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International Journal of Clinical and Experimental Neurology

ISSN (Print): 2379-7789

ISSN (Online): 2379-7797

Editor-in-Chief: Zhiyou Cai, MD




Behavioral and Neurochemical Characteristics of Two Months Old WAG/Rij Rats with Genetic Absence Epilepsy

1Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia

2State Zakusov Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, Russia

International Journal of Clinical and Experimental Neurology. 2015, 3(2), 32-44
doi: 10.12691/ijcen-3-2-2
Copyright © 2015 Science and Education Publishing

Cite this paper:
E. A. Fedosova, K. Yu. Sarkisova, V. S. Kudrin, V. B. Narkevich, A. S. Bazyan. Behavioral and Neurochemical Characteristics of Two Months Old WAG/Rij Rats with Genetic Absence Epilepsy. International Journal of Clinical and Experimental Neurology. 2015; 3(2):32-44. doi: 10.12691/ijcen-3-2-2.

Correspondence to: A.  S. Bazyan, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia. Email:


WAG/Rij rats are genetic animal model of absence epilepsy with comorbidity of depression. The first spike-wave discharges (SWDs) in WAG/Rij rats begin to appear at the age of 2-3 months and are fully manifested by 5-6 months. Occurrence of SWDs in the EEG is the main index of absence epilepsy. Previously it has been shown that the extensive absence epilepsy in 5-6 months old WAG/Rij rats is accompanied by decrease of dopamine and its metabolites concentrations in the meso-cortico-limbic and nigro-striatal dopaminergic brain systems, resulting in the expression of depression-like behavioral symptoms, and impairments of the learning and memory processes. In 36 days old WAG/Rij rats, SWDs are not manifested, deficiency of the mesolimbic dopamine is not revealed, and symptoms of depression-like behavior are not expressed. In this study, behavior in the open field, light-dark choice, forced swimming tests, monoamines and their metabolites concentrations in 5 brain structures (prefrontal cortex, nucleus accumbens, hypothalamus, striatum, hippocampus) were investigated in two months old WAG/Rij rats in comparison with age-matched Wistar rats. Reduced concentration of the dopamine and its metabolites, and increased concentration of the serotonin was found in WAG/Rij rats compared with Wistar rats only in the prefrontal cortex, indicating that the prefrontal cortex is the brain structure where neurochemical abnormalities appear first. No substantial changes in the monoamine and their metabolites concentrations have been revealed in other brain structures. Two months old WAG/Rij rats didn’t exhibit depression-like behavior in the forced swimming test, and learning/memory deficits in the passive avoidance test, but they showed behavioral changes, indicating increase anxiety/stress-reactivity, and alterations in learning/memory in the active avoidance test. Results suggest that two month-old WAG/Rij rats are at the stage of so called “pre-pathology” (increased anxiety and stress reactivity) preceding the development of depression-like behavior and substantial cognitive impairments which are co-morbid to fully expressed absence epilepsy in 5-6 months old rats of this strain.



[1]  Barson JR, Morganstern I, Leibowitz SF (2011). Similarities in hypothalamic and mesocorticolimbic circuits regulating the overconsumption of food and alcohol. Physiol Behav; 104 (1): 128-137.
[2]  Bazyan AS (1999). Neuromodulators and integrative mechanisms of emotional and motivation states. Neurochemical Journal; 16 (2): 88-103.
[3]  Bazyan AS, Orlova NV, Getsova VM (2000). Modulation of the activity of monoaminergic brain systems and emotional condition by dalargin in rats during development of emotional resonance response. Zh Vyssh Nerv Deiat Im I P Pavlova; 50(3): 500-508.
[4]  Bazyan AS (2001). Divergent and convergent mechanisms of the integrative activity of the mammalian brain. Zh Vyssh Nerv Deiat Im I P Pavlova; 51(4): 514-528.
[5]  Bazyan AS, Segal OL (2009). Synaptic and paracrine nonsynaptic systems of the mammalian brain. Neurochemical Journal; 3(2): 77-86.
Show More References
[6]  Bazyan AS, Grigir'ian GA, Ioffe ME, 2011. Regulation of motor behaviour. Usp Fiziol Nauk; 42(3): 65-80.
[7]  Bazyan AS, and van Luijtelaar G (2013). Review article. Neurochemical and behavioral features in genetic absence epilepsy and in acutely induced absence seizures. ISRN Neurology. Art. ID 875834.
[8]  Bechara A, Damasio AR (2005). The somatic marker hypothesis: a neural theory of economic decision. Games and Econom. Behav; 52 (2): 336-372.
[9]  Braw Y, Malkesman O, Dagan M, Bercovich A, Lavi-Avnon Y, Schroeder M, Overstreet DH, Weller A (2006). Anxiety-like behaviors in pre-pubertal rats of the Flinders Sensitive Line (FSL) and Wistar-Kyoto (WKY) animal models of depression. Behav. Brain Res; 167 (2): 261-269.
[10]  Calatayud F, Belzung C, Aubert A (2004). Ethological validation and the assessment of anxiety-like behaviors: methodological comparison of classical analysis and structural approaches. Behav Processes; 67(2): 195-206.
[11]  Carlezon WAJr, Thomas MJ (2009). Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis. Neuropharmacol; 56 (1): 122-132.
[12]  Costall B, Jones BJ, Kelly ME, Neylor RJ, Tomkins DM, (1989). Exploration of mice in a black and white test box: validation as a model of anxiety. Pharmacol Biochem Behav; 32(3): 777-785.
[13]  Cryan JF, Lucki I (2000). Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine (2C) receptors. Pharmacol. Exp. Ther; 295(3): 1120-1126.
[14]  Deneve S, (2012). Making decisions with unknown sensory reliability. Front Neurosci. 6:75.
[15]  Espejo EF (1997). Selective dopamine depletion within the medial prefrontal cortex induces anxiogenic-like effects in rats placed on the elevated plus maze. Brain Res; 762(1-2): 281-284.
[16]  Garcia-Cairasco N, Oliveira JAC, Wakamatsu H, Bueno ST, Guimaraes FS (1998). Reduced exploratory activity of audiogenic seizure susceptible Wistar rats. Physiol Behav; 64(5): 671-674.
[17]  Gonzalez C, Kramar C, Garagoli F, Rossato JI, Weisstaub N, Cammarota M, Medina JH (2013). Medial prefrontal cortex is a crucial node of a rapid learning system that retrieves recent and remote memories. Neurobiol. Learn. Mem; 103: 19-25.
[18]  Griebel G., Rodgers R., Perrault C.H, Sanger D.J., 1997. Risk assessment behavior: evaluation of utility in the study of 5-HT-related drugs in the rat elevated plus-maze test. Pharmacol Biochem Behav. 57(4): 817-827.
[19]  Gruber A.J., McDonald R.J. 2012. Context, emotion, and the strategic pursuit of goals: interactions among multiple brain systems controlling motivated behavior. Front Behav Neurosci; 6: 50.
[20]  Hascoët M., Bourin M., Nic Dhonnchadha B.Á., 2001. The mouse ligth-dark paradigm: A review. Prog. Neuropsychopharmacol. Bio. Psychiatry; 25(1): 141-166.
[21]  Ho S.S., Gonzalez R.D., Abelson J.L., Liberzon I., 2012. Neurocircuits underlying cognition-emotion interaction in a social decision making context. Neuroimage; 63(2): 843-537.
[22]  Jüngling K, Seidenbecher T, Sosulina L, Lesting J, Sangha S, Clark SD, Okamura N, Duangdao DM, Xu Y-L, Reinscheid RK, Pape H-C (2008). Neuropeptide S-mediated control of fear expression and extinction: Role of intercalated GABAergic neurons in the amygdala. Neuron; 59(2): 298–310.
[23]  King D, Zigmond MJ, Finlay JM (1997). Effects of dopamine depletion in the medial prefrontal cortex on the stress-induced increases in extracellular dopamine in the nucleus accumbens and shell. Neurology; 77(1): 141-153.
[24]  Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, Henn F, Malinow R (2011). Synaptic potentiation onto habenula neurons in learned helplessness model of depression. Nature; 470(7335): 535-539.
[25]  Lucki I (1997). The forced swimming test as a model for core and component behavioral effects of antidepressant drugs. Behav. Pharmacol; 8(6-7): 523-532.
[26]  Matveeva MI, Shtemberg AS, Timoshenko GN, Krasavin EA, Narkevich VB, Klodt PM, Kudrin VS, Bazyan AS (2013). The effects of irradiation by 12C carbon ions on monoamine exchange in several rat brain structures. Neurochemical Journal; 7(4): 303–307.
[27]  Mink JW (2003). The basal ganglia. Fundamental neuroscience. 2nd/Ed. Scuire LR, Bloom FT, McConnell SC, Roberts JL, Spitzer NC, Zigmond MJ. Elsevier Sci.: Acad. Press; 815-839.
[28]  Morrow A.L., Porcu P., Boyd K.N., Grant K.A., 2006. Hypothalamic-pituitary-adrenal axis modulation of GABAergic neuroactive steroids influences ethanol sensitivity and drinking behavior. Dialogues Clin. Neurosci; 8(4): 463-477.
[29]  Naitoh H, Nomura S, Kunimi Y, Yamaoka K (1992). "Swimming-induced head twitching" in rats in the forced swimming test induced by overcrowding stress: a new marker in the animal model of depression? Keio J Med; 41(4): 221-224.
[30]  Nozek K, Dennis K, Andrus BM, Ahmadiyeh N, Baum AE, Woods LC, Redei EE (2008). Context and stress-dependent behavioral response to stress. Behav. Brain Functions; 4:23.
[31]  Porsolt RD, Lenegre A (1992). Behavioral models of depression. In Elliot J.M., Heal D.J., Marsden C.A. (Eds) Experimental approaches to anxiety and depression. Willey, New York; 73-85.
[32]  Prut L, Belzung C (2003). The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol; 463(1-3): 3-33.
[33]  Przybycien-Szymanska MM, Gillespie RA, Pak TR (2012). 17β-Estradiol is required for the sexually dimorphic effects of repeated binge-pattern alcohol exposure on the HPA axis during adolescence. PLoS One; 7 (2):e32263.
[34]  Sarkisova KYu, Kolomeitseva IA, Kulikov MA (1996). Effects of substance P on behavioral measures in the open field and forced swimming tests in rats with different type of behavior. Bull Exp Biol Med; 121: 244-247.
[35]  Sarkisova KYu, Kulikov MA, (1994). Individual differences in reaction to acute stress associated with type of behavior. Prediction of the resistance to stress. Bull Exp Biol Med; 117: 89-92.
[36]  Sarkisova KYu, Kulikov MA (2001). Prophylactic action of the antioxidant agent AEKOL on behavioral (psycho-emotional) disturbances induced by chronic stress in rats. Neurosci Behav Physiol; 31(5): 503-508.
[37]  Sarkisova KYu, Midzyanovskaya IS, Kulikov MA (2003). Depressive-like behavioral alterations and c-fos expression in the dopaminergic brain regions in WAG/Rij rats with genetic absence epilepsy. Behav Brain Res; 144(1-2): 211-226.
[38]  Sarkisova KYu, Kulikov MA (2006). Behavioral characteristics of WAG/Rij rats susceptible and non-susceptible to audiogenisc seizures. Behav Brain Res; 166(1): 9-18.
[39]  Sarkisova KYu, Kulikov MA, Midzyanovskaya IS, Folomkina AA (2008). Dopamine-dependent nature of depression-like behavior in WAG/Rij rats with genetic absence epilepsy. Neurosci Behav Physiol; 38(2): 119-128.
[40]  Sarkisova KYu, Kulikov MA, Folomkina AA (2011). Does antiabsence drug ethosuximide exert antidepressant effect? Zh Vyssh Nerv Deiat Im I P Pavlova: 61(2):227-235.
[41]  Sarkisova K, van Luijtelaar G (2011). Review article. The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry; 5(4): 854-876.
[42]  Sarkisova KYu, Kulikov MA, Kudrin VS, Narkevich VB, Midzyanovskaya I.S., Birioukova LM, Folomkina AA, Bazyan A.S (2013a). Neurochemical mechanisms of depression-like behavior in WAG/Rij rats. Zh. Vyssh. Nerv. Deiat. Im I P Pavlova; 63(3): 303-315.
[43]  Sarkisova KYu, Kulikov MA, Midzyanovskaya IS, Birioukova LM, Kudrin VS (2013b). Neurochemical mechanisms of depression in absence epilepsy. Abstracts IX International interdisciplinary congress "Neuroscience for medicine and psychology", Sudak, Crimea, Ukraine, June 3-13, P. 279-280.
[44]  Shumake J, Ilango A, Scheich H, Wetzel W, Ohl FW (2010). Differential neuromodulation of acquisition and retrieval of avoidance learning by the lateral habenula and ventral tegmental area. J Neurosci; 30(17): 5876-5883.
[45]  Tanji J, Hoshi E (2008). Role of the lateral prefrontal cortex in executive behavioral control. Physiol Rev; 88(1): 37-57.
[46]  Takao K., Miyakawa T., 2006. Light/dark transition test for mice. J Vis Exp. Nov; 13(1): 104.
[47]  Zaitsev AV, Lewis DA (2013). Functional properties and short-term dynamics of unidirectional and reciprocal synaptic connections between layer 2/3 pyramidal cells and fast-spiking interneurons in juvenile rat prefrontal cortex. Eur J Neurosci; 38(7): 2988-2998.
[48]  Zhou WL, Antic SD (2012). Rapid dopaminergic and GABAergic modulation of calcium and voltage transients in dendrites of prefrontal cortex pyramidal neurons. J Physiol; 590(16): 3891-3911.
Show Less References


Neuropsychiatric Symptoms of Urbach-Wiethe Disease

1School of Psychology, Kean University, Union, NJ, USA

2Department of Nursing, Kean University, Union, NJ, USA

International Journal of Clinical and Experimental Neurology. 2015, 3(2), 45-50
doi: 10.12691/ijcen-3-2-3
Copyright © 2015 Science and Education Publishing

Cite this paper:
Richard P. Conti, Jacqueline M. Arnone. Neuropsychiatric Symptoms of Urbach-Wiethe Disease. International Journal of Clinical and Experimental Neurology. 2015; 3(2):45-50. doi: 10.12691/ijcen-3-2-3.

Correspondence to: Richard  P. Conti, School of Psychology, Kean University, Union, NJ, USA. Email:


Urbach–Wiethe (or lipoid proteinosis) disease (UWD) is a rare autosomal recessive disorder characterized by dermatological, psychiatric, and neurological symptoms. Presentation occurs during childhood, but can be observed from birth. While benign, the disease is progressive and chronic with no known cure. Treatment modalities are palliative for symptoms. The extant literature consists mainly of anecdotal reports and case studies that are limited by small sample sizes and paucity of controlled studies. Incidence and prevalence rates are unknown. There are less than 500 documented cases reported worldwide, and of those, less than 50 cases demonstrate neurological and neuropsychiatric conditions. Worldwide occurrence of the disease is documented, with the largest cohort living in a remote area of South Africa. The affected individuals are mainly Caucasian, born to consanguineous parents, and from Dutch or German heritage. Patients affected have been reported in China, Pakistan and Iran. Current and earlier studies focus primarily on the most visible signs of disease, dystonia and dermatological symptoms, while other studies have reported calcification in the amygdala, hippocampus, parahippocampal gyrus, and the striatum. While central nervous system involvement can lead to a wide range of clinical manifestations such as epilepsy and neuropsychiatric symptoms, there is not a consensus of reported cases with amygdala calcifications accompanied by neurological symptoms. Quantitative research is warranted to further identify the role and relationship between amygdala calcification and neurologic and neuropsychiatric symptoms, while qualitative research will afford insights into the lived experience of individuals and families living with UWD.



[1]  Siebert M., Markowitsch H.J., and Bartel P. “Amygdala, affect and cognition: evidence from 10 patients with Urbach-Wiethe disease,” Brain, 2003; 126: 2627-2637.
[2]  Thornton H.B., Nel D., Thornton D., van Honk J., Baker G.A., and Stein D.J. “The neuropsychiatry and neuropsychology of lipoid proteinosis,” J Neuropsychiatry Clin Neurosci, 2008; 20: 86-92.
[3]  Goncalves F.G., de Melo M.B., de L. Matos V., Barra F.R., and Figueroa R.E. “Amygdalae and striatum calcification in lipoid proteinosis,” Am J Neuroradiol, 2010; 31: 88-90.
[4]  Appenzeller S., Chaloult E., Velho P., et al. “Amygdalae calcifications associated with disease duration in lipoid proteinosis.” J Neuroimag, 2006; 16: 154-156.
[5]  Aziz M.T., Mandour M.A., El-Ghazzawi I.F., Belal A.-E.-A., and Talaat A.M. “Urbach-Wiethe disease in ORL practice (A clinical and histochemical study of the laryngeal lesions),” J Laryngol Otol, 1980; 94: 1309-1319.
Show More References
[6]  Yakout Y.M., Elwany S., Abdel-Kreem A., and Seif S.A. “Radiological finding in lipoid proteinosis,” J Laryngol Otol, 1985; 99: 259-265.
[7]  Urbach E., and Wiethe C. “Lipoidosis cutis et mucosa,” Virchows Archiv Pathol, 1929; 27: 286-319.
[8]  Hamada T., McLean W.H.I., Ramsay M., Ashton G.H.S., Nanda A., Jenkins T., Edelstein I., South A.P., Bleck O., Wessagowit V., Mallipeddi R., and Orchard G.E. “G. Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1),” Hum Molec. Genet, 2002; 11: 833-840.
[9]  Hamada T., Wessagowit V., South A.P., Ashton G.H.S., Chan I., Oyama N., Siriwattana A., and McGrath J.A. “Extracellular matrix protein 1 gene (ECM1) mutations in lipoid proteinosis and genotype-phenotype correllation,” J Invest Dermatol, 2003; 120: 345-350.
[10]  Kachewar, S.G., and Kulkarni, D.S. “A novel association of the additional intracranial calcification in lipid proteinosis: A case report.” J Clin and Diag Res, 2012; 9: 1579-1581.
[11]  Morgan B., Terburg D., Thornton H.B., Stein D.J., and van Honk J. “Paradoxical facilitation of working memory after basolateral amygdala damage,” Plos One, 2012; 7(6): e38116.
[12]  Emsley R.A., and Paster L. “Lipoid proteinosis presenting with neuropsychiatric manifestations,” J Neurol Neurosurg Psychiatry, 1985; 48:1290-1292.
[13]  Holme S.A., Lenane P., and Krafchik B.R. “What syndrome is this? Urbach-Weithe syndrome (Lipoid proteinosis),” Pediatr Dermatol, 2005; 22(3): 266-267.
[14]  Kachewar S., Singh B.H., Sasane A.G., and Bhadane S. “Full blown case of lipoid proteinosis,” Med J Armed Forces of India, 2011; 67: 90-91.
[15]  Nanda A., Alsaleh Q.A., Al-Sabah H., Ali A.M., and Anim J.T. “Lipoid Proteinosis: Report of four siblings and brief review of the literature,” Pediatr Dermatol, 2001; 18(1): 21-26.
[16]  Sainani M.P., Muralidhar R., Parthiban K., and Vijayalakshmi P. “Lipoid proteinosis of Urbach and Wiethe: A case report,” Int Opthalmol, 2011; 31: 141-143.
[17]  Hofer P.A. “Urbach-Wiethe disease (lipoglycoproteinosis; lipoid proteinosis; hyalinoses cutis et mucosae). A review,” Acta Dermato Venereologica Supplementum, 1973; 53: 1-52.
[18]  Toosi S., and Ehsani A.H. “Treatment of lipoid proteinosis with acitretin: A case report,” J Eur Acad Dermatol, 2009; 23: 482-483.
[19]  Wong C.K., and Lin C.S. “Remarkable response of lipid proteinosis to oral dimethylsulphoxide,” Brit J Dermatol, 1988; 119: 541-544.
[20]  Zhang R., Liu Y., Xue Y., Wang Y., Wang X., Shi S., Cai T., and Wang Q. “Treatment of lipoid proteinosis due to the p.C220G mutation in ECM1, a major allele in Chinese patients,” J Transl Med, 2014; 12(85).
[21]  Hamann S.B., Ely T.D., Hoffman J.M., and Kilts C.D. “Ecstasy and Agony: Activation of the human amygdala in positive and negative emotion,” Psychol Sci, 2002; 13(2): 135-141.
[22]  Markowitsch, H.J., and Staniloiu A. “Amygdala in action: Relaying biological and social significance to autobiographical memory,” Neuropsychologia, 2011; 49 (4): 718-733.
[23]  Terburg D., Morgan B. E., Montoya E. R., Hooge I.T., Thornton H.B., Hariri A.R., ... and van Honk J. “Hypervigilance for fear after basolateral amygdala damage in humans,” Transl Psychiatry, 2012; 2e115.
[24]  Bach, D. R., Talmi, D., Hurlemann, R., Patin, A., and Dolan, R. J. “Automatic relevance detection in the absence of a functional amygdala,” Neuropsychologia, 2011; 49(5): 1302-1305.
[25]  Yang, T. T., Menon, V., Eliez, S., Blasey, C., White, C. D., Reid, A. J.... and Reiss, A. L. “Amygdalar activation associated with positive and negative facial expressions,” Neuroreport, 2002; 13(14): 1737-1741.
[26]  Tranel, D., Gullickson, G., Koch, M., and Adolphs, R. “Altered experience of emotion following bilateral amygdala damage,” Cogn Neuropsychiatry, 2006; 11(3): 219-232.
[27]  Chan I., Liu L., Hamada T., Sethuraman G., and McGrath J.A. “The molecular basis of lipoid proteinosis: mutations in extracellular matrix protein,” Exp Dermatol, 2007; 16: 881-890.
[28]  Boudouresque J., Cosset A., and Sayag J. “Maladie d’Urbach-Whiethe: Crises temporales avec phenomenes extatiques et calcification des deux lobes temporaux,” Bull Acad Med Paris, 1972; 156: 416-442.
[29]  Claeys K.G., Claes L.R.F., Van Goethem J.W.M., et al. “Epilepsy and migraine in a patient with Urbach–Wiethe disease,” Seizure, 2007; 16: 465-468.
[30]  Omrani H.G., Tajdini M., Ghelichnia B., et al. “Should we think of Urbach–Wiethe disease in refractory epilepsy? Case report and review of the literature,” J Neurol Sci, 2012; 320: 149-152.
[31]  Matthies S., Rüsch N., Weber M., et al. “Small amygdala–high aggression? The role of the amygdala in modulating aggression in healthy subjects,” World J Biol Psychiatry, 2012; 13(1): 75-78.
[32]  Newton F.H., Rosenberg R.N., Lampert P.W., and O'Brien J.S. “Neurologic involvement in Urbach‐Wiethe's disease (lipoid proteinosis) A clinical, ultrastructural, and chemical study,” Neurol, 1971; (12), 1205-1213.
[33]  Lupo I., Cefalu A.B., Bongiorno M.R., et al. “A novel mutation of the extracellular matrix protein 1 gene (ECM1) in a patient with lipoid proteinosis (Urbach-Wiethe disease) from Sicily,” Brit J Dermatol, 2005; 153(5): 1019-1022.
[34]  Kleinert R., Cervos-Navarro J., Kleinert G., et al. “Predominantly cerebral manifestation in Urbach-Wiethe's syndrome (lipoid proteinosis cutis et mucosae): A clinical and pathomorphological study,” Clin Neuropathol, 1986; 6(1): 43-45.
[35]  Adolphs R., Tranel D., Damasio H., and Damasio A. “Impaired recognition of emotion in facial expression following bilateral damage to the human amygdala,” Nature, 1994; 372: 669-672.
[36]  Adolphs R., Tranel D., Damasio H., and Damasio A.R. “Fear and the human amygdala,” J Neurosci, 1995; 15: 5879-5891.
[37]  Paul L.K., Corsello C., Tranel D., and Adolphs R. “Does bilateral damage to the human amygdala produce autistic symptoms?,” J Neurodev Disord, 2010; 2(3): 165-173.
[38]  Adolphs, R., and Tranel, D. “Impaired judgments of sadness but not happiness following bilateral amygdala damage,” J Cogn Neurosci, 2004; 16(3): 453-462.
[39]  Adolphs R., Gosselin F., Buchanan T.W., Tranel D., Schyns P.G, and Damasio A. “A mechanism for impaired fear recognition after amygdala damage,” Nature, 2005; 433: 68-72.
[40]  Adolphs R., Spezio M.L., Parlier M., and Piven J. “Distinct face-processing strategies in parents of autistic children,” Curr Biol, 2008; 18: 1090-1093.
[41]  Böhme M., and Wahlgren C.F. “Lipoid proteinosis in three children,” Acta Paediatrica, 1996; 85(8): 1003-1005.
[42]  Bahadir S., Cobanoglu U., Kapicioglu Z., et al. “Lipoid proteinosis: A case with ophthalmological and psychiatric findings,” J Dermatol, 2006; 33(3): 215-218.
[43]  Salih M.A., Abu-Amero K.K., Alrasheed S., et al. “Molecular and neurological characterizations of three Saudi families with lipoid proteinosis,” BMC Med Genet, 2011; 12(3).
[44]  Markowitsch H.J., Calabrese P., Würker M., Durwen H.F., et al. “The amygdala's contribution to memory-a study on two patients with Urbach-Wiethe disease,” Neuroreport, 1994; 5(11): 1349-1352.
[45]  Cahill L., Haier R.J., Fallon J., Alkire M.T., Tang C., Keator D., et al. “Amygdala activity at encoding correlated with long‐term, free recall of emotional information,” Proc Natl Acad Sci USA, 1996; 93(15): 8016-8021.
[46]  Adolphs R, Cahill L., Schul R., and Babinsky R. “Impaired declarative memory for emotional material following bilateral amygdala damage in humans,” Learn Memory, 1997; 4(3): 291-300.
[47]  Hurlemann R., Wagner M., Hawellek B., et al. “Amygdala control of emotion-induced forgetting and remembering: Evidence from Urbach-Wiethe disease,” Neuropsychologia. 2007; 45(5): 877-884.
[48]  Claeys K.G., Claes L.R.F., Van Goethem J.W.M., et al. “Epilepsy and migraine in a patient with Urbach–Wiethe disease,” Seizure, 2007; 16(5): 465-468.
[49]  Wiest G., Lehner-Baumgartner E., and Baumgartner C. “Panic attacks in an individual with bilateral selective lesions of the amygdala,” Arch Neurol, 2006; 63(12): 1798-1801.
[50]  Brand M., Grabenhorst F., Starcke K., Vandekerckhove M.M., and Markowitsch H.J. “Role of the amygdala in decisions under ambiguity and decisions under risk: evidence from patients with Urbach-Wiethe disease,” Neuropsychologia, 2007; 45(6): 1305-1317.
[51]  Becker, B., Mihov, Y., Scheele, D., Kendrick, K. M., Feinstein, J. S., Matusch, A.,... and Hurlemann, R. “Fear processing and social networking in the absence of a functional amygdala,” Biol Psychiatry, 2012; 72(1): 70-77.
Show Less References


Age-related Volumetric Changes of Prefrontal Gray and White Matter from Healthy Infancy to Adulthood

1Department of Psychology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan

2Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan

3Department of Radiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan

4Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

5Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA

International Journal of Clinical and Experimental Neurology. 2016, 4(1), 1-8
doi: 10.12691/ijcen-4-1-1
Copyright © 2016 Science and Education Publishing

Cite this paper:
Mie Matsui, Chiaki Tanaka, Lisha Niu, Kyo Noguchi, Warren B. Bilker, Michael Wierzbicki, Ruben C. Gur. Age-related Volumetric Changes of Prefrontal Gray and White Matter from Healthy Infancy to Adulthood. International Journal of Clinical and Experimental Neurology. 2016; 4(1):1-8. doi: 10.12691/ijcen-4-1-1.

Correspondence to: Mie  Matsui, Department of Psychology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan. Email:


Despite increasing evidence of the role of the prefrontal cortex in providing the neural substrate of higher cognitive function and neurodevelopment, little is known about neuroanatomic changes in prefrontal subregions during human development. In this prospective study, we evaluated prefrontal gray and white matter volume in healthy infants, children, adolescents, and adults. Magnetic resonance imaging was performed on 107 healthy people aged one month to 25 years. Gray and white matter volumes of the dorsolateral, dorsomedial, orbitolateral, and orbitomedial prefrontal cortex were quantified. The results indicated that both children and early adolescents had larger dorsolateral gray matter volume than infants and adults. Dorsolateral white matter volumes in children, early adolescents, and late adolescents were larger than those of infants. Dorsomedial white matter volumes of early adolescents, late adolescents, and adults were also larger than those of infants. There was no significant difference among age groups in both orbital prefrontal regions. These findings suggest that there are two important stages of structural change of the prefrontal cortex from infancy to young adulthood. First, growth spurts of both gray matter and white matter during the first 2 years of life have been shown to occur specifically in the dorsal prefrontal cortex. Second, gray matter changes have been shown to be regionally specific, with changes in the dorsal, but not orbital, prefrontal cortex peaking during late childhood or early adolescence. Thus, developmental differences within sectors of the prefrontal lobe and evidence of neural pruning and myelination may be useful in understanding the mechanisms of neurodevelopmental disorders.



[1]  Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, Paus T, Evans AC, Rapoport JL (1999) Brain development during childhood and adolescence: a longitudinal MRI study. Nature Neurosci 2:861-863.
[2]  Dekaban A, Sadowsky D (1978) Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 4:345-356.
[3]  Toga AW, Thompson PM, Sowell ER. (2006) Mapping brain maturation. Trends Neurosci 29:148-159.
[4]  Paus T, Keshavan M, Giedd JN. (2008) Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci 9:947-957.
[5]  Matsuzawa J, Matsui M, Konishi T, Noguchi K, Gur RC, Bilker W, Miyawaki T. (2001) Age-related volumetric changes of brain gray and white matter in healthy infants and children. Cereb Cortex 11:335-342.
Show More References
[6]  Yakovlev PL, Lecours AR (1967) The myelogenetic cycles of regional maturation of the brain. In: Resional development of the brain in early life (Minkowski A, eds), pp 3-70. Oxford: Blackwell.
[7]  Huttenlocher PR (1990) Morphometric study of human cerebral cortex development. Neuropsychologia 28:517-527.
[8]  Huttenlocher PR, Dabholkar AS (1997) Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 387: 167-178.
[9]  Peters A, Sethares C, Luebke JI. (2008) Synapses are lost during aging in the primate prefrontal cortex. Neuroscience 152:970-981.
[10]  Elston GN, Oga T, Fujita I (2009) Spinogenesis and pruning scales across functional hierarchies. J Neurosci 29:3271-3275.
[11]  Stuss DT, Benson DF (1986) The frontal lobes. New York: Raven Press.
[12]  Fuster JM (1997) The prefrontal cortex. Third edition. Philadelphia: Lippincott-Raven Publishers.
[13]  Fuster JM (2002) Frontal lobe and cognitive development. J Neurocytol 31:373-385.
[14]  Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, Nugent TF 3rd, Herman DH, Clasen LS, Toga AW, Rapoport JL, Thompson PM. (2004) Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci 101:8174-8179.
[15]  Tanaka C, Matsui M, Uematsu A, Noguchi K, Miyawaki T. (2012) Developmental trajectories of the fronto-temporal lobes from infancy to early adulthood in healthy individuals. Dev Neurosci 34: 477-487.
[16]  Kohn MI, Tanna NK, Herman GT, Resnick SM, Mozley PD, Gur RE, Alavi A, Zimmerman RA, Gur RC. (1991) Analysis of brain and cerebrospinal fluid volumes with MR imaging. Radiology 178:115-22.
[17]  Yan MXH, Karp JS (1994a) Image registration of MR and PET based on surface matching and principal axes fitting. Proc IEEE Med Imaging Conf 4:1677-1681.
[18]  Borgefors G (1986) Distance transformations in digital images. Comput Vis Graph Image Process 34:344-371.
[19]  Yan MXH, Karp JS (1994b) Segmentation of 3D brain MR using an adaptive K-means clustering algorithm. Proc IEEE Med Imaging Conf 4: 1529-1533.
[20]  Yan MXH, Karp JS (1995) An adaptive bayesian approach to three-dimensional MR brain segmentation. In: Information processing in medical imaging (Bizais Y, Barillot C, Di Paola R, eds), pp 201-213. Dordrecht: Kluwer Academic Publishers.
[21]  Gur RC, Turetsky BI, Matsui M, Yan M, Bilker W, Hughett P, Gur RE (1999) Sex differences in brain gray and white matter in adults: correlation with cognitive performance. J Neurosci 19: 4065-4072.
[22]  Gur RE, Cowell PE, Latshaw A, Turetsky BI, Grossman RI, Arnold SE, et al (2000). Reduced dorsal and orbital prefrontal gray matter volumes in schizophrenia. Arch Gen Psychiatry 57: 761-768.
[23]  Hastie, T.J., Tibshirani, R.J. (1990) Generalized Additive Models. London: Chapman and Hall, Print.
[24]  Wood, SN. (2006). Generalized Additive Models: An Introduction with R. Boca Raton, FL: Chapman and Hall/CRC, Print.
[25]  Maxwell WE, Delaney HD (1990) Designing experiments and analyzing data: a model comparisons approach. Belmont, CA: Wadsworth.
[26]  Durston S, Hulshoff Pol HE, Casey BJ, Giedd JN, Buitelaar JK, van Engeland H. (2001) Anatomical MRI of the developing human brain: what have we learned? J Am Acad Child Adolesc Psychiatry 40:1012-1020.
[27]  Pfefferbaum A, Mathalon DH, Sullivan EV, Rawles JM, Zipursky RB, Lim KO (1994) A quantitayive magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Arch Neurol 51:874-887.
[28]  Reiss AL, Abrams MT, Singer HS, Ross JL, Denckla MB (1996) Brain development, gender and IQ in children: a volumetric imaging study. Brain 119:1763-1774.
[29]  Jernigan TL, Trauner DA, Hesselink JR, Tallal PA (1991) Maturation of human cerebrum observed in vivo during adolescence. Brain 114:2037-2049.
[30]  Huttenlocher PR (1979) Synaptic density in human frontal cortex: developmental changes and effects of aging. Brain Res 163: 195-205.
[31]  Sowell ER, Thompson PM, Tessner KD, Toga AW. (2001) Mapping continued brain growth and gray matter density reduction in dorsal frontal cortex: Inverse relationships during postadolescent brain maturation. J Neurosci 21: 8819-8829.
[32]  Lenroot RK, Gogtay N, Greenstein DK, Wells EM, Wallace GL, Clasen LS, Blumenthal JD, Lerch J, Zijdenbos AP, Evans AC, Thompson PM, Giedd JN. (2007) Sexual dimorphism of brain developmental trajectories during childhood and adolescence. Neuroimage 36:1065-1073.
[33]  Ho KC, Roessmann U, Straumfjord JV, Monroe G (1980) Analysis of brain weight. 1. Adult brain weight in relation to sex, race, and age. Arch Pathol Lab Med 104: 635-639.
[34]  Filipek PA, Richelme C, Kennedy DN, Caviness VS Jr (1994) The young adult human brain: an MRI-based morphometric analysis. Cereb Cortex 4: 334-360.
[35]  Blatter DD, Bigler ED, Gale SD, Johnson SC, Anderson CV, Burnett BM (1995) Quantitative volumetric analysis of brain MR: normative database spanning 5 decades of life. Am J Neuroradiol 16: 241-251.
Show Less References