Article Type: Review
Received : 29/09/2018.
Accepted : 01/10/2018.
Published : 15/10/2018.
*Correspondence to: Marcelo José da Silva de Magalhães, Professor of Medicine at Faculdades Unidas do Norte de Minas (FUNORTE) and Faculdades Integradas Pitágoras de Montes Claros (FIPMoc); Neurosurgeon and Nerve Surgeon, Vila da Serra Hospital, Belo Horizonte-MG, Brazil; Master of Science (Faculdade Inforium).
Article Type: Review
Received : 29/09/2018.
Accepted : 01/10/2018.
Published : 15/10/2018.
This review aims to analyze the cognitive functions of the insula as well as anatomical, histological and historical aspects. The insular lobe has a conical shape, is located deep in the lateral sulcus or fissure of Sylvius in each of the cerebral hemispheres. The insula is considered a "multisensory node" because it is connected with the anterior cingulate cortex, rostral and dorsolateral prefrontal cortex, regions of the parietal and temporal lobes, entorhinal cortex, amygdala, hypothalamus and dorsal thalamus to which it emits projections and receives fibers that contribute for the formation of its tracts and delimitation of its functions, especially the cognitive ones, that include: processing of emotions, process of eating, perception and modulation of pain, social correlation and empathy, and intelligence. In addition, alexithymia, an inability to identify and describe one's own emotions and bodily sensations, has a relation with the neurodegeneration of the von Economo neurons of the insula, which reaffirms the importance of studies related to this lobe, for a long time considered isolated as an "island".
KEYWORDS: telencephalon; cognition; neuroanatomy, insula
The insula is a small area of the telencephalon first described by Johann Christian Reil in the late 18th century. The insula is a hidden structure within the lateral sulcus and forms part of the formation of the floor of this sulcus. The difficult access to this structure explains the negligence and scarcity of studies related to it.
The insula lobe has a conical shape and presents some sulcus and gyrus, for instance the circular sulcus of the insula, the central sulcus of the insula, the short gyrus and the long gyrus of the insula. [¹] [Figura 1]
Histologically the posterior part of the insula cortex is granular and the anterior part is agranular, thus resembling the neighboring cortical areas. Its nerve connections are poorly understood, but it is believed that this area is important in planning or coordinating the articulatory movements necessary for speech. [²]
Functionally it is known that the insula acts together with the prefrontal cortex and the amygdala. It is involved with sounds, tastes, smells and emotions. In addition, it also contributes to the processing of emotions and perception, emotions and modulation of pain, social correlations and empathy, and also intelligence, having a significant role in the limbic system. [³]
The insula exerts control over several functions, such as motor, autonomic, language and behavioral control. The insula study has gained visibility in the scientific field for its participation in the epileptogenic process. In the last decade there has been a growing interest in the anatomy of the insula, generated by the need to explore this "hidden" region of the brain in the investigation with electrode implantation, identification and removal of epileptogenic areas whether they are tumor or not. 
The insular cortex is still important for the modulation of afferent information and its integration with cognitive mechanisms for the construction of individual perception. The insula has the function of interconnecting the cortical circuit and the afferent and efferent connections with a large cortical and limbic area, in other words, it is involved with the cognitive, autonomic and sensorial processes. [5, 6]
Taking into account the importance attributed to the insula, this work aims to analyze, based on studies of the last four decades, the anatomical, histological, and functional characteristics of the insula lobe, as well as to perform anatomical-clinical correlations with prominence for alexithymia.
The study is a review of the literature that aimed to analyze and discuss the theme from the search of works that address the main neuroanatomic aspects, anatomical-clinical relations with alexitima, inter-specific correlations between primates and neurofunctional studies focusing on cognitive activities in which insula participates.
The articles were accessed between March and June 2017 in the following databases: PubMed and Scielo, using the following descriptors in Portuguese and English: "cognitive aspects of the insula", "functions of the insular cortex", "anterior insular cortex", "Historical aspects of the insular cortex", "amygdala and its relations with the insula", "alexithymia", "alexithymia scale", "neurotransmitter concentrations in the insula and anterior cingulate", "relation of anxiety with the insula", "functions of the insula "," insula neuroanatomy " and" insula physiology ".
1.1 Historical aspects
The human insular cortex was first described by Johann-Christian Reil in 1796 and since then known as the "Island of Reil". Due to its position relative to other cortical areas, the insula has been described as an extension of the temporal lobe as well as a component of deeper limbic structures. The cortical development process begins at the 6th week of fetal life in a lower cortical region. This region will later bend to become the boundary of the insula. Studies on human development suggest that in the cortex the insula is the first cortical structure to develop in the fetus. 
1.2 Anatomy of the insula
The insular lobe lies between the neocortex and the paleopallium, it is conical in shape and is located deep in the lateral sulcus or fissure of Sylvius in each of the cerebral hemispheres. Due to the reduced growth during its embryonic development, it becomes involved by the frontal, parietal and temporal lobes, this contributed to its denomination of "hidden island of Reil". In addition, the insula is divided in two parts, anterior and posterior, by the central sulcus of the insula and has other sulcus and gyrus that help to identify it, namely: circular sulcus of the insula, short gyrus, limen and long gyrus of the insula [picture 1]. The insula is considered the fifth lobe of the brain and corresponds to the areas of Brodmann 13 to 16 and is connected to the anterior cingular cortex, rostral and dorsolateral prefrontal cortex, parietal and temporal lobe regions, entorhinal cortex, amygdala, hypothalamus and thalamus dorsal. [1, 8]
From the apex of the insular lobe the transverse gyrus originates, which is located inferiorly along the insular limen (apex of the insula on its lower margin) and connects its surface with the postero-medial orbital lobe, and accessory gyrus of the insula, which form the pole of the insula. [9, 10]
The insula has an anterior surface and a lateral surface, both surrounded by its opercula, immediately more developed regions of the cerebral hemispheres. The anterior insular surface is related to the frontal-orbital operculum, formed by the posterior part of the posterior orbital gyrus and the medial portion of the inferior frontal gyrus. The lateral insular surface is covered in the upper portion by the frontoparietal operculum, consisting of the triangular and opercular portions of the inferior frontal gyrus, inferior frontoparietal fold and upper part of the supramarginal gyrus, and in the inferior part by the temporal operculum, formed by the superior temporal gyrus and region of the supramarginal gyrus. The surfaces of the frontoparietal and temporal operculum also contribute to the delimitation of the Sylvius fissure between the temporal and parietal lobes. 
The portions of the circular sulcus of the insula, called upper and lower limiting gyrus, are characterized as true gyrus that help delineate the transitions and sinuosities between the lateral insular surface and the frontoparietal and temporal operculum. The anterior limiting sulcus of the insula is much deeper and consists structurally in a true cleft that separates the anterior surface of the insula from the posterior portion of the posterior orbital gyrus. Beneath the cortex of the insula and its subcortical white substance or extreme capsule is a thin sheet of gray matter forming the claustrum and under it is the putamen, surrounded by the outer and inner capsules. 
The middle cerebral artery originates at the beginning of the sylvian fissure, lateral to the optic chiasm and is responsible for irrigation of the insula. It is divided into four segments, M1 to M4. The M1 or sphenoid segment originates in the bifurcation of the internal carotid artery and the middle cerebral artery and extends to the main bifurcation of the middle cerebral artery, located near the insula limen. The M2 or island segment has its path from the bifurcation of the middle cerebral artery to the circular sulcus. The M3 or opercular segment begins in the peri-insular gyrus, traverses the operculum and ends in the lateral surface of the gyrus. The segment M4 corresponds to the branches that supply cerebral convexity. 
1.3 Histology of the insula
The histology of the posterior insular cortex consists of granular heterotypic isocortex found in the primary projection areas, for example the visceral and gustatory sensory areas, whereas the anterior insular cortex has isocortex similar to the association areas.[¹] The insular lobe can be divided into three parts according to its cytoarchitecture: its ventral and anterior portion, which is classified as agranular neocortex, its posterior and dorsal portion presenting granularity and its middle portion with dysgranularity. In addition, in large monkeys and humans there is a subdivision of the agranular insular cortex in the ventral anterior section located near the orbital cortex called the frontoinsular cortex, where groups of neurons called Von Economo Neurons (VENs) are present. The VENs present in the frontoinsular cortex and those of the agranular insular cortex of the ventral and anterior part of the insula are related to social consciousness, whereas the granular and disgranular insular cortexes receive information about the internal homeostatic state of the body and the somatosensory periphery. 
1.4 Afferent and efferent pathways of the insula
Studies of white matter tracts have shown that the insular lobe has complex structures and is closely associated with the surrounding lobes as well as the limbic and paralimbic system through fibers of white matter, which refutes the theory that the insular lobe would be an isolated island as its eponym, Reil Island, may suggest. [15, 16]
The anterior insula is an important site of emotional, motivational, cognitive processing and sensory stimuli such as tasting. The middle part of the insula is widely connected with all other parts of the insula involved in motor, somatosensory and pain processing. The posterior part of the insula forms a representation of the state of the body, which is constantly receiving information about autonomic functions.. The impulse is then taken to the anterior part of the insula which is responsible for integrating the interoceptive impulse with the cognitive information, adding subjective feelings to the sensation experienced. In this sense, new studies have described the insula as a "multisensory node" that constantly receives information from the periphery, processes and sends it to the upper parts of the cortex. 
The insular lobe in primates including humans has connections to the cerebral cortex, nuclei of the base, amygdaloid body, other limbic areas and dorsal thalamus as shown in [Tables 1 and 2]. 
Another form of division of the island projections consists of anterior, with agranular and dysgranular anteroventral cytoarchitectural portions, and posterior, granular and dysgranular dorsoposterior cytoarchitectural portions.
The connections of the anterior region of the insula consist of: anterior cingular cortex, orbitofrontal cortex, amygdala and hippocampus (limbic system), inferior temporal gyrus (visual), superior temporal sulcus (auditory), tuber and olfactory bulb (olfactory), mediodorsal nucleus (thalamic) and posterior insula (intra-insula).
Connections of the posterior region of the insula are represented by: inferior temporal (visual) gyrus, primary and secondary auditory cortex, posterior superior temporal sulcus, upper temporal auditory (auditory), primary and secondary somatosensory cortex (somatosensory), ventroposterolateral nucleus (thalamic) and anterior insula (intrainsular). [19, 21]
1.5 Functional considerations of the insula
The insular cortex is functionally subdivided into anterior and posterior, but there are authors who add the medial region. The anterior portion is related to subjective questions of experience and perception, medially with polymodal integration and posterior with conscious interception of body state. [³]
1.5.1 Processing of emotions and their perception
Together with the amygdala, anterior cingulate gyrus, and the prefrontal cortex, the ventral portion of the anterior insular cortex is involved with emotional issues, specifically in the identification, regulation, judgment of emotions, and generation of affective responses. [3, 22]
There is a differentiation in the roles of the right and left hemicortex, the first involving the inhibition of negative feelings and emotional pain, and the latter with positive ones, but anyway all emotions processed in the insula pass through the left hemisphere , even the negatives that are referred to it by right. [³]
These functions are important since negative thoughts influence the well-being of the individual and the damage of this cortical function can be associated with diseases, for example depression, in which the patient develops a tendency towards pessimistic behaviors with physiological impairment: insomnia, unwillingness to personal hygiene, lack of appetite and social isolation. 
For reasons not yet elucidated, the male right side is more active than the female.[³] According to research involving neuroimaging, the insula is hyperactive in normative anxiety, the physiological one that is aroused in stressful moments, but soon healed, manifesting fear in greater proportion in the left hemicortex. In contrast, pathological anxiety has equivalent distribution on both sides characterizing such emotional disorders. 
The perception of the own feelings is developed mainly by the limbic system, being the participation of the anterior insula and other cortical components. An example of this participation is the physiopathology of alexithymia, inability to identify and describe one's own emotions, as well as bodily sensations / responses, arising from the neurodegeneration of the VEN cells of the insula, characterizing the error of emotional processing of such disorder. 
In frontotemporal dementia there is also a reduction of VEN cells, thus causing bipolarity, emotional uncontrol and disinhibition, that is, the individual does not feel repressed in speaking improprieties, defecating and urinating or even being naked in the public environment. 
1.5.2 Insulating the food process
After leaving the postero-medial ventral nucleus of the thalamus, the third neuron of the gustatory pathway reaches the insula and the inferior frontal gyrus, where the palate is processed. This special sensitivity, however, is accompanied by general (texture, temperature) and olfactory, to complement the concept of flavor and individual perception about food, thus influencing the decision to eat. [1,25]
The gustatory neural activity suffers interference from the expectation about the taste of the food making the food more attractive or disgusting.  In addition, the observed experience also influences the individual perception. Research done with individuals who witnessed third-party reactions to food and odors (neutral reaction, acceptance, and disgust) proved that there was a mimicry of feeling and thus the observer tended to follow the same view of the observed, rejecting or accepting the food later introduced. In addition, observations of neutral and disgusting feelings further activated the anterior region of the left hemicortex insula, in addition to a small exacerbation of the right anterior cingular cortex. 
Neophobia was also found, characterized by the aversion to new experiences, in this case, food, and gustatory memory with the insula. For example, if after eating a certain type of food, the individual feels nauseous, he will soon associate that food with the feeling of illness and discomfort, and thus avoid such food. This situation is particularly reversible and depends on the plasticity of the gustatory cortex. 
The insular activity on the sensation of disgust has a very important adaptive value: after nausea and / or vomiting with the ingestion of something, the individual develops revulsion to unconsciously avoid the physiological damages arising from him; this idea can expand into odors, sight of feces and sewage or even situations given as disgusting. [¹]
It is observed that the electrical stimulation of the anterior insula evokes nausea and the sensation of "stomach turning" during the vomit; with this information the insula interconnects the unpleasant sensations with the visceromotor reactions and increases the sensation of disgust. 
Neuroimaging studies demonstrated activations of different cortical areas during experiences of hunger and satiety; the insular cortex was most strongly activated during hunger, whereas in satiety and excessive consumption, such a region was depressed. We also observed an inversely proportional relationship between insular activation and serum levels of insulin, a pancreatic hormone released after feeding, interrelating findings in neuroimaging research. In addition, the abnormal action of the insula is associated with thinness and obesity. 
1.5.3 Individual perception and pain modulation
The insular cortex participates in the modulation of information afferent to pain and its integration with cognitive mechanisms for the construction of individual perception of a painful experience.  In this sense, it is possible to subdivide the insular cortex into regions where the former is related to cognitive and affective aspects of pain and the medial and posterior regions are related to the discrimination and sensation of pain. The imagination and premonition of pain are also computed by the insula and can influence the final pain, that is, something becomes more painful the more idealized it is. 
In addition, there is a relation of the insula with the moderation of the pain together with the anterior cingular gyrus and the dorsolateral prefrontal cortex determining its intensity through efferences directed to the periaquedutal gray matter of the mesencephalon, which sends fibers to the magnum nucleus of the rafa reticular formation. This, in turn, sends fibers to the encounter of the I and II neurons of the lateral spinothalamic pathway, and through a cholinergic neuron, negatively modulates the information of pain and temperature having participation in the gate of pain. [1, 25]
1.5.4 Social relations and empathy
In the last years the understanding of the thoughts and feelings has advanced in the sense of two ways to be recognized: the one of Theory of the Empatic Mind. The first involves individual beliefs and the ability to interact, including the activity of the medial prefrontal cortex, superior temporal sulcus and adjacent temporoparietal junction, while the latter involves the ability to share feelings with others and has activation of the insular and cingular cortex previous. Because of this function, the insular cortex is also known as the "interoceptive cortex". 
The concept of "interoception" comes from radical behaviorism - a movement postulated by Burrhus Frederic Skinner in the field of psychology - which defines behavior as a result of stimulation and emotion. [³] This relationship is important for the determination of empathy, the ability to identify and emotionally socialize with another person, which substantially influences social interaction.
Empathy is further subdivided into two components: the affective, which allows the sharing of feelings and a cognitive, which relates to the notion of emotional individuality. 
In spite of the first subtype, the anterior insula and the inferior frontal gyrus are activated in the observation, judgment and imitation of facial expressions, even being able to absorb and follow the emotions of the observed. Thus, by identifying a semblance of sadness or suffering in the other, these two cortical regions work so that the individual feels compassion and even develops sadness, imitating the feelings of the observed.  This explains why the viewer cries after watching a dramatic scene from a movie, feels horror at seeing someone's frightened face or despair, and even creates expectations from a new experience after seeing someone else's reaction.
Psychopaths, for example, seem to have a deficit for empathy, living thus in social isolation, but not to understand the intentions and goals of others, a pattern of thought that is well reported in the Machiavellian nature of this disorder. To do so, when presenting photos with facial mimics such as anger, crying and happiness, psychopaths usually do not demonstrate empathy. 
Another disturbance that generates a certain social isolation is autism: the hypofunction of the right anterior insula and reduction of its integration with the amygdala and frontal cortex, cause disinhibition and mobilization of the individual's attention to his inner world, making him less than external stimuli, so the autistic person does not react to the presence or demonstrations of affection of third parties, not being able to relate to the world and with stimuli coming from him. 
In spite of the emotional individuality, the clinical correlation found in the research was the manifestation of narcissism, in which there is a hyperfunction of the right anterior insular cortex, causing the individual's emotions to surpass those of any other person, interfering in their interpersonal reactions and generating consequences such as exaggerated self-confidence and self-centeredness. 
The insula is more active in young people than in adults, thus determining a greater learning capacity in the first ones, which anticipate the detection of errors, correcting them more quickly. 
1.6 Clinical correlation with insula disorders: Alexithymia
Alexithymia is characterized as a psychosomatic disorder in which the individual has difficulty identifying and describing their feelings, as well as being unable to define and distinguish the bodily sensations aroused by the autonomic system from emotional moments, such as palpitation and sweating from a stressful situation. [26, 27]
It is possible that approximately 10% of the world population is alexithemic [26, 27, 28] There are also data that point out the relationship between this disease and the propensity for chronic alcoholism.  Its various aetiological possibilities are grouped into two branches: that of biological origin - primary alexithymia - and that of psychosocial cause - secondary alexithymia. The primary form arises from a neuroanatomic structural defect or neurobiological deficiency, involving the anterior cingular cortex (ACC) and left anterior insular. [27, 28] The secondary is a consequence of a trauma experienced in childhood or adult life of the individual, in which psychological stress can be from family negligence, abandonment, kidnapping, physical abuse or war, which generate changes in the psychic functioning of the patient who avoids the awareness and expression of their emotions, serving as a personal defense to avoid suffering. 
Alexithymia is subdivided into Type I and Type II. In the first variable, the affective and cognitive emotional components are compromised due to lesion of the right hemisphere, prefrontal structures or even their hypoactivity, being the main ones, the ACC and the insular cortex. In type II, on the other hand, there is affection only of the cognitive aspect of the emotions due to injury in the corpus callosum, thus preventing the integration of information between the hemispheres. 
Neuroimaging studies indicate a crucial role of the anterior insula and ACC in alexithymia: in both augmented or augmented characteristic regions they result in the characteristic emotional traits of the disorder, such as the ACC and its decreased volume, medial temporal gyrus and anterior insula, aspects more common in women than men. 
The observation of neurotransmitter levels in the two main structures is important, since psychiatric disorders are usually the result of the biochemical dysfunction of the nervous system; for the affective disorder in question, research points to the negative correlation of the increased concentration of glutamate in the insula and GABA in the ACC, which are determinants for the introverted behavior, highly neurotic, aversion to personal contacts, tendency to social isolation a lack of frankness and empathy , therefore they can not project themselves in the situation of others, because they are not altruistic. 
The association between alexithymia and empathy is part of the 'shared network' model of empathy: which suggests that the pathway responsible for the processing of one's own emotions is the one responsible for representing the emotions of others. Therefore, the difficulty of representing one's own emotions results in a deficit in the representation of the emotions of others, thus also influencing the social development of the subject. 
Another interesting fact is that 50% of autistic individuals also present alexithymia as a spectrum. In a study evaluating such relationship related to the decrease in empathy, it was observed that when the individual was suffering from pain and suffering, the anterior insula region presented decreased activation, thus proving that the difficulty of autistic relationships arises from alexithymia and not of their own attention deficit to visualize faces. 
The evaluation of the alexithemic patient relies on the use of the Toronto Alexithymia Scale (TAS),  an instrument of self-evaluation in the form of a questionnaire that covers cognitive and affective factors of the disorder, such as: a) Difficulty of identifying feelings; b) Difficulty of describing feelings; and c) If it is easy to feel touched by the feelings of others.[26, 29] In the test, the patient is asked to report their level of agreement with the situations presented in 26 questions in which he must choose between totally disagreeing, partially disagreeing, disagreeing or disagreeing, agreeing in part and totally agreeing with accounting from 1 to 5 points. [29, 30] In the results, the total scores ranged from 26 to 130, and in the original version for a score equal to or greater than 74 it is considered as alexithymic and equal or less than 62 is considered non-alexithymic. 
The insula lobe is located between the anterior cingular cortex, rostral and dorsolateral prefrontal cortex, parietal and temporal lobe regions, entorhinal cortex, amygdala, hypothalamus and dorsal thalamus, and this fact contributes to the design of its pathways and cognitive functions which are: its relation to the identification, perception, processing and regulation of emotions, as well as its participation in memory, sexual behavior, affective involvement and social interaction. In addition, knowledge of its histology provides a theoretical basis for understanding the pathophysiology of Alexithymia, a psychosomatic disorder that affects 10% of the population and is also related to empathy, which is not only one of the cognitive aspects of the insula, but also one of the criteria covered by the Toronto Alexithymia Scale (TAS) to diagnose this disorder.
In this scenario, it is imperative to carry out new research in order to promote a better understanding of the influence of the insula in coping with everyday situations.
1. Machado A,Haertel LM. Neuroanatomia funcional.3.ed.São Paulo: Atheneu; 2013.
2. Snell, Richard S. Neuroanatomia Clínica. 7. ed. Guanabara Koogan; 2011.
3. Gu X, Hof P R, Friston K J, Fan J. Anterior Insular Cortex and Emotional Awareness. The Journal of Comparative Neurology;
Research in Systems Neuroscience 521:3371–3388, 2013.
4. Ribas GC, Oliveira E. A insula e o conceito de bloco cerebral central. Arq. Neuropsiquiatria. 2007;65: 92-100.
5. Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans.
Brain Research Reviews. 1996;22: 229-244.
6. Shelley BP, Trimble MR. The insular lobe of Reil its anatamicofunctional, behavioural and neuropsychiatric attributes in humans a
review. World J Biol Psychiatry. 2004; 5: 176 –200.
7. Kalani MYS, Kalani MA, Gwinn R, Keogh B, Tse VC, et al. Embryological development of the human insula and its implications for the
spread and resection of insular gliomas. Neurosurg Focus.2009; 27 (2):E2.
8. Molnár Z, Kaas JH, de Carlos JÁ, Hevner RF, Lein E, et al. Evolution and development of the mammalian cerebral córtex.
Brain Behav Evol.2014;83(2):126-39.
9. Türe U, Yasargil DCH, Al-Mefty O, Yasargil MG. Topographic anatomy of the insular region. J Neurosurg 1999;90(4):720-33.
10. Türe U, Yasargil MG, Al-Mefty O, Yasargil DCH. Arteries of the insula. J Neurossurg 2000; 92:676-87.
11. Yasargil MG, Teddy PJ, Roth P. Selective amigdalo-hippocampectomy: operative anatomy and surgical technique. Adv Tech Sand
Neurosurg 1985; 12:93-123.
12. Ribas, GC, Oliveira E de. A ínsula e o conceito de bloco cerebral central. Arq Neuro-Psiquiatr.2007;65(1):92-100.
13. Isolan GR, Campero A, Dini LI, Frigeri T, Arai JY. O lobo da ínsula anatomia tridimensional anaglífica e correlação clínico-cirúrgica.
14. Allman JM, Tetreault NA, Hakeem AY, Manaye KF, Semendeferi K, Erwin JM,et al. The von economo neurons in frontoinsular and anterior
cingulated cortex in great apes and humans. Brain Struct Funct.2010;214(5-6):495-517.
15. Wang F, Sun T, Li X, Xia H, Li Z, et al. Microsurgical and tractographic anatomical study of insular and transsylvian transinsular approach.
Neurol Sci.2011;32: 865-74.
16. Wang F,Sun T,Li XG,Liu NJ. Diffusion tensor tractography of the temporal stem on the inferior limiting sulcus.
J Neurosurg.2008; 108: 775-81.
17. Kurth F, Zilles K, Fox PT, Laird AR,Eickhoff SB, et al. A link between the systems: Functional differentiation and integration within the
human insula revealed by meta-analysis. Brain Struct Funct.2010; 214(5-6):519-34.
18. Craig AD. Significance of the insula for the evolution of human awareness of feelings from the body. Ann N Y Acad Sci. 2011;1225:72-82.
19. Nieuwenhuys R.The insular cortex: a review. Prog Brain Res.2012;195:123-63.
20. Augustine, JR. The insular lobe in primates including humans. Neurol. Res.1985 Mar; 7(1): 2–10.
21. Wylie KP, Tregellas JR.The role of the insula in schizophrenia. Schizophr Res. 2010;123(2-3):93-104.
22. Wicker B, Keysers C, Plailly J, Royet J, Gallese V. Rizzolatti G, et al. Both of Us Disgusted in My Insula: The Common Neural Basis of Seeing
and Feeling Disgust. Neuron.2003; 40: 655–64.
23. Pavuluri M, May A. I Feel, Therefore, I am: The Insula and Its Role in Human Emotion. AIMS Neuroscience.2015;2(1): 18-27.
24. Stein MB, Simmons AN, Feinstein JS, Paulus MP, et al. Increased Amygdala and Insula Activation During Emotion Processing in
Anxiety-Prone Subjects. Am J Psychiatry.2007;164:2.
25. Janes AC, Farmer S, Peechatka AL, Frederick BB, Lukas SE, et al. Insula–Dorsal Anterior Cingulate Cortex Coupling is Associated with
Enhanced Brain Reactivity to Smoking Cues. Rev. Neuropsychopharmacology. 2015; 40(7): 1561–1568.
26. Bird G, Silani G, Brindley R, White S, Frith U, Singer T. Empathic brain, et al, responses in insula are modulated by levels of alexithymia but
not autism. Brain: A Journal of Neurology 2010;133:1515–25.
27. Ernst J, Boker H, Hattenschwiller J, Schupbach D, Northoff G, Seifritz E, Grimm S, et al. The association of interoceptive awareness and
alexithymia with neurotransmitter concentrations in insula and anterior cingulate. Scan. 2014; 857-63.
28. Carneiro BV,Yoshida EM. Alexitimia: Uma Revisão do Conceito. Psicologia: Teoria e Pesquisa. 2009;25(1): 103-108.
29. Maciel MJN,Youshida EMP. Avaliação de alexitimia, neuroticismo e depressão em dependentes de álcool. Avaliação Psicológica,
30. Praceres N, Parker DA, Taylor G. Adaptaçao Portuguesa da Escala de Alexitimia de Toronto de 20 Itens (tas-20). RIDEP.2000;9(1): 9-21.
31. Netter PH. Atlas de anatomia humana. 3.ed. Porto Alegre: Artmed; 2000.