Pain Sensation: Nociceptive receptors and transduction

Pain Sensation: Nociceptive receptors and transduction Pain is a subsystem of somatic sensation which includes a wide range of unpleasant sensory and emotional experiences usually associated with actual or potential tissue damage (Das et al., 2005). Over the years, by means of the evolutive process of natural selection, nature has made sure that pain is a bodily signal we cannot ignore. As a matter of fact, sensitivity and reactivity to noxious stimuli are essential to the well-being and survival of an organism. In dangerous circumstances pain tells the subject to get out of that situation immediatly, this is its main function. Without these attributes provided by pain mechanisms, the organism would have no means to prevent or minimize dangerous circumstances (individuals congenitally insensitive to pain are easily injured and most of them die at an early age1). While most of the sensory and somatosensory modalities are primarily informative, pain is a protective modality. Pain perception (also called nociception) doesnt come from excessive stimulation of the same receptors that generate somatic sensations, as someone could even think, it is a properly devoted subsystem. Nociception (from the Latin nocere, to hurt) in fact depends on specifically dedicated receptors and, due to its vital importance, this kind of information travels through redundant pathways. Pain also differs from the classical senses (hearing, smell, taste, touch, and vision) because it is both a discriminative sensation and a graded emotional experience. In the big picture, pain appears as a more complex whole experience than simple somatic sensation; that is why there are still many obscure aspects not completely understood, especially in the field of pain physiology and pharmacology. For this and other reasons, even nowadays, nociception remains an extremely active area of scientific research. 2. Pain Sensation Nociceptive receptors and transduction Pain sensation begins with relatively unspecialized free nerve cell endings called nociceptors. Like other somatic sensory receptors, they transduce a variety of noxious stimuli into receptor potentials, which in turn trigger action potentials in the pain nerve fibers (afferents). These action potentials are transmitted to the spinal cord and then, through the brainstem, to the thalamus and the somatic sensory cortex according to specific pathways2. Nociceptors are widespread distributed, they also show different degrees of sensitiveness and specialization. There are nociceptors in the skin, in the joints and also in visceral organs, but none of them is found inside the central nervous system (CNS)1. In contrast with somatic sensory receptors (responsible for the perception of innocuous mechanical stimuli), the axons associated with nociceptors conduct relatively slowly, being only lightly myelinated or, more commonly, unmyelinated2. Thus, according to the different kind of axon, there are faster or slower pain pathways. In particular, pain receptors can fall into four major categories depending on their response to the different types of stimulation caused by the damage: mechanosensitive nociceptors: respond to mechanical stimulation and have A-delta fibers, bigger axons with faster conduction velocity; mechanothermal nociceptors: respond to thermal stimuli, A-delta fibers; chemical nociceptors: respond to chemical substances, A-delta fibers; polymodal nociceptors: respond to high intensity stimuli of the previous three types and have C fibers, smaller and unmyelinated axons with slower conduction velocity. The cell bodies of these primary pain-neurons are located in the dorsal root ganglia (for body afferents) and in the trigeminal ganglia (for face afferents)1,2. The transduction of nociceptive signals, which starts with the nociceptive receptors, is a complex task. Tissue damage results in the release of a variety of chemical substances which triggers the response of nociceptors. Some of these substances activate the transmembrane transient receptor potential (TRP) channels, which in turn initiate action potentials2. Another characteristic feature of nociceptors is their tendency to be sensitized by prolonged stimulation, making them respond to other sensations as well in certain circumstances. This prolonged stimulation increases the release of chemical substances, making nociceptors sensitized and reducing their response threshold. Actually, within a few seconds after the injury, an area of some centimeters around the injured site shows reddening caused by vasodilation. This inflammation becomes maximal after about ten minutes and this region shows a lowered pain threshold (hyperalgesia) in response to additional noxious stimuli. This effect is also referred to as peripheral sensitization, in contrast to central sensitization that can occur at higher levels in the dorsal horn1. Although it is still unknown whether nociceptors respond directly to the noxious stimulus or indirectly by means of one or more endogenous chemical intermediaries released from the traumatized tissue, the activation of nociceptors initiates the process by which pain is experienced: these receptors relay information to the CNS about the intensity and location of the painful stimulus. Pain classification The result of sudden painful stimulation can be divided into two categories of sequential sensations separated by a short time interval. A sharp first pain, immediately after the damage, its followed some seconds later by additional, diffuse and longer-lasting second pain sensation. The temporal interval between these two separate sensations is due to the difference between fast transmitting A-delta fibers and slow transmitting C fibers. This phenomenon is also known as double pain sensation. Pain has also been classified into three major types1: Pricking pain: is also called fast pain or sensory pain (first pain) and arises mainly from the skin, carried by A-delta fibers which permit discrimination and localization of the pain. Burning pain: is caused by inflammation, burned skin and is carried by C fibers. This type of pain is a more diffuse, slower to onset, and longer in duration (second pain). Like pricking pain, burning pain arises mainly from the skin, but it is not distinctly localized. Aching pain: is a sore pain which arises mainly from the viscera and somatic deep structures. This pain is carried by the C fibers from the deep structures to the spinal cord and is not distinctly localized. Pain pathways The neural pathway that conveys pain (and temperature) information from the periphery of the body to the higher centers of the CNS is often referred as the anterolateral system (or ventrolateral column). This pathway is physically separated from the system that conveys mechanosensory information like touch and pressure (dorsal column-medial lemniscus pathway). However, even though the dorsal route has been always considered a touch pathway functionally separate from the anterolateral pathway, recent reports indicate that the dorsal column can carry noxious information from the viscera and widespread skin regions as well1. Anyway, the main difference between these two systems remains the site of decussation: while the dorsal column is an ipsilateral tract until the medulla (where synapses and decussates), the anterolateral system makes early synaptic connections and decussates right away in the spinal cord, becoming a contralateral tract. Composing the anterolateral system, there are three major ascending tracts: the neospinothalamic tract (the main, central pain pathway, phylogenetically younger, with few synapses), the paleospinothalamic tract and the archispinothalamic tract (which constitute minor parallel pain pathways, phylogenetically older and multisynaptic tracts)1. Every pain tract is made of three kinds of pseudounipolar neurons: first-order, from free nerve endings (nociceptors) to the dorsal horns of the spinal cord; second-order, from the dorsal horns to the thalamus; and third-order, from the thalamus to the primary somatic sensory cortex. The cell bodies of first-order neurons are located in the dorsal root ganglia (DRG) for all three pathways. a) The neospinothalamic tract (central pathway) constitutes the classical anterolateral system. This pathway is responsible for the immediate awareness of a painful sensation and for the understanding of the exact location of the painful stimulus. The first-order nociceptive afferents enter the spinal cord via the dorsal roots of the DRG and, when these projecting axons reach the dorsal horns of the spinal cord, they branch into ascending and descending collaterals, forming the tract of Lissauer2. Once within the dorsal horn, these afferents make synaptic connections with second-order neurons located in Rexeds laminae (layer I to V). Axons of these second-order neurons then cross the midline of the spinal cord, decussating in the anterior white commissure, and ascend to the brainstem in the contralateral (anterolateral) quadrant. Most of the pain fibers from lower extremities of the body and below the neck terminate, through the brainstem, in the ventral posterior lateral nucleus (VPL) of the thalamus. The VPL, which serves as a relay station, is thought to be mainly concerned with discriminatory functions1. Finally, here axons of second-order neurons synapse with third-order neurons that send the signal to the primary and secondary somatosensory cortex (SCI and SCII, respectively). Unlike the rest of bodily afferents, first-order nociceptive neurons from the head, face and intraoral structures have somata in the trigeminal ganglion. Trigeminal fibers enter the pons, descend to the medulla (forming the spinal trigeminal tract) and make synaptic connections in the spinal trigeminal nucleus, then cross the midline and ascend as trigeminothalamic tract (or trigeminal lemniscus). Axons from the second-order neurons terminate in a variety of targets in the brainstem and thalamus, but the discriminative aspects of facial pain are thought to be mediated by projections to the ventral posterior medial nucleus (VPM) of the thalamus and by projections (from here) to primary and secondary somatosensory cortex2. All of the fibers terminating in VPL and VPM are somatotopically oriented and still here the information supplied by different somatosensory receptors remains segregated. Axons from the thalamus synapse with third-order neurons of the SCI, which includes Brodmanns Areas 3a, 3b, 1 and 2. Each of these cortical areas contains a separate and complete representation of the body: they are somatotopically organized maps representing the human body (from the foot up to the face) in a medial to lateral arrangement2. b) The paleospinothalamic tract is a parallel pathway where the emotional response to pain is mediated1. This tract also activates brainstem nuclei which are the origin of descending pain-suppression pathways which regulate the sesation of noxious inputs at the spinal cord level. In the paleospinothalamic tract the majority of the first-order nociceptive neurons make synaptic connections with second-order neurons in Rexeds layer II (substantia gelatinosa). These second-order neurons also receive input from mechanoreceptors and thermoreceptors, and thats why the anterolateral system is also responsible for temperature perception1. The nerve cells that compose the paleospinothalamic tract are multireceptive or wide dynamic range nociceptors. Most of their axons cross and ascend in the spinal cord primarily in the anterior region and thus form the anterior spinal thalamic tract (AST). These second-order fibers contain several tracts and each of them makes a synaptic connection in different locations: in the mesencephalic reticular formation (MFR) and in the periaqueductal gray (PAG), forming the spinoreticular tract; in the tectum, also known as the spinotectal or spinomedullary tract; in the midline thalamic nuclei, forming the spinothalamic tract. Altogether these three fiber tracts are thus known as the paleospinothalamic tract, which is in part bilateral, because some of the ascending fibers do not cross to the opposite side of the cord1. Finally, from the thalamic nuclei, these fibers synapse bilaterally in the somatosensory cortex. Pain is a complex experience processed by a diverse and distributed network of neurons and brain regions. In addition to the sensory-discriminative aspects (carried by the neospinothalamic tract) there are also affective-motivational components of pain2. In the paleospinothalamic pathway there are extensive connections between the thalamic nuclei and the limbic areas such as the cingulate gyrus and the insular cortex. The insular cortex integrates the sensory input with the cognitive components. The limbic structures (amygdala, superior colliculus) project to the hypothalamus and initiate visceral responses to the pain. The thalamic nuclei also projects to the frontal cortex, which in turn is linked to the limbic structures involved in processing the emotional components of pain1. c) The archispinothalamic tract is another parallel pathway, phylogenetically the oldest that carries noxious information1. The characteristics of this tract are very similar to the ones found in the previous pathway. First-order nociceptive neurons make synaptic connections in Rexeds layer II (substantia gelatinosa). From here, second-order fibers ascend and descend in the spinal cord surrounding the grey matter to end synapsing with cells in the reticular formation and in the periaqueductal gray. Further diffuse multisynaptic pathways ascend to the diverse nuclei of thalamus and send collaterals to the hypothalamus as well as the limbic system nuclei. These fibers, like for the paleospinothalamic tract, mediate visceral, emotional and autonomic reactions to painful stimuli. In short, because of the importance of warning signals of dangerous circumstances, several nociception pathways are involved to transmitting these signals and some of them are redundant. The neospinothalamic tract conducts fast pain (via A-delta fibers) and provides information of the exact location of the noxious stimulus. The multisynaptic paleospinothalamic and archispinothalamic tracts conduct slow pain (via C fibers), a pain which is chronic and harder to localize. Through these patways, pain activates many different brain areas which link together sensation, perception, emotion, memory and motor reaction1. 3. Pain Modulation When talking about pain, we always have to consider and keep in mind the discrepancy between the objective reality of a painful stimulus and the subjective rsponse to it. Modern studies have provided considerable insight into how circumsatnces affect pain perception-interpretation and, ultimately, into the pharmacology of the pain system2. For many years it has been suggested that somewhere in the CNS there should be some neuronal circuits modulating incoming painful informations. Evidence for an intrinsic analgesia system was demonstrated by intracranial electrical stimulation of certain brain sites1,3. The circuit consisting of the periaqueductal gray matter (PAG), the raphe nuclei (RN), the locus coeruleus (LC) and the caudate nucleus (CN) contributes to the descending pain suppression mechanism, which inhibits incoming pain information at the spinal cord level6. Stimulation of such areas produce analgesia without behavioral suppression; indeed, touch, pressure and temperature sensation remain intact1. At the interneuronal level, opiate receptors activation causes hyperpolarization of the neurons, which in turn results in the inhibition of firing and in the release of substance P (a neurotransmitter involved in pain transmission) that blocks pain transmission1. In addition to descending projections, also local interactions between mechanoreceptive afferents and neural circuits within the dorsal horn can modulate the transmission of nociceptive informations to higher centers2. Observations by Melzack and Wall led to the idea that concomitant activation of the large myelinated fibers associated with low-threshold mechanoreceptors can mediate the flow of pain. This mechanism, also known as Gate Control Theory13, predicts that (at the spinal cord level) non-noxious stimulation will produce presynaptic inhibition on dorsal root nociceptor fibers and thus blocking incoming noxious information from reaching the CNS1 (i.e. non-painful input closes the gates to other painful inputs, which results in prevention and suppression of pain sensation). This explains also why if you, for example, stub a toe, a natural and effective reaction is to vigorously rub the site of injury for a couple of minutes2. However, there are many different factors that can influence the way we understand pain. Doubtless, three of these are: drugs, prior injuries and, more broadly speaking, circumstances. a) Drugs The brain has a neuronal circuit and endogenous substances to modulate pain. There are two primary types of drugs that work on the brain: analgesics and anesthetics1. The term analgesic refers to a drug that relieves pain without loss of consciousness, whereas the term anesthetic refers to a drug that depresses the CNS. Anesthetics are characterized by the absence of perception for all sensory modalities, including loss of consciousness, but without loss of vital functions. The areas that produce analgesia when stimulated are also responsive to exogenously administered opiate drugs2. As a matter of fact, the most effective clinically used drugs for producing temporary relief from pain are the opioid family, which includes morphine and heroin1. Unluckily, several side effects resulting from opiate use include tolerance and drug dependence (addiction). In general, these drugs modulate the incoming pain information as well as relieve pain temporarily, and are also known as opiate producing analgesia (OA). Opioidergic neurotransmission is found throughout the brain and spinal cord and appears to influence many CNS functions: opioids exert marked effects on mood, cognition and motivation1 (e.g. producing euphoria). The analgesic action of opiates implied the existence of specific brain and spinal cord receptors for these drugs long before the receptors were actually found. Since such receptors are unlikely to have evolved in response to the exogenous administration of opium and its derivates, the convinction grew that endogenous opiate-like compounds must exist in order to explain the evolution of these receptors in the body2. Nowadays, three classes of opioid receptors have been identified: ÃŽÂ ¼ (mu), ÃŽÂ ´ (delta) and ÃŽÂ º (kappa). All three classes are widely distributed in the brain, and particularly in the PAG, which is the site for higher cortical control of pain modulation in humans8. Moreover, three major classes of endogenous opioid peptides that interact with them have been recognized in the CNS: ÃŽÂ ²-endorphins, enkephalins and the dynorphins. Enkephalins are considered the putative ligands for the ÃŽÂ ´ receptors, ÃŽÂ ² endorphins for the ÃŽÂ ¼-receptors, and dynorphins for the ÃŽÂ º receptors1. The opioid peptides modulate nociceptive input mainly in two ways: blocking neurotransmitter release by inhibiting Ca2+ influx into the presynaptic terminal; or opening potassium channels, which hyperpolarizes neurons and inhibits spike activity. The various types of opioid receptors are distributed differently within the central and peripheral nervous system and this can explain many unwanted side effects following opiate treatments1. (For example, ÃŽÂ ¼-receptors are widespread in the brain stem parabrachial nuclei, which is a respiratory center. Inhibition of these neurons elicits also respiratory depression). In addition to opiates, the other big family of analgesia producing drugs is represented by the cannabinoids. Like opiates, cannabinoids produce analgesia when microinjected in the PAG and pain itself serves as a trigger for endocannabinoid release3. Results from the study by Walker et al. (1999) indicate that anandamide (an endogenous cannabinoid) fulfills the requirements for a nonopiate mediator of endogenous pain suppression and these data support the existence of endogenous cannabinergic circuitry in the dorsal and lateral PAG. Even if the opiate and cannabinoid mechanisms partially overlap anatomically, the endogenous opiate system is activaetd by intense and prolonged stimuli (such as high threshold electrical stimulation), while endogenous cannabinoids occur mostly in tonic pain suppression, during tests that do not produce significant stress or fear3. Cannabinoids have been used to treat pain for centuries and cannabis is still used despite its illegal status in most parts of the world. The spontaneous and stimulated release of anandamide in a pain-suppression circuit suggests that such drugs may form the basis of a modern pharmacotherapy for pain, particularly in instances where opiates are ineffective3. b) Previous injury A curious effect, well known and documented in clinical literature, is referred to as phantom limb sensation. Following the amputation of an extremity, nearly all patients have an illusion that the missing limb is still present. Although this illusion usually diminishes over time, it persists in some degree throughout the amputees life, and can often be reactivated2. A reasonable explanation for this phenomenon is that the central sensory processing apparatus continues to operate indipendently of the periphery, giving rise to these bizarre sensations. Indeed, considerable functional reorganization of the somatotopic maps in the primary somatosensory cortex occurs immediately after the amputation and tends to evolve for several years2. Neurons that have lost their original inputs respond to tactile stimulation of other (near) body parts, and so it is not unusual for the patient to perceive a phantom limb as a whole and intact, but displaced from the real location. These and further ev idences suggested then that a full representation of the body exists indipendently of the peripheral elements that are mapped2. Anyways, the major problem following phantom limbs phenomena is constituted by the fact that up to 85% of the amputated patients develop also phantom pain4. The description of this common unease can vary from a tingling or burning sensation to some more serious and debilitating issues. Phantom pain, in fact, is one of the more frequent causes of chronic pain syndromes and is extraordinarily difficult to treat2. Neverthless there is no really effective treatment, a study by Jahangiri et al. (1994) demonstrated that preoperative epidural infusion of morphine, bupivacaine and clonidine significantly reduces the incidence of phantom limb pain and phantom limb sensation. Moreover, this kind of treatment has been shown as safe for use on general surgical wards with a low incidence of minor side-effetcs4. Other than amputations, pain perception may also be modulated in certain stressful situations. Exposure to a variety of painful or stressful events produces an analgesic reaction, and this phenomenon is called stress induced analgesia (SIA). It has been considered that SIA can provide insights into both the psychological and physiological factors that activate endogenous pain control and opiate systems1. (For example, soldiers wounded in battle or athletes injured in sports events sometimes report that they do not feel pain during the battle or game; however, they will experience the pain later after the battle or as game has ended). Some studies demonstrated in animals that electrical shocks cause stress-induced analgesia3 and it has been suggested that endogenous drugs, (opiates or cannabinoids) released in response to stress, inhibit pain by activating the midbrain descending system1. Based on these and other experiments, it is assumed that the stress experienced by the soldiers and the athletes suppressed the pain which they would later perceive. c) Circumstances The experience of pain is highly variable between individuals: this highly subjective perception has a complex and often non linear relationship between nociceptive input and pain sensation5. From human experimentation we know that a variety of pain modulatory mechanisms exist in the nervous system, and these systems can be accessed either pharmacologically or through contextual and cognitive manipulation7,6. Various mental processes such as attention, emotional state, past experiences, memories, beliefs and feelings have been shown to influence pain perception and bias nociceptive processing in the humain brain9. All these top-down factors can be grouped together in the category of circumstances that either enhance or diminish pain sensation in regard to dedicated modulatory circuits. Among the cognitive variables influencing pain, the brain mechanisms underlying attentional control have been probably the most extensively studied5. A number of reports show the important role of attentional state in modulating the activity of primary somatosensory areas7. Thus, pain is perceived as less intense when individuals are distracted from it, as proved in an interesting study by Das et colleagues (2005). This research provides strong evidence supporting virtual reality (VR) based games in providing analgesia and positive influence on children with acute burn injuries, with minimal side effects10. VR can be considered an intermediary between reality and computer technology, and its ability to immerse the user interacting with the artificial environment is central in this kind of approach. However, attentional processes interact with mechanisms supporting the formation of expectations about pain and reappraisal of the experience5. The ability to predict the likelihood of an aversive event is an important adaptive capacity11. Our subjective sensory experiences are thought to be heavily shaped by interactions between expectations and incoming sensory information12 and this cognitive factor is important also for pain perception: positive expectations (i.e., expectations for decreased pain) produce a reduction in perceived pain that rivals the effects of a clearly analgesic dose of morphine12. These evidences provide also a neural mechanism that can, in part, explain the positive impact of optimism in chronic disease states. In fact, perceived control, attentional control and the descending pain modulatory system are involved in the placebo-induced analgesia, which is a clinical example of cognitive pain modulation that decreases pain intensity and cerebral responses to pa in5. Such top-down modulatory mechanism is a robust and clinically important phenomenon, which can be demonstrated in approximately one-third of the population9. Moreover, placebo analgesia requires the activation of endogenous opioid-mediated inhibition and neuroimaging techniques showed that there is also overlapping among brain sites activated by opioids and those that are activated during placebo analgesia9. Also the emotional state driven by the (experimental) context alters the attitude of patients and can produce powerful effects on pain perception7. In general, negative emotions increase pain, whereas positive ones decrease it14,7. Neverthless the brain mechanisms underlying these effects remain largely unknown, the prefrontal cortex, as well as parahippocampal and brainstem structures, are thought to be involved in the emotional regulation of pain14. According to Roy et al. (2009) cognitive and emotional processes induced by pleasant or unpleasant pictures interact with pain perception and modulate the responses to painful electrical stimulations in the right insula, paracentral lobule, parahippocampal gyrus, thalamus, and amygdala14. Not only, recent studies suggested that emotionally laden images representing human pain had a unique capacity to enhance pain reports15, in the suggestive perspective that search for the neural bases of human empathy with huge social implications. Thus, even though is well-established that mood selectively alters the affective-reactive response to pain (also called pain tolerance), the interpretation for some of these studies is sometimes difficult, since they do not always clearly dissociate changes in mood from changes in attention7. In fact, other studies showed that emotions can have a direct effect on attention to pain, leading to what is called attentional bias toward pain-related informations, which does not ensure the absence of covariate processes7. In the end, the available data indicate that emotion and selective attention may both interact modulating pain perception and cortical responses. But the observations that emotional manipulations alter pain unpleasantness more than pain sensation, while attention alters both pain sensation and unpleasantness, suggest that different modulatory circuits are involved7 and that they act through at least partially distinct mechanisms, which can be separated by appropriate experimental settings15. All this multiplicity of mechanisms underlying the emotional modulation of pain is reflective of the strong and reciprocal interrelations between pain and emotions, and emphasizes even more the powerful effects that emotions can have on pain perception14. 4. Conclusions In conclusion, in the CNS, much of the information from the nociceptive afferent fibers results from excitatory discharges of multireceptive neurons. The pain information in the CNS is controlled by ascending and descending inhibitory systems that can exert both facilitatory and inhibitory effects on the activity of neurons using endogenous opioids or other substances as mediators. In addition, a powerful inhibition of pain-related information occurs in the spinal cord. These inhibitory systems can be activated by brain stimulation, intracerebral microinjection of morphine, and peripheral nerve stimulation1. However, pain is an extremely complex perceptual and cognitive experience that is influenced also by many top down factors such as past sensations, expectations, the context within which the noxious stimulus occurs, the attentional and emotional state. Therefore, for all these reasons, the response to pain can often vary considerably from subject to subject. Case Report: Use of Valproate in Kleine Levin Syndrome Case Report: Use of Valproate in Kleine Levin Syndrome Successful use of Valproate in Kleine Levin Syndrome: a case report and review of cases reported from India Abstract Kleine-Levin Syndrome (KLS) is characterized by recurrent episodes of hypersomnia and other symptoms and it is a really challenging for the physician, since its causes are not yet clear, and available treatment options are not having adequate support. Here we are reporting a case with successful use of Valproate in KLS and also reviewing the cases reported from India. Introduction Kleine-Levin Syndrome (KLS) is a rare disorder which mainly affects adolescent boys and characterized by recurrent episodes of hypersomnia, and sometime along with hyperphagia, behavioral and cognitive disturbances, and hypersexuality (Yao et al., 2013). Several medications (stimulants, lithium, valproate, antipsychotics, antidepressants) have been reported to provide variable benefit in different symptoms, with lithium being the most widely used drug (Arnulf et al., 2005 2012). We are presenting a case of KLS, who had complete remission with valproate and also reviewing the cases reported from India. Case details: A 17 year old single male student of 12th standard, presented to our psychiatric outpatient clinic in September 2004 with hypersomnolence, low mood, decreased appetite and interest in studies, social and sexual disinhibition (such as singing obscene songs loudly at home, and touching unconsenting females’ including mother’s body parts- limbs, face and genitalia). Onset was acute, without any elicitable precipitating factor and course was episodic with average 7-10 days episode in every month for last four months and he maintained completely well in interepisodic period. Provisional diagnosis of recurrent depressive disorder (brief episodes) was kept and he was started on Sertraline (50 mg), on which he responded well. He remained asymptomatic for nearly nine months, but started having similar episodes again from mid 2005, due to which Sertraline was gradually hiked up to 150 mg/day, but of no use. Hence he was admitted in our inpatient setting in March, 2006 for diagnostic evaluation and further management. After detailed evaluation, it was found that his sadness was not pervasive and depressive cognitions and associated disturbances were not present and hypersomnia remained predominant complaint as initially he was sleeping 16-20 hours per day. He was also not responding with these medications, hence differential diagnosis of KLS vs. depression was kept and later finalized to KLS. His heamogram, renal functions, liver functions, blood sugar, routine urine, thyroid functions were within normal limits and chest X ray, ECG, EEG, and MRI brain were nor mal. In view of good literature support Lithium was started from 600 mg/day and hiked to 900 mg/day (serum level 0.8 mEq/liter). On which he has shown significant improvement initially for six month but later again started experiencing similar symptoms. He also had three episodes of fall, unresponsiveness and epileptiform discharge in EEG twice. Hence in view of seizure disorder and lack of response, Neurologist’s consultation was sought, who opined to start antiepileptic medication. Hence lithium was switched to Valproate (750 mg/day) in December 2006, on which he maintained completely well for 4 years, except brief reemergence of symptoms on discontinuing Valproate, which improved completely on resuming the medication. Valproate was gradually tapered and stopped in January 2011 on insistence of patient and family with discussing its pros and cons. Now index case has been maintaining well off Valproate for last three years without any episode of hypersomnolence, sexual disin hibition, sadness, or epileptic seizure. Discussion Based on historical reports by Kliene and Levin, KLS was essentially described and termed by Critchley (1962). Thereafter many researchers have reported their cases and reviewed cases with KLS (Arnulf et al., 2005 2012). Here we are reporting a case with KLS, who responded well with Valproate, after diagnostic dilemma and different psychotropic medications and also reviewing the other cases reported from India. In our electronic search for Indian studies on Kliene-levin syndrome, by using PUBMED and Google Scholar, we could find 15 cases reported from India (Aggarwal et al., 2011; Mendhekar et al., 2001; Prabhakaran et al., 1970; Shukla et al., 1982; Sagar et al., 1990; Narayanan et al., 1972; Agrawal Agrawal, 1979; Malhotra et al., 1997; Gupta et al., 2011). Of them 13 were males and 2 females, similar to male preponderance reported in the literature (Arnulf et al., 2005 2012). While presenting to psychiatric services their age was between 9 to 26 years and they had onset between 7 to 24 years of age. In two-third of patients (10 out of 15 patients) it was preceded with fever and their episodes of somnolence were lasted from 3 days to 10 weeks. Hypersomnia and hyperphagia were present in all, while two-third of patients also had social and sexual disinhibition (11 out of 15 patients). Other symptoms were cognitive disturbances (low intelligence quotient, impaired memory, confusion, and a cademic decline), irrelevant talk, and perceptual disturbances. Nearly one-third of patients improved spontaneously without any medication, while rest was given lithium, carbamazepine, methyl amphetamine, dextro amphetamine, and modafinil. Longest asymptomatic follow-up period is reported for 2 years (Aggarwal et al., 2011) (as depicted in table-1). Though literature supported lithium for higher response rate (Arnulf et al., 2005 2012), but index patient had remarkable response with Valproate, not with lithium, like earlier two reports (Crumley, 1997; Adlakha Chokroverty, 2009). Like earlier report (Adlakha Chokroverty, 2009), index patient also improved on lower dose of Valproate (divalproate 750 mg vs. 500 mg Valproate). Compared to other cases reported from India (Aggarwal et al., 2011; Gupta et al., 2011), index patient had longest follow-up (7 years) and remained asymptomatic in this period, except small exacerbation on discontinuation of Valproate treatment, which improved completely on resuming the drug. Similar to our patient, anticonvulsants (like Valproate) are the preferred treatment for KLS patient, and may also offer benefits in case of comorbid epilepsy (Yao et al., 2013). Valproate may be a good alternative to lithium in terms of efficacy as well as side effect profile. References Yao, C.C., Lin, Y., Liu, H.C., Lee, C.S., 2013. Effects of various drug therapies on Kleine–Levin syndrome: a case report. Gen Hosp Psychiatry. 35, 102.e7-102.e9. Arnulf, I., Zeitzer, J.M., File, J., Farber, N., Mignot, E., 2005. Kleine-Levin syndrome: a systematic review of 186 cases in the literature. Brain. 128, 2763-76. Arnulf, I., Rico, T.J., Mignot, E., 2012. Diagnosis, disease course, and management of patients with Kleine-Levin syndrome. Lancet Neurol. 11, 918-28. Critchley, M., 1962. Periodic hypersomnia and megaphagia in adolescent males. Brain. 85, 627–56. Aggarwal, A., Garg, A., Jiloha, R.C., 2011. Kleine-Levine syndrome in an adolescent female and response to modafinil. Ann Indian Acad Neurol. 14, 50-2. Mendhekar, D.N., Jiloha, R.C., Gupta, D., 2001. Kleine-levin syndrome : a report of two cases. Ind J Psychiatry. 43, 276-8. Prabhakaran, N., Murthy, G.K., Mallya, U.L., 1970. A Case of Kleine-Levin Syndrome in India. Br J Psychiatry. 117, 517-519. Shukla, G.D., Bajpai, H.S., Mishra, D.N., 1982. Kleine-levin syndrome: a case report from India. Br J Psychiatry. 141, 97-98. Sagar, R.S., Khandelwal, S.K., Gupta, S., 1990. Interepisodic morbidity in Kleine-Levin syndrome. Br J Psychiatry. 157, 139-141. Narayanan, H.S., Narayanan Reddy, G.N., Rama Rao, B.S., 1972. A case of Kleine-levine syndrome. Ind J Psychiatry. 14, 356-358. Agrawal, A.K., Agrawal, A.K., 1979. Kleine-levin syndrome: a case report. Ind J Psychiatry. 21, 286-287. Malhotra, S.M., Das, M.K., Gupta, N., Muralidharan, R, 1997. A Clinical Study of Kleine-levin syndrome evidence for hypothalamic-pituitary axis dysfunction. Biol Psychaitry. 42, 299-301. Gupta, R., Lahan, V., Srivastava, M., 2011. Kleine-Levin syndrome and idiopathic hypersomnia: Spectrum disorders. Ind J Psychol Med. 33, 194-8. Crumley, F.E., 1997. Valproic acid for Kleine-Levin syndrome. J Am Acad Child Adolesc Psychiatry. 36, 868-9. Adlakha, A., Chokroverty, S., 2009. An adult onset patient with Kleine-Levin syndrome responding to valproate. Sleep Med. 10, 391-3. Table-1: Reported cases with Kleine Levin syndrome from India

Comparing The Haitian To The French Revolution Essay

Haiti, known as Saint-Domingue before the revolution, it was the richest colony in the Americas in 1789. Almost half a million slaves toiled on its sugar, coffee, indigo, and cotton plantations. More than thirty thousand new African slaves arrived each year, both to replace the many that died of overwork or disease and also to fuel the rapid economic expansion that the colony experienced in the 1780s. Before the French revolution, the masters were, first of all, the King; after him, the nobles and clergy. From the King at the head to the poorest noble, they used their power badly. The rulers treated the ruled, the vast mass of the nation, as people created for their convenience, to supply them with money and to serve them. The King demanded great sums to provide armies for his wars, to surround himself with a brilliant and luxurious Court, to defray the expenses of government. As we go further in the French and Haitian revolution, they were both cruel and bloody, were there any signi ficant similarities and differences? They both were spurred for similar reasons by oppressed people, but they were significantly different economically, very different leaders and events. The causes for the French and Haitian revolutions were fairly uniform. An unfair distribution of power between social classes, restricted liberties and representation, and a large gap between the rich and the poor were the main catalysts for both revolutions. The social class situations of Haiti and France were main causes of both revolutions. Social mobility was nearly nonexistent in both societies. The Haitian social class system was particularly stratified because it was based on race. The highest positions in the government and military were only held by Peninsulares. Peninsulares were individuals that were born in Europe and had come over to the colony to rule. Directly under the Peninsulares in the social class system were the Creoles. These individuals controlled most of the land and the bus iness. Creoles were defined as individuals whose parents were both Peninsulares in the colonies. The next social classes were the Mestizo and the Mulattoes, who were half European and half Native American or African. Finally, all pure Africans or Natives were condemned to slavery. Slaves had no property, money, or rights. Most of the individuals in Haiti were slaves. Conversely,  the French social system was also very stratified and consisted heavily of the lowest class. The system is broken down between three estates: the clergy, nobility, and the 3rd estate which consisted of a lower, middle and upper class. Most of the third estate consisted of peasants. The clergy encompassed one percent of the population. The one percent controlled twenty percent of the land and did not pay taxes. The 2nd estate encompassed the nobility, two percent of the population. The nobility owned twenty-five percent of the land and did not pay taxes. The remaining ninety-seven percent of France belonge d to the third estate. The third estate held less than half the land in France and was forced to support the heavy burden of taxation in the bankrupt nation. The overwhelming gap between the political and economic power of the high and low classes caused resentment in both societies. A miniscule number of people, had privilege, comfort and luxury while the majority of people suffered. Social inequalities would a huge catalyst for both revolutions. The lowest class of each society realized their strength in numbers and passion for their cause. The 3rd estate broke free from France and created the Declaration of the Rights of Man. This document outlined a set of rights that pertained to every man from any class. From there, the 3rd estate moved forward in taking the country. The Haitian slaves utilized their massive population and excellent leadership to overthrow their oppressors. Toussaint Louverture was the leader of the revolution and a pivotal factor in defeating the Europeans. S ignificant overall economic differences were present between Haiti and France before the revolutions occurred. France was nearly bankrupt by the time the revolution began. Wars with England and the American Revolution had been extremely costly for France. The nation was in debt and the social elite were not paying taxes to aid the dying economy. The large economic strain on France caused heavy taxation of the bottom social class. In contrast, the economy of Haiti was not a factor that fueled the revolution. The Haitian economy was thriving. Free labor from slaves created a surplus of goods. Also these two countries had two very different leaders leading the revolutions; the Haitian revolution leader Toussaint Louverture began his military career as a leader of the 1791 slave rebellion in the French colony of Saint Domingue. Initially allied with the Spaniards of neighboring Santo Domingo, Toussaint switched allegiance to the French when they  abolished slavery. He gradually established control over the whole island, expelled British invaders and used political and military tactics to gain d ominance over his rivals. Throughout his years in power, he worked to improve the economy and security of Saint Domingue. He restored the plantation system using paid labor, negotiated trade treaties with Britain and the United States and maintained a large and well-disciplined army. Whereas the French revolution leader Maximilien de Robespierre. Maximilien Marie Isidore de Robespierre was born in Arras on 6 May 1758, the son of a lawyer. He was educated in Paris and entered the same profession as his father. He was elected a deputy of the estates-general (a form of parliament, but without real power) that met in May 1789, and subsequently served in the National Constituent Assembly. He was a politician, and one of the best-known and most influential figures of the French Revolution. Robespierre became increasingly popular for his attacks on the monarchy and his advocacy of democratic reforms. In April 1790, was elected president of the powerful Jacobin political club. After the dow nfall of the monarchy in August 1792, Robespierre was elected first deputy for Paris to the National Convention. The convention abolished the monarchy, declared France a republic and put the king on trial for treason, all measures strongly supported by Robespierre. The king was executed in January 1793. Haitians usually relate the Bois Caà ¯man ceremony as a historical event that started their war of independence, but modern scholarship suggests that details about the episode might owe more to myth than to reality. There probably was not one, but two slave gatherings, one held at the Normand de Mà ©zy plantation in Morne Rouge on August 14, which the French uncovered by torturing slave participants, and another one in Bois Caà ¯man held a week later, about which very little is known. According to Là ©on-Franà §ois Hoffmann’s Haitian the second meeting were invented by Antoine Dalmas in his Histoire de la rà ©volution de Saint-Domingue (1793) in order to portray the slav e gathering as a bloody, satanic assembly. On the other side, The Women’s March on Versailles was one of the earliest and most significant events of the French Revolution. The march began among women in the marketplaces of Paris who, on the morning of 5 October 1789, were near rioting over the high price and scarcity of bread. Their demonstrations quickly became intertwined with the activities of revolutionaries who were  seeking liberal political reforms and a constitutional monarchy for France. The market women and their various allies grew into a mob of thousands and, encouraged by revolutionary agitators, they ransacked the city armory for weapons and marched to the Palace of Versailles. The crowd besieged the palace and in a dramatic and violent confrontation they successfully pressed their demands upon King Louis XVI. The next day, the crowd compelled the king, his family, and most of the French Assembly to return with them to Paris. These events effectively ended the independent authority of the king. The marc h symbolized a new balance of power that displaced the ancient privileged orders of the French nobility and favored the nation’s common people, collectively termed the Third Estate. Bringing together people representing disparate sources of the Revolution in their largest numbers yet, the march on Versailles proved to be a defining moment of that Revolution. To conclude, the series of events that transformed the French colony of Saint-Domingue into the independent nation of Haiti lasted from 1791 to 1804, and the French revolution lasted around ten years, from 1789 until 1799. They both were around the same time, both successful, but had some differences between them such as racial, leadership, also economically different. Popkin, Jeremy D.. A concise history of the Haitian revolution. Malden, MA: Wiley-Blackwell, 2012. Print. † World at War: Understanding Conflict and Society – Username.† World at War: Understanding Conflict and Society – Username. http://worldatwar.abc-clio.com/Search/Display/1469759?terms=haitian+revolution (accessed May 26, 2013). â€Å"Jean-Jacques Dessalines (emperor of Haiti) — Encyclopedia Britannica.† Encyclopedia Britannica. http://www.britannica.com/EBchecked/topic/159337/ (accessed May 26, 2013). Mikaberidze, Alexander . † World at War: Understanding Conflict and Society – Username.† World at War: Understanding Conflict and Society – Username. N.p., n.d. Web. 29 May 2013. . Hugo, Victor. Les miseÃŒ rables. New York: Modern Library, 1992. Print. french revolution.† Gale Virtual Reference Library. N.p., n.d. Web. 27 May 2013.

Beowulf Deeper Understanding Essay

In the epic poem Beowulf there is a more universal understanding that can be seen once a reader has taken the time to look deeper into the text of the poem. A characters intentions are not always seen instantaneously. To understand the full meaning of why someone might go out of their way to help another is not always in the kindness of their own heart. A more intense and complicated plot is behind the thoughts of a character named Beowulf. Everything he does always has a catch to it and requires more then a personal thank you. In the poem Beowulf has three battles against foes. The first foe that he encountered was the man beast Grendel. Grendel lived in Denmark, which was a great distance from Beowulf’s homeland. On his journey to Grendel he came upon and slayed nicors. Nicors are sea demons and their occurrence in his journey brought Beowulf more honors. The significance of Beowulf’s journey and the killing of those beasts was that they brought him glory. This glory was not only shown through his pride although it was also shown through the inhabatince of the land towards Beowulf. The people of the land also gave him precious gifts. These gifts brought out the self-centered and materialistic sides of Beowulf. He didn’t slay Grendel to help the people, because his intentions of getting a reward were not accepted out of the kindness of his heart. They were accepted in the sense that he knew that he deserved them and that they should be required to pay him tribute to his greatness. The following foe the Beowulf slayed was Grendel’s mother. His mother wasn’t of any threat to the Danes until Beowulf killed her son. This caused a sedate and low key monster to take offense to the people who she has never tried to revenge against. Beowulf’s ways in which he killed Grendel would be offensive to any parent either human or beast. When your sons arm is seen lying torn off his body symbolizing the greatness of his death and the excellence of a human being revenge is the only answer to the situation. The point in which Beowulf was trying to make when killing Grendel’s mother was that he was showing them that he not only got rid of their biggest  problem but he got rid of the following problem as well. He knew that if he slayed the mother following the son that a more exceptional reward would be given to him. The battle with the mother was more intense then the battle with Grendel because it took place underwater and in that place Beowulf found the deceased body of Grendel. To tip off his fame amongst the Danes he cut off Gredel’s head and returned home with it to signify his notability once again. Since the first and second beasts were off the hands of the Danes and Beowulf has receive enough personal gratification to meet his needs he now travels back home. All of his gifts of gratitude are brought back with him and a few outstanding items are given to the king in honor of Beowulf’s loyalty towards him, although his intentions are not what they seem. His true intentions are to rule the kingdom and he does get his wish once the king dies in battle. While Beowulf is king the people gain much security in him due to his strength in battle. Knowing that Beowulf is less likely to be defeated in battle causes the people to want to treat him better because of the protection that he posses. The last foe the Beowulf goes into battle with is the fire-breathing dragon. The dragon has been in slumber for 300 years until one of Beowulf’s peasants disturbs him by stealing his gold from his cave. Once this occurs the dragon periodically comes out of the cave and torments the Geats. Since the dragon is disturbing Beowulf’s people he takes it upon himself to slay the dragon, although this will end up being the last battle that he is going to be alive to fight in. Once he returns home he dies shortly after asking to see the treasure that he has won from fighting the dragon. In the battle between the dragon and Beowulf him wanting to see his treasure before he dies acknowledges his materialistic ways. He doesn’t ask to see any of his loved ones of the people who have been with him along his journeys, he asks to see what is in his possession before he dies. Beginning the battle he shows his loyalty to his people although his people don’t show loyalty towards him because when he went to fight the dragon majority of them ran away. Therefore, Beowulf’s dignity and strength traits are not  passed on to majority his people and they are only supporting him when they are not involved in dangerous battles. Beowulf wanted to be appreciated. He knew that his strength was rare and he wanted to be treated as a rare stone would be treated. Everything that he did had to be praised and had to have treasure in the end or it wouldn’t be good enough for Beowulf. The fact that he made his people build him a grave and put all of his treasures in it with him shows that his peoples love towards him was not voluntary given. He forced the people to understand that with out him they were nothing and that they would be unable to survive in battle with out him. I believe that he made himself out to be more then he was to make himself feel more out of the crowd then anyone else that obtained a special talent. A person’s innermost feelings are never clearly visible physically. To understand how a person thinks and why they feel the way that they feel is a very hard task. One may never understand the human feelings and what their results may concluded too, although ones inner thoughts or feelings (such as Beowulf’s) may bring upon a deeper level of frustration. In the epic poem of Beowulf such human actions are expresses once a reader looks deeper into the poems story to see that there are more interpretations that can be made on a larger, more universal level.

Cubism, Orphism And Futurism Share A Common Language,...

The early 20th century in Europe was a time of rapid change. Modern art movements explored new ways of communicating this new modern condition – what is was like to live in an environment that was advancing and developing with incrediable speed . Dynamism became a means for the artists of the time to communicate what has been termed the modern condition. Cubism, Orphism and Futurism share a common language, Dynamism. Dynamism is a mechanism for communicating a sense of change or movement.. Artists also invested their own emotions of what they were experiencing through the use of dynamism. Viewers can understand that there was an excitement, anxiety and uncertainty associated with living this bustling, changing society. The movements reflected societies appreciation and interest in freedom of movement in art across Europe prior World War One. People were immensely excited by speed, technology and new forms of transport and communication. They all felt the world around them was begining to quickly change. The artists of the time employed dynamism in their works to express this rapid movement. Cubism responded to the world changing at a revoulutionary speed dynamically communicated through abstract art. Cubists disregarded traditonal ways of portraying a subject, and instead broke down the subject matter into scattered shapes and objects. According to Spain’s National Museum of Art, â€Å"Cubism demonstrated conclusively that the experience of moderity was bound to a dynamic and