiaolong Jiang"},{id:"49436",title:"Dr.",name:"Chen",surname:"Aiqin",slug:"chen-aiqin",fullName:"Chen Aiqin"},{id:"49438",title:"Dr.",name:"Stanley",surname:"Smerin",slug:"stanley-smerin",fullName:"Stanley Smerin"}],corrections:null},{id:"17570",title:"Adenosine Signaling in Anxiety",doi:"10.5772/19423",slug:"adenosine-signaling-in-anxiety",totalDownloads:4046,totalCrossrefCites:2,totalDimensionsCites:4,hasAltmetrics:0,abstract:null,signatures:"Christina L. 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We will examine the literature to reveal how current treatments for ADHD affect these neurotransmitter levels in specific areas of the brain that are thought to be dysfunctional in ADHD. Additionally, we will detail new data on dopamine and glutamate dysfunction utilizing approaches that are capable of accurately measuring levels of these neurotransmitters in two separate rodent models of ADHD. Finally, we will speculate on the role that the dopamine-glutamate interaction will play in the future neuropharmacology of ADHD and how measuring these neurotransmitter levels in rodent models of ADHD may aid in furthering the future pharmacotherapy of ADHD.
Throughout the text, we will use ADHD (Attention-Deficit/Hyperactivity Disorder) without reference to the DSM-IV type, unless a specific reference pertains to combined, inattentive or hyperactive subtypes.
When the Diagnostic and Statistical Manual of Mental Disorders (DSM-1) was first published in 1952, childhood psychiatric disorders were thought to be caused by environment and referred to as ‘reactions’ [1]. It wasn’t until the DSM-2 was published in 1968 that ADHD began to be separated from general reactions and become its own diagnosis, referred to as the ‘hyperkinetic reaction of childhood.’ This reaction was characterized by a short attention span, hyperactivity, and restlessness [2], and in 1980, with the publication of the DSM-3, the ADHD diagnosis became more specific and was described as ADD (attention-deficit disorder) [3]; however, by this time, this disorder was already being treated with stimulant medications, a treatment still used to this day.
Stimulant medications were initially discovered to treat hyperactivity in the early 1900s when the psychiatrist Charles Bradley used amphetamines to treat children with headaches caused by pneumoencephalography and found it improved their school performance, social interactions and emotional responses. However, amphetamine as a treatment for ADHD was ignored until years later due to a variety of reasons [4]. In the 1950s, researchers were beginning to look for the underlying mechanisms causing behavioral problems and it was at this time that Bradley’s discovery of amphetamine as a treatment for hyperactivity was uncovered and investigations into the mechanism of action of amphetamine began. The amphetamine formulation Bradley used in his patients was called Benzedrine, a racemic mixture of 50/50 d- and l-amphetamine, produced by the company Smith, Kline and French [4]. Treatment with this medication in a variety of experimental paradigms reduced hyperactivity [5]; however, of particular note is a study published in 1976 showing decreased hyperactivity when treated with amphetamine in rodents with dopamine depletion [6]. This was the first time that hyperactivity was linked to dopamine, but far from the last.
Dopamine, classified as a catecholamine neurotransmitter, is produced in the cells of the substantia nigra (SN, A9) and ventral tegmental area (VTA, A10) of the midbrain and project to numerous brain regions, including the prefrontal cortex (PFC), striatum and nucleus accumbens (NA, see Figure 1). Projections from the VTA to the NA are identified as the mesolimbic pathway, or the “reward pathway,” because these dopamine projections are involved in rewarding behaviors, [7] firing when a reward is greater than expected or when a reward is anticipated [8-10]. Projections from the SN to the striatum are referred to as the nigrostriatal pathway and play a role in many aspects of motor control [11]. The mesocortical system consists of dopaminergic projections from the VTA to the PFC, and it is implicated in many cognitive functions including, but most certainly not limited to, attention and memory [11]. The mesocortical system will be the main focus in this chapter.
Dopamine is produced from tyrosine into 3,4-dihydroxyphenylalanine (DOPA) by the enzyme tyrosine hydroxylase. DOPA is then made into dopamine via DOPA-decarboxylase. Conversely, dopamine is broken down or converted by a number of mechanisms: 1) dopamine-β-hydroxylase converts dopamine into norepinephrine, 2) monoamine oxidase (MAO) converts dopamine into 3,4-dihydroxyphenylacetic acid (DOPAC), and 3) catechol-
Modulatory dopaminergic neurons (blue) project to the dorsal striatum via the substantia nigra (SN, A9) and the ventral striatum and prefrontal cortex (PFC) via the ventral tegmental area (VTA, A10) in the rodent brain. From the striatum, inhibitory GABA neurons (green) extend to multiple regions including the thalamus, which has reciprocal excitatory glutamate connections (red) to the striatum, as well as connections to the PFC. Prefrontal cortical efferent excitatory glutamate neurons extend to the striatum, nucleus accumbens (NA), SN, as well as the VTA.
Intracellularly, dopamine is packaged into vesicles via the vesicular monoamine transporter (VMAT-2). The release of dopamine from the vesicle is Ca2+ and Na+ dependent and occurs when an action potential raises the Ca2+ levels in the presynaptic neuron, causing vesicles stored with dopamine to bind to the cellular membrane and release their contents. The resulting synaptic dopamine is then able to bind to dopamine receptors on both the pre- and postsynaptic neurons. These receptors are classified into two major categories: 1) D1-type receptors, consisting of D1 and D5 and expressed postsynaptically, and 2) D2-type receptors expressed both pre- and postsynaptically, consisting of D2 (short), D2 (long), D3 and D4. Stimulation of D1-type receptors causes increased cAMP production (activating), whereas stimulation of D2-type receptors causes inhibition of cAMP production (inhibiting). The effects of these receptors give dopamine the classification of a modulatory neurotransmitter. For a simplified PFC dopamine synapse diagram, see Figure 2.
Dopaminergic and glutamatergic synapses in the PFC, simplified. Left: pre-synaptically, dopamine is transported into vesicles, which release their contents upon increase of the Ca2+ concentration. Synaptic dopamine is then able to stimulate dopamine receptors on both the pre- and postsynaptic neurons before it is cleared by the DAT or metabolism. Right: presynaptically, glutamate is stored in vesicles and then released into the extracellular space. Synaptic glutamate is then able to stimulate glutamate receptors (here represented as the NMDA and mGluR) on both the pre- and postsynaptic neurons before it is cleared by the EAAT located on nearby glial cells.
Recent clinical evidence has implicated glutamate in ADHD. Much of the initial evidence stems from proton magnetic resonance spectroscopy studies of children and adults with ADHD. These studies have shown increased levels of a marker for glutamate in the striatum and anterior cingulate cortex of the PFC [13-15]. Based on this evidence, new investigations into glutamatergic function in ADHD are ongoing. Glutamate is the major excitatory neurotransmitter in the central nervous system and must be tightly regulated for proper neuronal signaling to occur [16]. Unlike dopamine, glutamate is in abundance in most areas of the brain. Glutamate projections originating in the PFC extend to the striatum, NA, VTA and SN of the midbrain (see Figure 1). Glutamate is produced in the nerve terminals of these projections from two sources: 1) the Krebs cycle and 2) glutamine produced and excreted into the extracellular space via glial cells. Once produced, glutamate is transported into vesicles via the vesicular glutamate transporter (VGLUT) and when Ca2+ levels increase to cause an action potential, vesicles stored with glutamate bind to the cellular membrane and release their contents. Clearance of glutamate after this calcium-dependent release into the extracellular space is primarily performed by the membrane-bound glutamate transporter, called the excitatory amino acid transporter (EAAT), located on the presynaptic neuron and to the greatest extent by surrounding glial cells. The glutamate is primarily taken up by the EAATs located on the glial cells and is converted by glutamine synthetase into glutamine and transported out of the glial cell by system N transporter. The glutamine is then taken up by the system A transporter on the presynaptic neuron to help replenish glutamate levels through the mitochondrial bound glutaminase [11]. Glutamate acts on synaptic glutamate receptors in the target brain region, which are classified into two major types: 1) ionotropic, which include the NMDA, AMPA and kainate receptors and 2) metabotropic, including the excitatory mGluRs 1 and 5 (postsynaptic) and the inhibitory mGluRs 2, 3, 4, 6, 7, and 8 (presynaptic). For a simplified PFC glutamate synapse diagram, see Figure 2.
A dysfunctional interaction between the dopamine and glutamate systems has been implicated in numerous neuropsychiatric disorders such as drug addiction, Alzheimer\'s disease, schizophrenia, and ADHD. The brain regions most often linked to these disorders and the dopamine-glutamate dysfunction are the PFC and striatum, as these regions both receive heavy innervation from the dopaminergic SN/VTA and glutamate innervation from thalamic relays and other glutamate rich regions, as described in the previous section.
Studies of signaling interactions between the dopaminergic and glutamatergic systems demonstrate that the NMDA receptor is crucial in activating dopamine neurons in the VTA/SN [17, 18]. Also, it has been found that stimulation of the D2-class dopamine receptor is involved in the downstream inhibition of the NMDA receptor, weakening the excitatory response to those neurons [19]. Likewise, it was found that activation of D4 receptors depressed AMPA receptor-mediated excitatory synaptic transmission in PFC pyramidal neurons, which was accompanied by a D4-induced decrease of AMPA receptors at the synapse [20]. These results provide substantial evidence that the dopamine and glutamate neuronal systems work in tandem to create a balance of neurotransmission in these regions.
The hypodopaminergic theory of ADHD asserts that the hyperactive and inattentive behaviors are caused by low levels of either tonic or phasic dopamine. If true, decreased dopamine released in the striatum and PFC would then be expected to lead to more active NMDA and AMPA receptors based on the studies mentioned above resulting in increased glutamatergic output to the striatum and SN/VTA, as well as an increased glutamate signal to the PFC. Glutamate coming into the SN/VTA would normally go on to release more dopamine [17]; however, in the ADHD brain, this feedback does not seem to occur.
Investigations into the effects of stimulant action on the dopaminergic system have revealed that these medications increase extracellular dopamine levels via numerous mechanisms. First, amphetamine has been found to increase dopamine through calcium-independent mechanisms such as increased release of dopamine and blocking the reuptake of dopamine through the DAT [21, 22]. Methylphenidate (MPH), another stimulant medication commonly used to treat ADHD, increases dopamine levels by inhibiting dopamine reuptake via the DAT [23-29].
The non-stimulant medication atomoxetine (ATX) is becoming increasingly popular as a treatment for ADHD compared to the stimulant medications because it has lower abuse liability. ATX has been found to increase levels of the catecholamines by selectively blocking the norepinephrine transporter (NET), which is also able to clear dopamine [30-32] and, like stimulants, is effective at lessoning the intensity of ADHD symptoms [33-36].
Using magnetic resonance spectroscopy, it was found that children treated with ATX, but not MPH, had decreased levels of a marker for glutamate/glutamine in the PFC, though MPH was able to decrease glutamate in the anterior cingulate cortex [38]. In the striatum, both ATX and MPH decreased the glutamate/glutamine marker levels compared to controls [13]. These results suggest that ATX may be regulating and activating prefrontal cortex neurons. However, another clinical study using a similar technique found that chronic long-acting MPH decreased glutamate levels in the PFC of children with ADHD [39]. Wiguna et al. (2012) also discovered that MPH treatment resulted in an increase in the amount of and functional state of the neurons in the PFC, supporting that the current ADHD stimulant treatment MPH can activate PFC neurons as well. Further evidence of PFC activation comes from a study of brain-derived neurotropic factor (BDNF), a marker for neuronal plasticity. ATX was found to increase BDNF expression in the PFC; however, MPH had the opposite effect and reduced BDNF expression in the PFC [40], though it must be noted that this study was completed in naïve rodents and may explain why these results do not match those seen in ADHD patients.
Many second-line and experimental treatments for ADHD are now targeting both the dopamine and glutamate systems. Memantine is an uncompetitive NMDA receptor antagonist [41] and has also been found to act as a D2 receptor agonist [42]. It has been approved and used as a treatment for Alzheimer’s disease; however, in an 8 week open-label pilot study in children with ADHD, memantine was found to improve ADHD symptoms (Findling et al, 2007). Surman et al. (2011) extended these findings to adults with ADHD in a separate open-label study lasting 12 weeks and found similar results, with memantine improving ADHD symptoms and neuropsychological performance [43]. The MAO-B inhibitor (deprenyl), which stops the degradation of dopamine and is used as a treatment in Parkinson’s disease, was found to alleviate ADHD symptoms [44, 45]. These clinical data using glutamate and dopamine altering drugs provide strong links for dysfunctional dopamine-glutamate interactions in ADHD, though the importance of this dysfunction is still unknown. Based on these data, we believe it’s important to not overlook the possible role of dysfunctional dopamine-glutamate interactions, but to instead focus on this relationship. Animal models of ADHD provide a unique opportunity to investigate neurotransmitter system dysfunction as well as to develop novel ways to treat ADHD targeting these systems. We will next highlight two separate models of ADHD and how they are implicating both dopamine and glutamate dysfunction in ADHD.
The spontaneously hypertensive rat (SHR) has been used as an animal model for ADHD combined type since the 1970’s because of its sustained attention deficits [46], motor impulsiveness [47-49], and hyperactivity [46] with the hyperactivity absent in novel situations [50]. Currently, there exists conflicting data on dopamine release and uptake levels in the brain areas thought to be involved in the pathophysiology of ADHD, including the PFC [51]. Our lab has previously reported enhanced dopamine uptake in the ventral striatum and nucleus accumbens core of the SHR [52]; however, investigations into PFC dopamine regulation are still not clear. The PFC of the SHR has been reported to have decreased dopamine uptake [53], yet a study found no differences in the levels of DAT, tyrosine hydroxylase, D1, D2, D3, D5 receptors, and dopamine-β-hydroxylase between the SHR and its progenitor strain, the Wistar Kyoto (WKY), in the PFC. Regional differences in the D4 receptors in the PFC were found, providing evidence that the SHR’s D4 levels are lower than those of the WKY [54]. Further, it was found that PFC AMPA receptor activity was increased in the SHR [55] and inhibitory dopaminergic activity was found to be decreased while noradrenergic activity increased in the SHR [56]. These findings all convey a message that dopamine regulation is dysfunctional in the PFC of the SHR model of ADHD; however, direct observation of in vivo dopamine dynamics in the separate PFC sub-regions (cingulate, prelimbic, and infralimbic) of the SHR have not yet been accurately defined.
The correlation between ADHD and the 7-repeat polymorphism in the dopamine D4 receptor (DRD4.7) is supported by neuroanatomical, neurochemical, molecular genetics and pharmacological studies [57-60]. Recently, the DRD4.7 was identified as having the most significant genetic relationship to ADHD in pooled family and case-controlled studies [61]. Clinical studies in adolescents report that ADHD patients with the DRD4.7 have thinner frontal cortical structures in comparison to age matched controls [62]. The highest concentration of DRD4s is in the frontal cortex, an area implicated in the pathophysiology of ADHD using neuroimaging and neuropsychological evaluation of ADHD patients [63-66]. There is evidence that changes in DRD4 expression can affect glutamate levels in the striatum of DRD4-/- mice [67]. Previous studies show that DRD4-/- mice are supersensitive to ethanol, cocaine and methamphetamine [68]; have enhanced reactivity to unconditioned fear [69]; reduced exploration of novel stimuli [70]; and hypersensitivity to amphetamine [71]. In the cortex, hyperexcitability has been demonstrated in DRD4-/- mice using immunohistochemical, electrophysiological, pharmacological and ultrastructural methods, indicating that DRD4 activation has an inhibitory influence on glutamate neurons in the frontal cortex [72]. At this time, no direct studies of in vivo glutamate have been investigated in the intact PFC of the DRD4-/- mouse. Therefore,
Recent studies point to the importance of a dysfunctional relationship between dopaminergic and glutamatergic neurotransmission in ADHD, therefore new investigations into this relationship are necessary to improve our understanding and may lead to improved therapeutics for ADHD. Based on our development of novel and revolutionary methods of measuring dopamine and glutamate in vivo, we realize we are in a unique position to test our hypotheses that dopamine and glutamate regulation play a major role in the pathophysiology of ADHD. The development of carbon fiber microelectrodes and glutamate oxidase-coated microelectrode arrays (MEAs) provide improved spatial resolution, sub-second temporal resolution, and low limits of detection (<10 nM for dopamine [52], <0.2 μM for glutamate [73]) over conventional techniques used in the past, such as microdialysis. The smaller size of these probes and decreased damage to tissue compared to microdialysis probes allows for the
Male, 8-10 weeks old, inbred spontaneously hypertensive rats (SHR, average 225 g, average PND 60), inbred Wistar Kyoto rats (WKY, average 210 g, average PND 61), and outbred Sprague Dawley rats (SD, average 289 g, average PND 69) were obtained from Charles River Laboratories (NCrl), Wilmington, Massachusetts. Animals were given access to food and water ad libitum and housed in a 12 hour light/dark cycle. Protocols for animal use were approved by the Institutional Animal Care and Use Committee, which is Association for Assessment and Accreditation of Laboratory Animal Care International approved. All procedures were carried out in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and all efforts were made to minimize animal suffering and to reduce the number of animals used.
High-speed chronoamperometric measurements (1 Hz sampling rate, 200 ms total) were performed using the FAST16mkII recording system (Fast Analytical Sensing Technology, Quanteon, LLC, Nicholasville, Kentucky) as previously described [52, 74]. Single carbon fiber electrodes (SF1A; 30 μm outer diameter × 150 μm length; Quanteon, LLC, Nicholasville, Kentucky) were coated with Nafion® (5% solution, 1–3 coats at 180oC, Aldrich Chemical Co., Milwaukee, Wisconsin) prior to an in vitro calibration used to determine selectivity, limit of detection, and sensitivity before use in vivo: average selectivity for all microelectrodes used in these experiments was 1877 ± 664 μM for dopamine vs. ascorbic acid; average limit of detection for the measurement of dopamine was 0.028 ± 0.008 μM (S/N of 3); average slope for the electrodes was -0.492 ± 0.111 nA/μM dopamine. After calibration, miniature Ag/AgCl reference electrodes were prepared as previously described [74]. The carbon fiber microelectrode was affixed to a micropipette (10 μm inner diameter) which was positioned approximately 200 μm from the carbon fiber electrode tip using sticky wax (Kerr USA, Romulus, Michigan).
Rats were anesthetized intraperitonealy (i.p.) using a 25% urethane solution (1.25 g/kg) and placed in a stereotaxic frame (David Kopf Instruments, Tujunga, California). A circulating heating pad (Gaymar Industries, Inc., Orchard Park, New York) was used to maintain body temperature. The skull was removed bilaterally for recordings in the PFC (AP +3.2, ML ±1.0, DV -2 to -6 in 0.5 mm increments) [75]. A small hole remote from the site of surgery was drilled for placement of the miniature Ag/AgCl reference electrode. Prior to experimentation, the micropipette was filled with filtered isotonic KCl (120 mM KCl, 29 mM NaCl, 2.5 mM CaCl2•2H2O) solution (pH 7.2-7.4) using a 4 inch filling needle (Cadence Inc., Staunton, Virginia) and a 5 ml syringe. Experiments were then initiated with the insertion of the micropipette/microelectrode assembly into a stereotactically selected region of the left or right hemisphere’s PFC. After a 30-45 minute baseline, the effect of a single local application of KCl on dopamine release was determined [52]. The KCl solution was locally applied by pressure ejection (5–25 psi for 0.5 seconds) and the single application of a set volume of KCl (75–125 nl) was delivered to each sub-region, measured by determining the amount of fluid ejected from the micropipette using a dissection microscope fitted with an eyepiece reticule that was calibrated so that 1 mm of movement was equivalent to 25 nl of fluid ejected [76, 77]. If the volume was determined to be greater or less than 75-100 nl, then that data point was excluded. After the KCl studies, the micropipette/microelectrode assembly was filled with filtered isotonic 200 μM dopamine solution containing 100 μM ascorbic acid (an anti-oxidant) in 0.9% saline (pH 7.2-7.4). The micropipette/microelectrode assembly was inserted stereotactically into the animal’s contralateral PFC. Again, a stable baseline was achieved before the dopamine solution was locally applied by pressure ejection (10-30 psi for 0.5-10 s) to achieve a maximum amplitude between the range of 0.5 to 1 μM dopamine. The maximum concentration of the dopamine in the extracellular space was measured by subtracting the apex of the recorded peak from the baseline recorded prior to the ejection. If the peak amplitude was greater or less than 0.5 to 1 μM dopamine, then that data point was excluded. Brains were removed and processed (frozen) for histological evaluation of microelectrode recording tracks. Only data from histologically confirmed placements of microelectrodes into the PFC were used for final data analysis. Based on histological analyses, no animals were excluded due to microelectrode placement errors.
Collected data were processed using a custom Matlab®-based analysis package. For KCl-evoked DA release, maximum amplitude of the evoked dopamine peak was used. The volume of KCl applied was kept constant across depths and strains (75–125 nl). For dopamine uptake the time to 80% decay of the dopamine signal (T80) was examined. dopamine signals were amplitude matched (ranging from 0.5 to 1 μM dopamine) to ensure accurate measurement of dopamine uptake kinetics [52, 74]. Outliers were excluded via the Grubb’s test before averaging if the conditions for homogeneity of variance were met. To compare dopamine dynamics in the separate PFC subregions, one-way ANOVAs followed by Bonferroni post-hoc comparisons were used. Significance was set at p<0.05 (GraphPad Prism 5.0). Urethane, dopamine, ascorbic acid, sodium chloride, potassium chloride, calcium chloride and Nafion® were obtained from Sigma (St. Louis, MO). Carbon fiber microelectrodes (SF1A’s) were fabricated by the Center for Microelectrode Technology.
Male mice (5-7 months; ~32 g) descended from the original F2 hybrid of mice with a truncated and non-expressing DRD4 gene (DRD4-/-; 129/SvEv × C57BL/6J) were derived by backcrossing the DRD4+/- mouse line for 20 generations [68]. In all experiments, the DRD4-/- mice (n=5-8) and DRD4+/- (n=5-9) were compared to litter-matched DRD4+/+ (n=5-8) animals. Mice were group-housed (2-4 per cage) with unlimited access to food and water. Mice were maintained on a twelve hour light/dark cycle. Protocols for animal use were approved by the Institutional Animal Care and Use Committee (IACUC), which is Association for Assessment and Accreditation of Laboratory Animal Care International approved, and all procedures were carried out in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals.
Ceramic-based microelectrode arrays (MEA) that contained 4 platinum (Pt) recording surfaces (sites 1-4) in an S2 configuration (two sets of side-by-side recording sites) were prepared to selectively measure glutamate. The electrodes were fabricated for in vivo recordings using published methods [73, 78, 79]. All 4 sites were electroplated with meta-phenylene diamine (mPD) by applying a potential of +0.5 V to the Pt sites vs. a silver/silver chloride (Ag/AgCl) reference electrode (Bioanalytical Systems, RE-5) in a deoxygenated 0.05 M phosphate buffered saline (PBS; pH 7.1-7.4) with 5 mM mPD. The mPD forms a size-exclusion layer over the sites, blocking dopamine, ascorbic acid (AA), DOPAC, and other electroactive compounds. Pt sites 1 and 2 were coated with glutamate oxidase (Glu-Ox) within an inert protein matrix of bovine serum albumin (BSA) and gluteraldehyde, enabling these sites to detect glutamate levels on a sub-second timescale with low levels of detection (0.2 µM). Sites 3 and 4 were coated with only BSA and gluteraldehyde [80, 81]. In the presence of Glu-Ox, glutamate is broken down into α-ketoglutarate and peroxide (H2O2). The H2O2 is small enough to traverse the mPD layer and is readily oxidized and recorded as current using the FAST-16 equipment (Fast Analytical Sensor Technology (FAST); Quanteon L.L.C., Nicholasville, KY). For calibration details, see [73, 78]. From the calibration, average values for slope were -7.7 ± 4.8 pA/µM, selectivity 214 ± 64 to 1 and LOD 0.59 ± 0.06 µM (n=26 electrodes; 51 glutamate recording sites). After the MEA was calibrated; a single barrel glass capillary with filament (1.0 x 0.58 mm2, 6”, A-M Systems, Inc., Everett, WA) was pulled using a Kopf Pipette Puller (David Kopf Instruments, Tujunga, CA) and bumped against a glass rod so that the inner diameter of the micropipette was 10-12 µm. The tip of the micropipette was placed between the 4 Pt recording sites, approximately 50-80 µm away from the electrode surface and secured using Sticky Wax (Kerr Manufacturing Co, Detroit, Michigan).
Mice were anesthetized using i.p. injections of 10% urethane solution (1.25 g/kg) and placed in a stereotaxic frame (David Kopf Instruments, Tujunga, CA) fitted with a Cunningham™ Mouse and Neonatal Rat Adaptor (Stoelting Co., Wood Dale, IL). A circulating heating pad (Gaymar Industries, Inc., Orchard Park, NY) was used to maintain body temperature. The skull overlying the PFC was removed bilaterally. The MEA–micropipette assembly was positioned in the brain according to the following stereotaxic coordinates where all anterior-posterior (AP) measures were from bregma, medial-lateral (ML) measures were from midline and dorsal-ventral (DV) measures were from dura: AP: +2 mm, ML: ±1 mm, DV: -1.8 to 2.6 mm at an angle of 8 degrees according to the atlas of The Mouse Brain in Stereotaxic Coordinates [82]. An additional hole, remote from the surgery site, was opened for a Ag/AgCl reference electrode. Prior to placement of the MEA-pipette assembly, the micropipette was filled with isotonic 125 µM glutamate (125 µM L-glutamate in 0.9% physiological saline; pH= 7.2-7.4) using a combination of a 1 ml syringe filled with glutamate solution, a 0.22 µm sterile syringe filter (Costar Corporation), and a 4” stainless steel pulled needle (30 gauge, beveled tip; Popper and Son, Inc., NY). A potential of +0.7 V was applied versus a miniature Ag/AgCl reference electrode and the data were displayed at a frequency of 2 Hz. Upon stereotaxic placement of the MEA-micropipette assembly, 10-20 minutes of baseline data were acquired. Extracellular levels of glutamate were measured by averaging 30 seconds of baseline recordings prior to application of glutamate or KCl. Then, a 125 µM glutamate solution was locally applied via pressure ejection using a Picospritzer II connected to the open end of the micropipette by plastic tubing (Parker Hannifin Corp., General Valve Corporation). Pressure was applied at 5-25 psi for 1 second in all of the experiments. Glutamate was applied every 30-60 seconds for a total of 10 recordings. The MEA was then lowered in 350 μm increments. Baseline recordings were acquired for 5-10 minutes and the recordings were repeated. Parameters from three of the ten signals ranging from 10-30 μM in amplitude were averaged for each Pt electrode site at each depth. Signals were analyzed for time required to rise to maximum amplitude (rise time), time for 80% of the signal to decay from maximum amplitude (T80), and the rate of uptake. The uptake rate was calculated by multiplying the first order rate constant (k-1, seconds-1) by the maximum amplitude (uptake rate = µM/s) [81]. All data from local applications of glutamate from a given site were pooled into a single point. Amplitude-matched signals were compared to assess genotypic differences in the rates of clearance of exogenous glutamate [83]. Brains were removed and processed for histological evaluation of microelectrode recording tracts. Only data from histologically confirmed placements of microelectrodes within the PFC were used for final data analysis.
Data from the side-by-side recordings were averaged and used as a single data point. If only one microelectrode site provided usable data, then the recordings were reported as from that site. Very few data points were omitted in this study due to outlier status, with exception for constraints on amplitude-matching. To determine statistical significance (p<0.05), processed data were analyzed using a one-way ANOVA with Tukey’s post-hoc comparisons across all genotypes (Graphpad Prism 4.0). Urethane, L-glutamate, dopamine, ascorbic acid, and 1,3-phenylenediamine dihydrochloride were obtained from Sigma-Alderich, St. Louis MO). Microelectrode arrays were provided by Quanteon L.L.C. (Nicholasville, KY).
High-speed chronoamperometry coupled with carbon fiber microelectrodes was used to evaluate KCl-evoked dopamine release because of its capability to record dopamine release within sub-regions of the striatum and the NA [52, 74] using a local application of 75-125 nl KCl in 500 μm increments. To examine potential differences in evoked dopamine release in the separate sub-regions of the PFC between the outbred SD, the WKY progenitor, and the SHR model of ADHD, one-way ANOVAs were used. No significant differences were found between strains (cingulate cortex, p=0.1295; prelimbic cortex, p=0.1998; infralimbic cortex, p=0.1050). These data suggests that the cingulate, prelimbic and infralimbic regions in all three strains have a similar capacity to release dopamine during an action potential event. It’s important to note that in both the SD and SHR strains, dopamine peak amplitudes increased as the microelectrode was moved ventrally; however, the WKY strain displayed the opposite effect. See Figure 3. Note that all dopamine signals were indicative of the detection of dopamine and/or norepinephrine based on the reduction/oxidation rations of the signals that averaged ~0.8-1.0 for all recordings.
No differences were observed between the outbred SD control strain, the WKY progenitor strain, and the SHR model of ADHD in the KCl-evoked dopamine peak amplitudes following a local application of KCl in any of the prefrontal cortical sub-regions. Values represent the mean ± SEM.
The SHR model of ADHD and the outbred SD control strain exhibited significantly faster dopamine uptake than the WKY strain in the cingulate cortex (*
To examine differences in dopamine uptake in the separate prefrontal cortical sub-regions, we used local applications of dopamine to directly observe the functional properties of the dopamine and norepinephrine transporters. One-way ANOVAs followed by Bonferroni post-hoc comparisons were used in each sub-region. It was discovered that the SHR model of ADHD (
In order to evaluate the effect of DRD4s on extracellular levels of glutamate, we compared extracellular glutamate levels across genotypes in the PFC. Extracellular resting levels of glutamate were higher by approximately 73% in the PFC of DRD4-/- mice in comparison to their DRD4+/+ littermates (DRD4+/+: 1.4 ± 0.2 µM, n=8, signals=22; DRD4+/-: 1.9 ± 0.3 µM, n=8, signals=23; DRD4-/-: 2.5 ± 0.3 µM, n=8, signals=24;
The
Extracellular resting levels of glutamate in the PFC. The top bar graph shows increased extracellular levels of glutamate in the PFC of DRD4-/- in comparison to DRD4+/+ mice (*
Based on current stimulant treatments for ADHD that target the dopaminergic system, such as MPH, the hypofunctional catecholamine theory has evolved and states that behaviors seen with ADHD are caused by decreased levels of catecholamines in the brain regions associated with attention and reward processing [84] including the striatum and PFC. In the spontaneously hypertensive rat (SHR) model of ADHD, there have been conflicting reports of dopamine levels in the striatum and PFC; however, the techniques used varied with each study. Some studies revealed a hypodopaminergic tone [85, 86], while others found no difference in dopamine levels [87, 88]. Microdialysis measures of dopamine levels in the SHR are at most unreliable and poorly reflect concentrations of dopamine near the synapse due to the limited spatial resolution (>1 mm), slow sampling rates (1-20 min), and significant damage to the surrounding tissue [89-91]. Based on this premise, it is necessary that a technique with increased spatial and temporal resolution over microdialysis, such as carbon fiber microelectrodes coupled to high-speed chronoamperometric recordings, be used to measure dopamine dynamics in this popular animal model [92].
Glutamate clearance in the PFC. The top bar graphs represent changes in glutamate clearance in the PFC as a function of DRD4 expression for amplitude-matched signals. The T80 is significantly longer in DRD4-/- mice in comparison to DRD4+/+ (*
Recent data from our lab using carbon fiber microelectrodes with high-speed chronoamperometry have shown decreased potassium-evoked dopamine signals in the dorsal striatum of the SHR model of ADHD compared to the WKY, as well as faster dopamine uptake in the ventral striatum and NA core in the SHR compared to both the SD and WKY controls [52]. Previous investigations have implicated the dopamine transporter (DAT) in the dopamine dysfunction of the SHR model of ADHD [93-98] and our data revealing differences in dopamine regulation in the striatum can be attributed to increased activity of the DAT in the striatum of the SHR. It is reasonable to assume that if the striatum has increased DAT activity, it’s likely that similar dopamine dysfunction exists in the PFC of the SHR. It’s important to clarify that the norepinephrine transporter (NET) is present in certain regions of the PFC in much greater concentrations than the DAT and dopamine uptake in the PFC is thought to be preferentially due to the NET instead of the DAT [99], so investigations into the mechanism of dopamine clearance in the PFC of the SHR should be examined in the future.
Using similar volumes of a potassium solution, evoked overflow of catecholamine nerve terminals surrounding the tip of the carbon fiber microeletrode was used to attempt to locate differences in vesicular dopamine storage in the different PFC sub-regions. Upon stimulation, no differences were observed between the inbred SHR model of ADHD, the inbred progenitor WKY and the outbred SD control strains. The lack of differences signifies to us that the separate PFC sub-regions all have the same capacity to store and release dopamine and/or norepinephrine in these strains. MAO and VMAT, both implicated in ADHD, can then be considered to be functional in the PFC of the SHR model of ADHD and drugs targeting these proteins, such as deprenyl, may not be useful in this model.
Though no differences were observed in the KCl-evoked dopamine signals, there were significant differences in the length of time required to clear exogenous dopamine applications between the SHR and control strains. Similar maximum dopamine amplitudes were achieved by applying various volumes of an exogenous dopamine solution in order to evaluate the uptake kinetics of the signals. The DAT is electrogenic and depolarization causes the DAT to change from the basal state [100-104] and in order to test the full uptake capabilities of the transporters, including both the DAT and NET, it was necessary to study the transporters in their more natural state using local applications of dopamine. Utilizing this approach, it was discovered that the SHR displayed faster uptake in the cingulate and infralimbic cortices compared to the WKY strain, but not the prelimbic cortex. The SHR model of ADHD was also discovered to have faster dopamine uptake compared to the SD strain in the infralimbic cortex. These results are significant because the cingulate cortex is involved with learning and memory, playing a vital role in the Papez circuit and the cortical control of emotions in humans [105]. These data further demonstrate that there exists a neurochemical dysfunction in a region important for linking behavioral outcomes to motivation [106, 107] in the SHR. Also, the infralimbic cortex in rodents is known to be involved with attention to stimulus features, task contingencies, and attentional set-shifting [108] – all behaviors known to be affected in individuals with ADHD [109-111].
The SHR has previously been found to have dysfunctional dopamine dynamics in the striatum and NA core [52], but here we also show evidence for faster dopamine uptake in the cingulate and infralimbic cortices of the medial PFC. These regions are heavily implicated in ADHD [66, 112, 113] and these data give further evidence for use of the SHR as a model of ADHD. Therapeutics targeting this dysfunction may prove to be useful in the SHR. However, MPH, a DAT blocker, has been investigated and found to not be useful in this model because instead of calming these animals as it does in humans, it increased locomotion in clinically relevant doses [46, 47, 114]. This signifies to us that targeting the NET instead of the DAT, such as with the use of ATX, may provide a more useful option of targeting PFC dopamine dysfunction in the SHR model of ADHD.
The 7-repeat polymorphism of the DRD4 has been implicated in ADHD. Little is known about the neurochemical effects of the DRD4 and thus the DRD4.7. While the DRD4-/- mouse is not an exact model for ADHD, it does provide insight to the neurochemistry of DRD4 signaling. In these studies we used
We found that lack of DRD4 expression resulted in increased extracellular resting levels of glutamate in the PFC. We are unaware of any extracellular glutamate levels reported from the PFC of anesthetized C57BL\\6 mice. Using similar technology, Hascup et al. (2007) found extracellular levels of glutamate in the PFC of awake, freely-moving C57Bl\\6 mice to be 3.3 ± 0.1 µM [81]. In this study, we reported approximately 60% of the extracellular levels recorded from these prior studies in awake animals (1.42 ± 0.19 µM). Urethane anesthesia has been documented to reduce extracellular glutamate levels by 58-80% in rats and may be contributing to the lower levels of glutamate measured here [81, 115]. The relative contributions of metabolic and neuronal pools of glutamate to extracellular levels of glutamate and the role of D4 receptors in astrocytic regulation of glutamate still requires investigation. Consequences of increased extracellular levels of glutamate in the PFC would cause alterations in signaling due to increased stimulation of glutamate receptors on astrocytes and presynaptic and postsynaptic neurons. Further studies are required to test these potential changes. There is also indication that the DRD4 is localized to GABA containing interneurons in the PFC [116, 117]. Lack of inhibition resulting from loss of expression of the DRD4 could result in decreased release of GABA. This loss of inhibition could also contribute to increased tonic levels of glutamate in the PFC.
Loss of DRD4 resulted in approximately a 20% increase in clearance times in DRD4-/- mice. The mechanism of the increased clearance time is unknown, but the capacity of this tissue to clear similar amounts of exogenous glutamate was not significantly altered in the DRD4-/- mice, suggesting that transporter expression was unchanged. It is not known whether the measured effects on uptake rate were a direct or indirect effect of DRD4 signaling loss. In all areas of the brain, 80-90% of glutamate transporters are located on astrocytes [16]. Increased activation of metabotropic glutamate receptors (mGluRs) on astrocytes could potentially affect glutamate clearance in this case, depending on the affinity for glutamate by the mGluRs on astrocytes [118]. Interestingly, there have been reports of the presence of dopamine D2-receptors on the astrocytes in the PFC [119]. Prior microdialysis data suggests that extracellular dopamine content and KCl-evoked release of dopamine are lower in the striatum and NAc of DRD4-/- mice [120]. Alterations in dopamine neurotransmission in the PFC of these mice may elucidate a special role for the D2 receptor on astrocytes in regulation of dopamine and glutamate interactions in DRD4-/- mice in PFC neurotransmission. Dopamine neurotransmission studies have not been done in these mice, but changes in whole tissue levels of dopamine and dopamine metabolites do not indicate any changes [72].
In multiple publications, the DRD4 has been indicated as having an important role in the cortico-striatal-thalamic loop. Previously, we measured increased extracellular glutamate and slower clearance of glutamate in the striatum, indicating DRD4 regulation in the corticostriatal projections [67]. In these experiments, we measured increased extracellular glutamate levels and slower glutamate clearance in the PFC, representing alterations in glutamatergic projections that primarily originate in the thalamus. Mrzljak et al. (1996) alluded that the DRD4s role in pallido-thalamic pathways may be as a regulator of GABA release [117]. By blocking these receptors, GABA release would be weakened and result in enhanced excitatory pathways beginning in the thalamus. This presents a feed forward situation in which lack of inhibitory modulation of the excitatory pathways of the cortico-striatal-thalamic loop results in increased levels of glutamate in the PFC and the striatum. Although measures of GABA in the pallido-thalamic and striatopallidal projections are necessary, our data continues to support the importance of the DRD4 in the cortico-striatal-thalamic loop, specifically in the regulation of tonic glutamate.
Region specific changes may be due to the concentration of DRD4s and cell types to which they are localized. In a study where bacterial artificial chromosomes expressed enhanced green florescent protein under the transcriptional control of the DRD4, DRD4 localization was found to be high in the orbital, prelimbic, cingulate and rostral agranular potions of the prefrontal cortex [116]. Our study found changes in the cingulate and prelimbic areas, but not the infralimbic area. Localization of DRD4s to interneurons vs. pyramidal neurons may be helpful in elucidating a relationship between altered extracellular glutamate levels in the cingulate cortex in comparison to altered clearance times in the prelimbic area. One caveat of transgenic mice is that compensatory effects may be contributing to the neurochemical effects that we measured. While compensatory effects in the PFC have not been evaluated, alterations in dopamine D1 receptor and NMDA receptor expression were reported in the striatum, nucleus accumbens and hippocampus [67, 120, 121]. Assessment of dopamine, glutamate, and GABA related receptors in the PFC would provide important information necessary for proper evaluation of receptors that could be contributing to the findings reported in this paper and need to be further investigated. Compensatory mechanisms can be indicative of developmental functions that are influenced by the absence of the DRD4 and are important to consider when evaluating glutamate function in the PFC of these knockouts.
The data presented above in the SHR and DRD4-/- rodent models of ADHD provide evidence for dopaminergic and glutamatergic system dysfunction in the PFC. Likewise, it has previously been demonstrated that in the striatum of both models, similar neurotransmitter system dysfunction exists [52, 67]. The DRD4 knockout mouse has also been found to exhibit decreased dopamine levels in the striatum [120]. These data in the DRD4-/- reveal that the D4 receptor is vital in the regulation of dopamine-glutamate interactions in the striatum and PFC. Recent pilot data from our lab (unpublished) reveal that in the SHR model of ADHD, there exists increased resting glutamate levels in the striatum and PFC; however, further experimentation is necessary to verify these results. Glutamate dysfunction in the SHR would then create the possibility that targeting the dopamine-glutamate interaction in this model of ADHD may prove useful as well.
These animal models grant us the ability to investigate neurotransmitter system regulation
As more and more research is beginning to implicate a dysfunctional glutamate system in ADHD, it’s hard to ignore that glutamate may be playing some role in the pathophysiology of ADHD. Although it is too early to know if pharmaceuticals that modulate glutamate will be able to benefit ADHD without their own set of side-effects, it is still our hope that through modification of these interactions, we will be able to better treat individuals with ADHD and greatly improve their quality of life.
In this chapter, we have reviewed dopamine and glutamate neurotransmission, as well as dopamine-glutamate interactions, specifically relating to ADHD. We have reviewed current literature and have shown the effects of ADHD treatments on these neurotransmitters. We have discussed and detailed two rodent models of ADHD as well as the techniques used to highlight novel data revealing dopamine and glutamate dysfunction in these models of ADHD. Finally, we’ve examined ways these data will enable the future neuropharmacology of ADHD to move forward. Ultimately, our goal is to find novel therapies targeting dopamine-glutamate interactions to better treat ADHD in individuals of all ages.
The World Health Organization defines health as: “A state of complete physical, mental and social well-being and not merely the absence of disease” [1]. Many of us perceive health merely as being physical fitness and neglect the importance of mental health. Depression, anxiety, and stress levels are considered as significant pointers for the psychological well-being of the population. It is predicted that by the year 2020, depression will become the second most common reason of disability globally [2]. Failure to identify and cure of these mental disorders might have unwanted bearings on the lives of individuals [3].
\nMental distress has been well identified in undergraduate medical students and is a matter of concern in both developed and developing countries [4]. The young students are the most susceptible group of the population to stressful life events, especially those who are pursuing a higher professional education in a competitive setting [5]. It is noted that medical undergraduates have higher levels of mental distress than the general population and their fellow peers [6]. Medical education encompasses challenging curriculum and clinical training [7]. The duration of the medical course is different across countries; some have 4-year graduate programs, and others have 5- or 6-year undergraduate programs [8]. The medical curriculum is usually divided into basic or preclinical (1st and 2nd years), clinical (3rd, 4th, and 5th years), and clinical house job (6th year) periods. The curriculum of preclinical phase focuses on basic medical science subjects, i.e., anatomy, physiology, and biochemistry, whereas the clinical phase emphasizes on clinical subjects, i.e., surgery, general medicine, pediatrics, community medicine, forensic medicine, and gynecology. In the clinical internship period, medical graduates have to rotate in different wards in the hospital and emergency units for 1 year under direct supervision. Medical students learn specialized knowledge, skills, and attitudes which prepare them to become a competent physician; this highly demanding medical curriculum may have undesirable effects on the learner’s physical and mental health [9, 10].
\nA high prevalence of stress, anxiety, and depression among medical students has been identified globally [11, 12, 13, 14]. Medical education can cause a considerable amount of psychological stress on undergraduates [7]. Various psychological morbidities have been reported among medical students, ranging from stress, anxiety, social problems, depression, burnout, and suicidal ideation [15]. Due to the heavy educational workload in undergraduate medicine, medical students are more prone to psychiatric complaints such as depression, anxiety, and stress than their nonmedical peers [16]. Depression and anxiety in medical undergraduates can also continue during internship and residency periods and later in the medical professional life [9].
\nOne of the major aims of medical education is to produce knowledgeable, skilled, and proficient doctors. The medical profession is considered as one of the prestigious professions in society. Students enter in the medical field for various reasons, including fulfilling their own passions, parental pressure, financial and job security, to secure a respected place in society, etc. [17].
\nStudies suggest that medical education may have an unintended harmful effect on students’ mental health, resulting in high prevalence of depression, anxiety, and stress among medical students [10, 17, 18, 19]. It has been hypothesized that various factors are responsible for the decline in mental health of medical students, including academic pressure [20], increased workload [13], financial issues [20], sleep deprivation, and exposure to patients’ suffering and deaths [7]. Mental distress adversely affects the learning and cognitive abilities of students [21] which might have an influence on their academic performance [10]. A study in the UK showed a high dropout rate in psychologically ill students [9]. It is crucial to recognize students’ mental distress and their causes so that it can help the medical educationist to develop necessary amendments in the curriculum to ensure production of graduates who are emotionally fit for their difficult training to deal with various aspects of life like human suffering and death [17].
\nA widely distributed body of literature indicates that the prevalence of mental distress is increasing among students studying medicine [16, 20, 22]. It is evident that mental health problems are prevalent in the whole society, but university students are significantly more affected than the general population [14, 23]. This might be due to numerous challenges that university students have to face such as competition to succeed, high academic demands, teacher and parent’s expectations, increased workload, financial problems, and apprehension about the future [24]. And among all university students, medical students exhibit higher mental distress than both the general population and their age-matched peers [20]. Worldwide medical undergraduates have been found at risk of mental distress and reduced life satisfaction [7, 24, 25]. Medical training involves many risk factors for mental illness, including academic burden, lack of sleep, minimal physical activities, and decreased time for social activities. A large study conducted in the USA, including six medical schools (582 students), concluded that when medical students enrolled in a medical institute, they had better or similar mental health than the general population. It shows that higher rates of distress reported in medical students are the result of the over-competitive training process of medical education that can have an unfavorable effect on the mental health of students [26].
\nDyrbye found the significantly higher frequency of mental distress among US and Canadian medical students than the general population [20]. Dahlin et al. [10] reported that 13% of Swedish medical students were depressed as compared to 7.8% in an age-matched control sample and, of further concern, one-third of the students reporting suicidal thoughts during the course of training. Another research study conducted in Australia involved 1811 medical students and concluded that one in five students reported suicidal thoughts over the past 1 year [27].
\nStudies from non-western countries also reported a high prevalence of mental distress [5, 7, 9, 13, 28, 29, 30]. There is a small but growing body of research that has recently emerged that attempts to determine the prevalence and the causes of mental distress among medical students of Pakistan. Pakistani study findings are not different from rest of the globe, and they also found high mental distress among medical students [17, 19, 31, 32, 33].
\nIt is clearly obvious from the above discussion that the prevalence of mental distress is higher in non-western countries than western ones. This might be due to low knowledge and awareness about mental health in developing countries [34]. But there is evidence that western institutes did introduce curricular changes, better assessment, and innovation to cope with stress [20].
\nThis section will explore the sources of psychological distress among medical students. Various potential sources of mental distress found in literature among medical students are discussed below.
\nThe medical curriculum had long been identified as one of the important risk factors for distress among students. Several studies recognized assessments and academic-associated elements as the most substantial stressors [7, 22, 25, 32]. A longitudinal study in the UK concluded that the enormous academic load is the most significant reason of mental distress among medical students [35]. Studies have shown that the mental health of many students deteriorates after their enrollment in medical school and remains low throughout their training [9, 17, 22]. The poor mental health of medical undergraduate affects not only their physical well-being but also their educational achievements during their training period [9]. Some degree of stress facilitates learning and performance, but intense pressure and huge demands of the medical curriculum may have undesirable effects on vulnerable students’ behavior which reduces their learning abilities [36]. There is evidence that prolonged stress exposure may affect the prefrontal area of the brain, which is responsible for higher cognitive functions and learning [37]. Stress and anxiety not only cause underachievement but also result in low-level self-esteem and reduced motivation and effort to complete educational tasks [6]. Poor and unsatisfactory academic achievement may further increase the mental distress among students [15] which may have serious consequences, e.g., dropout from medical course or suicide in extreme cases [38].
\nFrequent examinations are found to be another main reason for mental stress. A study revealed that the amount of stress almost doubled during or near the examination [25]. Moreover, due to frequent examination and assessments throughout the academic year, it becomes difficult for students to prepare for the exams properly; as a result, they get an average or poor grade [39]. Adults are motivated to learn mostly by internal factors, but external sources such as assessments also contribute strongly to motivate the learner to learn [40]. Too many examinations do not let students study deep, and they failed to produce intended outcome or good grades, hence becoming demotivated and distressed [41].
\nDahlin et al. [10] mention that insufficient feedback is also related to increased distress of students. It is very crucial to give effective feedback to students because it enables the learner to analyze their actions and helps them plan for the future; learners can be confused if left unsupervised [42]. Effective feedback practice from teachers permits students to develop positive insights about the task, and corrective feedback is essential for effective learning; without it the level of performance attained is lower [40].
\nIn a semi-structured interview-based study, students revealed that huge academic tasks render them to have limited or no time for sleep and recreational activities; this lack of sleep might reduce the emotional well-being of students [43]. Due to high academic demands of medical education, most of the medical students fail to take time out for physical activities like exercise and other healthy activities [39]. People who have minimal physical activity are at higher risk of mood disorders like depression, anxiety, and stress [44]. Medical students get fewer opportunities for extracurricular activity, and that might have a negative effect on their mental health. Due to lack of time and the heavy burden of study, students could not find enough time for self-care; they are not able to take proper sleep and time for leisure activities which have a further bad effect on their well-being [45].
\nThe literature offers evidence of the association between transitions and students’ mental distress [5, 7, 10, 16, 31]. Transition is a dynamic process in which students experience cultural, social, and cognitive challenges while passing from a familiar to a less familiar environment. The medical curriculum is interrupted by two major transitions, first from the high school to the first year of medicine and another from preclinical to clinical, i.e., third year. Dahlin et al. [10] explored the distress among different years of students and found higher mental distress among first-year and third-year students than senior level year students.
\nStudents of the first year are overburdened with huge subjective curriculum, the pace of study is too fast, and they have little time to cover the syllabus. However, Dyrbye et al. [20] argued that many junior students might face the challenges of being displaced from friends and family and experience difficulty in adjusting to a new environment along with heavy academic toll. So this high mental distress might be a part of the adjustment process to the new educational setting. According to the U-curve theory, this stage of adjustment is known as “culture shock” in which a medical student faces isolation, stress, anxiety, and emptiness [46, 47]. The successful adjustment at this stage depends on the self-confidence of students in their ability to cope with the stressors [48, 49]. In this stage, a student must face numerous challenges to adapt in a new environment as well as meet academic demands [48, 49]. So, in this context, self-efficacy seems to be the most suitable principle to deal with stress [50]. Bandura [21] concludes that cooperative learning strategies, in which learners work together and help one another, tend to improve both self-efficacy and academic achievement. Furthermore, constructive feedback is also important in developing self-efficacy in students [21].
\nA study done in a Thai school revealed a higher mental stress among third-year medical students [5]. Students are susceptible to become depressed during their initial clinical years of study when they rotate through the hospitals, because at that time students often detach from their friends and peer group and must work with constantly changing groups of residents and attending physicians at different hospitals [43]. Furthermore, clinical rotations anticipate a number of stress-provoking tasks, such as interactions with senior doctors and staff during ward rounds; dealing with patients, diseases, and death may also contribute to the poor mental health of medical students during their initial clinical years [15], because at this stage, students are not able to contribute enough to the patient care which makes them feel insecure about not having enough knowledge and skills [43]. Students, when entering into the clinical stage, are not confident enough to communicate effectively with clinical staff and are hesitant to participate in teamwork. It is evident that stress has been associated with poor communication, reduced quality of patient care, and medical errors [51].
\nStudents find it difficult to deal with newly added tasks and interacting with critically ill patients. Undergraduate curriculum mostly does not contain any information about communication skills. Effective communication builds a strong relationship between students, clinical staff, and patient which ultimately reduces the distress of students and enhances learning [52], and this will ultimately affect the quality of care delivered to the patient and quality of life [53]. These transitions might have negative effects on the learning process due to the lack of social interaction. Students who are distressed may face isolation and stigma which further affect their learning. Social constructivism theory describes that the adult learner learns through interaction and collaboration with other people in their natural setting [54]. Students learn better when they interact with their friends and peers regularly [55].
\nThese large changes during the period of transitions need coping strategies in order to function effectively in the new environment. Critical reflection is the most desirable quality for a smooth transition [56, 57]. Experience is converted into learning by reflection, and this process can be improved by the cooperation of a facilitator or teacher [58]. Encouraging reflection in learners will lead to the development of reflective practice which is a significant element of professionalism [59]. Learners should be involved in assessing their own learning process. Critical reflection on experience promotes deep and self-directed learning among students [40]. Mann [53] argues that introduction of activities like reflective portfolios, feedback, and peer review helps students cope with the stress during the transition and avail opportunity of learning during the transition phase. It is also noted that early introduction of clinical medicine also aids to stimulate smooth transitions [60].
\nIn addition to the aforementioned reasons, some other causes are also mentioned in the literature, e.g., personal life events, the death of family members, marriage, the birth of a child, family history of depression, etc. These reasons are also recognized to contribute to depression, anxiety, and stress in medical students, the same as the general population [61]. Financial problems are another factor mentioned in various studies, as a cause of increased stress levels in medical students [25]. A study discovered that the poorer the background, the more stress is experienced by students [25]. Medical education is considered a costly course which is also associated with other demands such as expensive textbooks, suitable clothing, and medical equipment. Some medical students suffer financial problems. Long academic hours do not allow students for part-time jobs to fulfill their financial needs [15]. Finances would be one of the main factors of the distress among students. As a medical educationist, we cannot do much about this issue, but we can suggest stakeholders create more scholarship opportunities for students.
\nLiterature is largely focused on the efforts to improve student mental health through improving access to mental health provider and decreasing the stigma to mental health treatment and implementing of wellness programs. But there are only a few studies focused on innovative models that build to address the root causes of stress, i.e., academic related. The few most frequent curricular-related recommendations to improve the well-being of students are as follows.
\nImplementation of the pass/fail grading is the most common curricular innovation mentioned in the literature. Reed et al. [60] found in a multi-institutional study that levels of mental distress are higher in students of the medical institute that used grading system with three or more levels than the students of the medical institute that used pass/fail grading [62]. Students always do a competition for getting better grades, and that consistently caused distress. Implementation of the pass/fail grading system, especially during the initial 2 years of medical school, helps students not to over-occupy themselves with competition for the high grade [15].
\nEvans and Brown [61] proposed that students can be helped to reduce academic burden by offering them a clear learning objective so that students will know what they have to learn. It reduces the distress and thus fosters the well-being of students [63]. A predetermined clear learning objective not only lets students focus on them but also motivates them to achieve those [64].
\nOffering a variety of teaching strategies for delivering of course material such as small group activities, team-based learning, and flipped class is also known to reduce mental distress [65]. Small group learning is a more effective tool in gaining student-teacher bonding than didactic traditional lectures and thus helps the transfer of knowledge efficiently [66]. Furthermore, a small group setup provides a secure state in which students can argue and discuss their perceptions and assumptions. This problem solving and peer interaction can result in deep understanding; group discussion complements the situational learning of professionalism [66] which is known to enhance the well-being of students [57].
\nThe practice of self-efficacy and reflection also mentioned reducing stress among medical students. The introduction of the reflective practice for students causes them to become the self-directed learner, and they become responsible for their own learning, which greatly alleviates mental distress [67]. The most frequently used tools for reflection are reflective journals, reflective dialogical exercises, and portfolios [68]. A learner should be involved in reflective practices because it provides them a chance to assess their own learning style. Reflection allows students’ knowledge to be actively integrated and thus encourages self-directed, deep, and continued learning [55]. Problem-based learning (PBL) is known to promote self-efficacy and self-directed learning and hence endorse easy transitions during medical education [67].
\nVertical curriculum, which is defined as the assimilation between the basic science and clinical segments of the curriculum [64], is known to reduce mental distress because in that there is the early introduction of clinical medicine and students can relate theory to practice [69]. Early exposure of students to clinical medicines gives them instantaneous opportunities to apply the basic science knowledge to the clinical setting and help them in smooth transition through their educational journey [64].
\nLongitudinal electives (e.g., communication skills or coping with stress) and other community-based activities seem promising in reducing stress among students [69]. Stress reduction teaching modules or electives intended to raise self-awareness and self-reflection and hence engage in self-care [26].
\nProfessionalism in medicine can be described as the collection of values, attitudes, and behavior that a health professional show when they deal with a patient, colleagues, and society [70]. Brazeau et al. [26] observed a positive relationship between medical mental well-being and professionalism [71]. Professionalism is mostly considered as a part of the hidden and informal curriculum [72]. The inclusion of professionalism in the formal curriculum is relatively a newer concept, but it becomes today’s requirement [73]. Every medical institute should develop their own institutional specific curriculum for professionalism with faculty and students’ help along with a structured teaching and learning methods and assessments [18].
\nMedical students experience a substantial amount of distress during their training, which has been shown to contribute to substandard academic performance, dishonesty, pessimism, and substance abuse [20]. A good physician requires the sound mental health to nurture and increase compassion, professionalism, and tolerance [20]. The main stresses identified during literature search are academic related. An undue amount of stress during medical education had the negative effect on students, who might have experienced difficulties in social encounters and a lack of concentration which leads to increased frequency of blunders, carelessness, and negligence [45]. Poor psychological health not only upsets students’ lives but also has undesirable effects on patients’ care in the long run [39]. Increased frequency of depression and anxiety within medical professionals may put the future of health care in danger; it may cause reduced productivity, low quality of life, and learning difficulties which will ultimately have a negative effect on the quality of patient care [20]. Depression, anxiety, and stress can have profound negative effects on the learning abilities of students [24], and this will ultimately affect the quality of care delivered to the patient and quality of life [53]. Evaluation of the literature shows that students and doctors who are suffering from mental distress are more likely to have poor professionalism, ranging from cheating, plagiarism, and providing substandard patient care [45]. So as a medical educator, this is a real state of urgency to introduce innovation in the curriculum to improve mental health, for this effort existing literature on curricular factors may serve as a model.
\nThe recommendations to reduce mental distress among medical students are discussed as follows:
Provide an engaging curriculum which offers different styles, e.g., small group tutorials, team-based learning, and flipped classes.
Exams should be prescheduled with proper gaps between different subjects. Proper time off should be given to students between their clinical rotations so that they can relax.
Promote reflective activities, e.g., reflective diaries and portfolios throughout the curriculum, and timely and constructive feedback should be provided to students.
Early introduction of clinical medicine, so that students can easily relate theory to practice.
Longitudinal workshops or module on communication skills and stress management should be part of the curriculum for the medical undergraduate to become self-aware of their own well-being during their course of training. Special presentations by the faculty should be given to students about challenges in work-life balance.
Provide opportunities for extracurricular activities to students, and encourage students to promote their well-being with regular physical exercise and sufficient sleep. Give students in the campus opportunity for sporting and cultural activities to lessen their distress.
Include elements of professionalism in the core curriculum.
It is needed to convince stakeholders of medical institute, i.e., head of medical education and principal, that we need to establish a strong support system for students for counseling, with whom they can discuss their problems, whether it is related to their psychological health or academics. Merely identifying the mental distress of a student does not seem to contribute to reducing the psychological morbidity; it is crucial to provide personalized support to the stressed students once they are recognized [15]. Students are reluctant to take available support because of the stigma related to the mental illness; they are not comfortable enough in taking consultations from their own institution. Such students should be given a chance to have an off-campus psychological support or online help with full confidentiality. These support systems increase the awareness and practice of positive coping approaches. These distress management programs should advise students about the negative effects of mental distress on human functioning and enlighten students on how to recognize the sources of mental distress and how to manage it. These groups provide an opportunity to students to express themselves and to share their feelings fearlessly, and thus it decreases the possibility of burnout. Such support groups help students to realize that they are not the only ones who are suffering but many others are also in the same situation. It also gives them a chance to realize how their colleagues solve such issues. Students should be given the chance to express their vision on the curriculum, so that they can give their unique insights to curriculum committees. Regular feedback from students on teaching and training can play a vital role in reducing the stress among students [15, 74, 75, 76, 77].
\nThe potential for mental health to improve medical undergraduates and graduates’ professionalism is also mostly unexplored. Large-scale, prospective, multicenter, and hypothesis-based or phenomenological-based qualitative studies are much needed to provide effective and generalized evidence about this issue. Both quantitative and qualitative research should be done in the future to see the long-term outcomes of the curricular change project. Support and funding for such research program are also limited, which must be alleviated. Research studies to explore the causes and consequences of medical students’ distress and to examine possible solutions are not only beneficial for the affected medical student but also useful for the patients to whom they deliver their services. Subsequently, the interventions to promote students’ mental health will advantage the student, the physician, the patients, and the community as a whole.
\nI dedicate this piece of writing to my loving father, Syed Azim-ur-Rahman (late), for his love and support throughout my life.
\nNone.
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The range of technical issues, associated technology development challenges and future commercial opportunities are explored, with a focus on magnetic confinement approaches.",book:{id:"6838",slug:"power-plants-in-the-industry",title:"Power Plants in the Industry",fullTitle:"Power Plants in the Industry"},signatures:"Shutaro Takeda and Richard Pearson",authors:[{id:"251254",title:"Prof.",name:"Shutaro",middleName:null,surname:"Takeda",slug:"shutaro-takeda",fullName:"Shutaro Takeda"},{id:"262366",title:"Mr.",name:"Richard",middleName:null,surname:"Pearson",slug:"richard-pearson",fullName:"Richard Pearson"}]},{id:"71264",doi:"10.5772/intechopen.90939",title:"Fast-Spectrum Fluoride Molten Salt Reactor (FFMSR) with Ultimately Reduced Radiotoxicity of Nuclear Wastes",slug:"fast-spectrum-fluoride-molten-salt-reactor-ffmsr-with-ultimately-reduced-radiotoxicity-of-nuclear-wa",totalDownloads:939,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"A mixture of NaF-KF-UF4 eutectic and NaF-KF-TRUF3 eutectic containing heavy elements as much as 2.8 g/cc makes a fast-spectrum molten salt reactor based upon the U-Pu cycle available without a blanket. It does not object breeding but a stable operation without fissile makeup under practical contingencies. It is highly integrated with online dry chemical processes based on “selective oxide precipitation” to create a U-Pu cycle to provide as low as 0.01% leakage of TRU and nominated as the FFMSR. This certifies that the radiotoxicity of HLW for 1500 effective full power days (EFPD) operation can be equivalent to 405 tons of depleted uranium after 500 years cooling without Partition and Transmutation (P&T). A certain amount of U-TRU mixture recovered from LWR spent fuel is loaded after the initial criticality until U-Pu equilibrium but the fixed amount of 238U only thereafter. The TRU inventory in an FFMSR stays at an equilibrium perpetually. Accumulation of spent fuel of an LWR for 55 years should afford to start up the identical thermal capacity of FFMSR and to keep operation hypothetically until running out of 238U. Full deployment of the FFMSR should make the entire fuel cycle infrastructures needless except the HLW disposal site.",book:{id:"9888",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",title:"Nuclear Power Plants",fullTitle:"Nuclear Power Plants - The Processes from the Cradle to the Grave"},signatures:"Yasuo Hirose",authors:[{id:"315264",title:"Dr.",name:"Yasuo",middleName:null,surname:"Hirose",slug:"yasuo-hirose",fullName:"Yasuo Hirose"}]},{id:"72177",doi:"10.5772/intechopen.92547",title:"Nuclear Power Plant or Solar Power Plant",slug:"nuclear-power-plant-or-solar-power-plant",totalDownloads:670,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Both solar energy and nuclear energy face significant economic challenges. Sustainable energy costs have traditionally been greater than any of those associated with the growth of fossil fuel power generation, although the costs of renewable energy technologies (especially photovoltaic) have dropped. Furthermore, capital costs remain a big challenge in the nuclear generation. In many nations, the cost of building small nuclear power plants is quite large due to time, technology, and environmental and safety challenges for consumers. Such problems might not be as big for state-owned corporations or controlled industries for which utilities have quick access to cheap resources, and this partially explains why the interest for nuclear reactors in Asia is far greater than in the United States or Europe. Learning could help decrease costs for both types of technologies, but the track record for learning-by-doing in the nuclear sector is not good.",book:{id:"9888",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",title:"Nuclear Power Plants",fullTitle:"Nuclear Power Plants - The Processes from the Cradle to the Grave"},signatures:"Mostafa Esmaeili Shayan and Farzaneh Ghasemzadeh",authors:[{id:"317852",title:"Ph.D.",name:"Mostafa",middleName:null,surname:"Esmaeili Shayan",slug:"mostafa-esmaeili-shayan",fullName:"Mostafa Esmaeili Shayan"},{id:"319145",title:"Prof.",name:"Farzaneh",middleName:null,surname:"Ghasemzadeh",slug:"farzaneh-ghasemzadeh",fullName:"Farzaneh Ghasemzadeh"}]},{id:"54655",doi:"10.5772/67858",title:"Key Technical Performance Indicators for Power Plants",slug:"key-technical-performance-indicators-for-power-plants",totalDownloads:3322,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"In this chapter, we will underline the importance of the key performance indicators (KPIs) computation for power plants’ management. The main scope of the KPIs is to continuously monitor and improve the business and technological processes. Such indicators show the efficiency of a process or a system in relation with norms, targets or plans. They usually provide investors and stakeholders a better image regarding location, equipment technology, layout and design, solar and wind exposure in case of renewable energy sources and maintenance strategies. We will present the most important KPIs such as energy performance index, compensated performance ratio, power performance index, yield, and performance, and we will compare these KPIs in terms of relevance and propose a set of new KPIs relevant for maintenance activities. We will also present a case study of a business intelligence (BI) dashboard developed for renewable power plant operation in order to analyze the KPIs. The BI solution contains a data level for data management, an analytical model with KPI framework and forecasting methods based on artificial neural networks (ANN) for estimating the generated energy from renewable energy sources and an interactive dashboard for advanced analytics and decision support.",book:{id:"5807",slug:"recent-improvements-of-power-plants-management-and-technology",title:"Recent Improvements of Power Plants Management and Technology",fullTitle:"Recent Improvements of Power Plants Management and Technology"},signatures:"Simona Vasilica Oprea and Adela Bâra",authors:[{id:"139804",title:"Prof.",name:"Adela",middleName:null,surname:"Bara",slug:"adela-bara",fullName:"Adela Bara"},{id:"188586",title:"Dr.",name:"Simona Vasilica",middleName:null,surname:"Oprea",slug:"simona-vasilica-oprea",fullName:"Simona Vasilica Oprea"}]},{id:"55841",doi:"10.5772/intechopen.68772",title:"Risk Assessment of NPP Safety in Case of Emergency Situations on Technology",slug:"risk-assessment-of-npp-safety-in-case-of-emergency-situations-on-technology",totalDownloads:1339,totalCrossrefCites:0,totalDimensionsCites:2,abstract:"The last accidents of the nuclear power plant (NPP) in Chernobyl and Fukushima give us the new inspiration to verify the safety level of the NPP structures. This paper presents the new requirements to test the safety and reliability of the NPP structures due to the recent accidents in the world. The IAEA in Vienna required in the document ‘Stress tests’ the verification of the safety of the NPP structures under impact of the extreme loads as the earthquakes, the extreme climatic actions and the technology accidents. The new recommendations to load combinations and design criteria were defined. The risk assessment to verify the safety and reliability of the NPP structures based on probabilistic and nonlinear analysis is presented. The uncertainties of material model (behaviour of the reinforcement and liner, concrete cracking and crushing), degradation effects, the loads level (dead and live loads, extreme climatic and accidental temperature and overpressure) as well as other effects following from the inaccuracy of the calculated model and numerical methods were taken into account in the response surface method (RSM) method. The results of the deterministic and probabilistic analysis of the NPP structures are presented.",book:{id:"5807",slug:"recent-improvements-of-power-plants-management-and-technology",title:"Recent Improvements of Power Plants Management and Technology",fullTitle:"Recent Improvements of Power Plants Management and Technology"},signatures:"Juraj Králik",authors:[{id:"139600",title:"Prof.",name:"Juraj",middleName:null,surname:"Králik",slug:"juraj-kralik",fullName:"Juraj Králik"}]}],mostDownloadedChaptersLast30Days:[{id:"54655",title:"Key Technical Performance Indicators for Power Plants",slug:"key-technical-performance-indicators-for-power-plants",totalDownloads:3324,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"In this chapter, we will underline the importance of the key performance indicators (KPIs) computation for power plants’ management. The main scope of the KPIs is to continuously monitor and improve the business and technological processes. Such indicators show the efficiency of a process or a system in relation with norms, targets or plans. They usually provide investors and stakeholders a better image regarding location, equipment technology, layout and design, solar and wind exposure in case of renewable energy sources and maintenance strategies. We will present the most important KPIs such as energy performance index, compensated performance ratio, power performance index, yield, and performance, and we will compare these KPIs in terms of relevance and propose a set of new KPIs relevant for maintenance activities. We will also present a case study of a business intelligence (BI) dashboard developed for renewable power plant operation in order to analyze the KPIs. The BI solution contains a data level for data management, an analytical model with KPI framework and forecasting methods based on artificial neural networks (ANN) for estimating the generated energy from renewable energy sources and an interactive dashboard for advanced analytics and decision support.",book:{id:"5807",slug:"recent-improvements-of-power-plants-management-and-technology",title:"Recent Improvements of Power Plants Management and Technology",fullTitle:"Recent Improvements of Power Plants Management and Technology"},signatures:"Simona Vasilica Oprea and Adela Bâra",authors:[{id:"139804",title:"Prof.",name:"Adela",middleName:null,surname:"Bara",slug:"adela-bara",fullName:"Adela Bara"},{id:"188586",title:"Dr.",name:"Simona Vasilica",middleName:null,surname:"Oprea",slug:"simona-vasilica-oprea",fullName:"Simona Vasilica Oprea"}]},{id:"55019",title:"Spatial Aspects of Environmental Impact of Power Plants",slug:"spatial-aspects-of-environmental-impact-of-power-plants",totalDownloads:1313,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"Strategic Environmental Assessment (SEA) is one of the key instruments for implementing sustainable development strategies in planning in general, namely for analysing and assessing the spatial development concepts, in this case in the field of energy and planning of power plants. The SEA in energy sector planning has become a tool for considering the benefits and consequences of the proposed changes in space, also taking into account the capacity of space to sustain the implementation of the planned activities. This chapter examines the multi-criteria evaluation (MCE) method for carrying out an SEA for the power plants in Energy Sector Development Strategy of the Republic of Serbia (case study). The MCE method has found its use in the analysis and assessment of the energy sector spatial impacts on the environment and elements of sustainable development and, in this context, also considering the importance of impacts, spatial dispersion of impacts, their probability and frequency of occurrence, along with the elaboration of the obtained results in a specific, simple and unambiguous way. The chapter focuses on the consideration of aspects of environmental impact of all kinds of power plants, without taking into account the details regarding other aspects of energy sector development that are dealt with in the case study.",book:{id:"5807",slug:"recent-improvements-of-power-plants-management-and-technology",title:"Recent Improvements of Power Plants Management and Technology",fullTitle:"Recent Improvements of Power Plants Management and Technology"},signatures:"Boško Josimović and Saša Milijić",authors:[{id:"125578",title:"Dr.",name:"Bosko",middleName:null,surname:"Josimovic",slug:"bosko-josimovic",fullName:"Bosko Josimovic"},{id:"200736",title:"Dr.",name:"Sasa",middleName:null,surname:"Milijic",slug:"sasa-milijic",fullName:"Sasa Milijic"}]},{id:"64317",title:"Hybrid Power Plants: A Case Study",slug:"hybrid-power-plants-a-case-study",totalDownloads:1142,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Energy can be treated as an essential element for the development of society. Therefore, aspects like process’ efficiency and environmental impacts must be considered when choosing the supply source. In Brazil, an event showed the fragility of a system that relies on in only one source to attend their necessities; a truckers strike made the whole country stop. The energy sector has a similar situation; more than 60% of Brazilian energetic matrix is represented by one source, hydroelectric power plants. The availability of solar radiation and wind in Brazil makes it possible to diversify its energetic matrix. Thus, the aim of this study is investigating the potential of hybrid solar-wind power plants in two basins of Minas Gerais—Brazil, São Francisco Basin and Jequitinhonha Basin, as well as compare their viabilities in order to address social issues. By analyzing INMET database and economic factors, the study has shown that it is feasible to implement renewable power plants in the basins of the study area, whether individually (solar or wind energy) or hybrid system. It shows in addition that hybrid system should be prioritized, since it presents lower cost, when compared to solar power plant, and more reliability due to seasonality of both sources.",book:{id:"6838",slug:"power-plants-in-the-industry",title:"Power Plants in the Industry",fullTitle:"Power Plants in the Industry"},signatures:"Eduarda Moreira Nascimento, Júnio de Souza Damasceno and\nSabrinne Kelly Souza",authors:[{id:"252477",title:"Dr.",name:"Junio",middleName:null,surname:"Damasceno",slug:"junio-damasceno",fullName:"Junio Damasceno"},{id:"262354",title:"Ms.",name:"Sabrinne",middleName:"Kelly",surname:"Souza",slug:"sabrinne-souza",fullName:"Sabrinne Souza"},{id:"262363",title:"BSc.",name:"Eduarda",middleName:null,surname:"Nascimento",slug:"eduarda-nascimento",fullName:"Eduarda Nascimento"}]},{id:"58753",title:"Detection of Malfunctions and Abnormal Working Conditions of a Coal Mill",slug:"detection-of-malfunctions-and-abnormal-working-conditions-of-a-coal-mill",totalDownloads:1140,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Coal mill malfunctions are some of the most common causes of failing to keep the power plant crucial operating parameters or even unplanned power plant shutdowns. Therefore, an algorithm has been developed that enable online detection of abnormal conditions and malfunctions of an operating mill. Based on calculated diagnostic signals and defined thresholds, this algorithm informs about abnormal operating conditions. Diagnostic signals represent the difference between the measured and the modeled values of two selected mill operating parameters. Models of mill motor current and outlet temperature of pulverized fuel were developed based on the linear regression theory. Various data analysis and feature selection procedures have been performed to obtain the best possible model. The model based on linear regression has been compared with two alternative models. The algorithm validation was carried out based on historical data containing values of operating parameters from 10 months of mill operation. Historical data were downloaded from distributed control system (DCS) of a 200-MW coal-fired power plant. Tests carried out on historical data show that this algorithm can be successfully used to detect certain abnormal conditions and malfunctions of the operating mill, such as feeder blockage, lack of coal and mill overload.",book:{id:"6332",slug:"thermal-power-plants-new-trends-and-recent-developments",title:"Thermal Power Plants",fullTitle:"Thermal Power Plants - New Trends and Recent Developments"},signatures:"Teresa Kurek, Konrad Wojdan, Daniel Nabagło and Konrad Świrski",authors:[{id:"179942",title:"MSc.",name:"Daniel",middleName:null,surname:"Nabagło",slug:"daniel-nabaglo",fullName:"Daniel Nabagło"},{id:"212957",title:"Dr.",name:"Teresa",middleName:null,surname:"Kurek",slug:"teresa-kurek",fullName:"Teresa Kurek"},{id:"212961",title:"Dr.",name:"Konrad",middleName:null,surname:"Wojdan",slug:"konrad-wojdan",fullName:"Konrad Wojdan"},{id:"212962",title:"Prof.",name:"Konrad",middleName:null,surname:"Świrski",slug:"konrad-swirski",fullName:"Konrad Świrski"},{id:"212963",title:"MSc.",name:"Łukasz",middleName:null,surname:"Śladewski",slug:"lukasz-sladewski",fullName:"Łukasz Śladewski"}]},{id:"72177",title:"Nuclear Power Plant or Solar Power Plant",slug:"nuclear-power-plant-or-solar-power-plant",totalDownloads:671,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Both solar energy and nuclear energy face significant economic challenges. Sustainable energy costs have traditionally been greater than any of those associated with the growth of fossil fuel power generation, although the costs of renewable energy technologies (especially photovoltaic) have dropped. Furthermore, capital costs remain a big challenge in the nuclear generation. In many nations, the cost of building small nuclear power plants is quite large due to time, technology, and environmental and safety challenges for consumers. Such problems might not be as big for state-owned corporations or controlled industries for which utilities have quick access to cheap resources, and this partially explains why the interest for nuclear reactors in Asia is far greater than in the United States or Europe. Learning could help decrease costs for both types of technologies, but the track record for learning-by-doing in the nuclear sector is not good.",book:{id:"9888",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",title:"Nuclear Power Plants",fullTitle:"Nuclear Power Plants - The Processes from the Cradle to the Grave"},signatures:"Mostafa Esmaeili Shayan and Farzaneh Ghasemzadeh",authors:[{id:"317852",title:"Ph.D.",name:"Mostafa",middleName:null,surname:"Esmaeili Shayan",slug:"mostafa-esmaeili-shayan",fullName:"Mostafa Esmaeili Shayan"},{id:"319145",title:"Prof.",name:"Farzaneh",middleName:null,surname:"Ghasemzadeh",slug:"farzaneh-ghasemzadeh",fullName:"Farzaneh Ghasemzadeh"}]}],onlineFirstChaptersFilter:{topicId:"803",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,annualVolume:11411,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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