Aging, Alzheimer's Disease, Anatomy, Autism, Brain, Brain Imaging, Cerebral Cortex, Comparative Anatomy, Demyelination, Epilepsy, Evolution, Glutamate (NMDA & AMPA) Receptors, Hippocampus, Magnetic Resonance Imaging, Memory, Mental Retardation, Morphometrics, Neural Networks, Neuro-degeneration/protection, Prefrontal Cortex, Quantitative Neuroanatomy, Synapses, Systems Neuroscience
Biophysics and Systems Pharmacology [BSP], Neuroscience [NEU]
MD, University of Geneva School of Medicine
, The Scripps Research Institute
Specific Clinical/Research Interest:
Experimental neuropathology, neurodegenerative disorders, brain aging; Functional anatomy of the cerebral cortex, comparative neuroanatomy; Computer-assisted morphometry, stereology, microscopy; Magnetic resonance microscopy, functional brain imaging
Current Students: Tuyen Nguyen (PhD)
Postdoctoral Fellows: Camilla Butti, PhD, Timothy Rumbell PhD, Merina Varghese PhD
Research Personnel: Bridget Wicinski, Daniel Dickstein
Summary of Research Studies:
Our research is directed towards the study of selective neuronal vulnerability in dementing illnesses using classical neuropathological as well as modern quantitative immunohistochemical methods. We intend to develop a quantitative, detailed and cohesive definition of neuronal susceptibility to degeneration in the cerebral cortex, by extending data on Alzheimer disease to other dementing disorders as well as animal models of age-related illnesses, and by defining the key neurochemical and morphological characteristics linked to relative vulnerability (or resistance to degeneration) of identified neuronal populations. The regional and laminar distribution in the cerebral cortex of specific neuronal populations is investigated in a variety of neurodegenerative disorders, and quantitatively compared to Alzheimer disease and control brains. In addition, a detailed study of brains from aged patients with no records of neurological and psychiatric disorders is performed in order to define further the limits of normal aging in the brain.
We employ advanced microscopy, high field magnetic resonance imaging, stereologic, and modeling approaches to develop an accurate quantitative assessment of such pathological changes in a region- and layer-specific manner. Neuronal morphology is analyzed in a quantitative manner using intracellular injection of hippocampal and neocortical neurons coupled with computerized reconstruction to assess the degree to which the accumulation of pathologic markers causes dendritic atrophy and spine loss in different subtypes of neocortical pyramidal cells subserving cortical circuits critical for memory and cognition. The characterization of such vulnerable neurons and circuits is fundamental to the design of therapeutic strategies aiming at their protection or rescue. Similar approaches are applied to the neuropathology of schizophrenia and autism.
Finally we are investigating mammalian brain evolution with a focus on cetaceans and great apes. These studies have led us to identify specific neuronal types in parts of the cerebral cortex known to be involved in social awareness, judgment, and attention that can be considered as markers of adaptive mechanisms and functions in response to particular ecological pressure.
Eilam-Stock T, Xu P, Cao M, Gu X, Van Dam NT, Anagnostou E, Kolevzon A, Soorya L, Park Y, Siller M, He Y, Hof PR, Fan J. Abnormal autonomic and associated brain activities during rest in autism spectrum disorder. Brain : a journal of neurology 2014 Jan; 137(Pt 1).
Guillozet-Bongaarts AL, Hyde TM, Dalley RA, Hawrylycz MJ, Henry A, Hof PR, Hohmann J, Jones AR, Kuan CL, Royall J, Shen E, Swanson B, Zeng H, Kleinman JE. Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia. Molecular psychiatry 2014 Apr; 19(4).
Wang X, Gu X, Fan J, Wang S, Zhao F, Hof PR, Liu P, Gao Z. Recovery of empathetic function following resection of insular gliomas. Journal of neuro-oncology 2014 Apr; 117(2).
Butti C, Ewan Fordyce R, Ann Raghanti M, Gu X, Bonar CJ, Wicinski BA, Wong EW, Roman J, Brake A, Eaves E, Spocter MA, Tang CY, Jacobs B, Sherwood CC, Hof PR. The cerebral cortex of the pygmy hippopotamus, Hexaprotodon liberiensis (Cetartiodactyla, Hippopotamidae): MRI, cytoarchitecture, and neuronal morphology. Anatomical record (Hoboken, N.J. : 2007) 2014 Apr; 297(4).
Uppal N, Gianatiempo I, Wicinski B, Schmeidler J, Heinsen H, Schmitz C, Buxbaum JD, Hof PR. Neuropathology of the posteroinferior occipitotemporal gyrus in children with autism. Molecular autism 2014; 5(1).
Bozek K, Wei Y, Yan Z, Liu X, Xiong J, Sugimoto M, Tomita M, Pääbo S, Pieszek R, Sherwood CC, Hof PR, Ely JJ, Steinhauser D, Willmitzer L, Bangsbo J, Hansson O, Call J, Giavalisco P, Khaitovich P. Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness. PLoS biology 2014 May; 12(5).
Barks SK, Bauernfeind AL, Bonar CJ, Cranfield MR, de Sousa AA, Erwin JM, Hopkins WD, Lewandowski AH, Mudakikwa A, Phillips KA, Raghanti MA, Stimpson CD, Hof PR, Zilles K, Sherwood CC. Variable temporoinsular cortex neuroanatomy in primates suggests a bottleneck effect in eastern gorillas. The Journal of comparative neurology 2014; 522(4).
Uppal N, Wicinski B, Buxbaum JD, Heinsen H, Schmitz C, Hof PR. Neuropathology of the anterior midcingulate cortex in young children with autism. Journal of neuropathology and experimental neurology 2014 Sep; 73(9).
Gu X, Liu X, Van Dam NT, Hof PR, Fan J. Cognition-emotion integration in the anterior insular cortex. Cerebral cortex (New York, N.Y. : 1991) 2013 Jan; 23(1).
DeFelipe J, López-Cruz PL, Benavides-Piccione R, Bielza C, Larrañaga P, Anderson S, Burkhalter A, Cauli B, Fairén A, Feldmeyer D, Fishell G, Fitzpatrick D, Freund TF, González-Burgos G, Hestrin S, Hill S, Hof PR, Huang J, Jones EG, Kawaguchi Y, Kisvárday Z, Kubota Y, Lewis DA, Marín O, Markram H, McBain CJ, Meyer HS, Monyer H, Nelson SB, Rockland K, Rossier J, Rubenstein JL, Rudy B, Scanziani M, Shepherd GM, Sherwood CC, Staiger JF, Tamás G, Thomson A, Wang Y, Yuste R, Ascoli GA. New insights into the classification and nomenclature of cortical GABAergic interneurons. Nature reviews. Neuroscience 2013 Mar; 14(3).
Bianchi S, Stimpson CD, Duka T, Larsen MD, Janssen WG, Collins Z, Bauernfeind AL, Schapiro SJ, Baze WB, McArthur MJ, Hopkins WD, Wildman DE, Lipovich L, Kuzawa CW, Jacobs B, Hof PR, Sherwood CC. Synaptogenesis and development of pyramidal neuron dendritic morphology in the chimpanzee neocortex resembles humans. Proceedings of the National Academy of Sciences of the United States of America 2013 Jun; 110 Suppl 2.
Van Dam NT, Sano M, Mitsis EM, Grossman HT, Gu X, Park Y, Hof PR, Fan J. Functional neural correlates of attentional deficits in amnestic mild cognitive impairment. PloS one 2013; 8(1).
Gu X, Hof PR, Friston KJ, Fan J. Anterior insular cortex and emotional awareness. The Journal of comparative neurology 2013 Oct; 521(15).
Perez SE, Raghanti MA, Hof PR, Kramer L, Ikonomovic MD, Lacor PN, Erwin JM, Sherwood CC, Mufson EJ. Alzheimer's disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla). The Journal of comparative neurology 2013 Dec; 521(18).
Zeng H, Shen EH, Hohmann JG, Oh SW, Bernard A, Royall JJ, Glattfelder KJ, Sunkin SM, Morris JA, Guillozet-Bongaarts AL, Smith KA, Ebbert AJ, Swanson B, Kuan L, Page DT, Overly CC, Lein ES, Hawrylycz MJ, Hof PR, Hyde TM, Kleinman JE, Jones AR. Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures. Cell 2012 Apr; 149(2).
Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. Journal of neuropathology and experimental neurology 2012 May; 71(5).
Jacot-Descombes S, Uppal N, Wicinski B, Santos M, Schmeidler J, Giannakopoulos P, Heinsen H, Heinsein H, Schmitz C, Hof PR. Decreased pyramidal neuron size in Brodmann areas 44 and 45 in patients with autism. Acta neuropathologica 2012 Jul; 124(1).
Fan J, Xu P, Van Dam NT, Eilam-Stock T, Gu X, Luo YJ, Hof PR. Spontaneous brain activity relates to autonomic arousal. The Journal of neuroscience : the official journal of the Society for Neuroscience 2012 Aug; 32(33).
Fan J, Bernardi S, Van Dam NT, Anagnostou E, Gu X, Martin L, Park Y, Liu X, Kolevzon A, Soorya L, Grodberg D, Hollander E, Hof PR. Functional deficits of the attentional networks in autism. Brain and behavior 2012 Sep; 2(5).
Gu X, Gao Z, Wang X, Liu X, Knight RT, Hof PR, Fan J. Anterior insular cortex is necessary for empathetic pain perception. Brain : a journal of neurology 2012 Sep; 135(Pt 9).
Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, van de Lagemaat LN, Smith KA, Ebbert A, Riley ZL, Abajian C, Beckmann CF, Bernard A, Bertagnolli D, Boe AF, Cartagena PM, Chakravarty MM, Chapin M, Chong J, Dalley RA, Daly BD, Dang C, Datta S, Dee N, Dolbeare TA, Faber V, Feng D, Fowler DR, Goldy J, Gregor BW, Haradon Z, Haynor DR, Hohmann JG, Horvath S, Howard RE, Jeromin A, Jochim JM, Kinnunen M, Lau C, Lazarz ET, Lee C, Lemon TA, Li L, Li Y, Morris JA, Overly CC, Parker PD, Parry SE, Reding M, Royall JJ, Schulkin J, Sequeira PA, Slaughterbeck CR, Smith SC, Sodt AJ, Sunkin SM, Swanson BE, Vawter MP, Williams D, Wohnoutka P, Zielke HR, Geschwind DH, Hof PR, Smith SM, Koch C, Grant SG, Jones AR. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 2012 Sep; 489(7416).
Yadav A, Gao YZ, Rodriguez A, Dickstein DL, Wearne SL, Luebke JI, Hof PR, Weaver CM. Morphologic evidence for spatially clustered spines in apical dendrites of monkey neocortical pyramidal cells. The Journal of comparative neurology 2012 Sep; 520(13).
Spocter MA, Hopkins WD, Barks SK, Bianchi S, Hehmeyer AE, Anderson SM, Stimpson CD, Fobbs AJ, Hof PR, Sherwood CC. Neuropil distribution in the cerebral cortex differs between humans and chimpanzees. The Journal of comparative neurology 2012 Sep; 520(13).
Barger N, Stefanacci L, Schumann CM, Sherwood CC, Annese J, Allman JM, Buckwalter JA, Hof PR, Semendeferi K. Neuronal populations in the basolateral nuclei of the amygdala are differentially increased in humans compared with apes: a stereological study. The Journal of comparative neurology 2012 Sep; 520(13).
Amatrudo JM, Weaver CM, Crimins JL, Hof PR, Rosene DL, Luebke JI. Influence of highly distinctive structural properties on the excitability of pyramidal neurons in monkey visual and prefrontal cortices. The Journal of neuroscience : the official journal of the Society for Neuroscience 2012 Oct; 32(40).
Miller DJ, Duka T, Stimpson CD, Schapiro SJ, Baze WB, McArthur MJ, Fobbs AJ, Sousa AM, Sestan N, Wildman DE, Lipovich L, Kuzawa CW, Hof PR, Sherwood CC. Prolonged myelination in human neocortical evolution. Proceedings of the National Academy of Sciences of the United States of America 2012 Oct; 109(41).
Luebke JI, Weaver CM, Rocher AB, Rodriguez A, Crimins JL, Dickstein DL, Wearne SL, Hof PR. Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models.. Brain Structure and Function 2010 Mar; 214(2,3): 181-199.
Butti C, Sherwood CC, Hakeem AY, Allman JM, Patrick R. Hof PR. Total number and volume of von Economo neurons in the cerebral cortex of cetaceans.. Journal of Comparative Neurology 2009 Jul; 515(2): 243-259.
Kabaso D, Koskren PJ, Henry BI, Hof PR, Wearne SL. The electrotonic structure of pyramidal neurons contributing to prefrontal cortical circuits in macaque monkeys is significantly altered in aging.. Cerebral Cortex 2009 Oct; 19(10): 2248-2268.
Rodriguez A, Ehlenberger DB, Dickstein DL, Hof PR, Wearne SL. Automated three-dimensional detection and classification of dendritic spines from fluorescence microscopy. Public Lib. Sci. One 2008; 3(4 ): e1997.
Akram A, Christoffel D, Rocher AB, Bouras C, Kovari E, Perl DP, Morrison JH, Herrmann FR, Haroutunian V, Giannakopoulos P, Hof PR. Stereologic estimates of total spinophilin-immunoreactive spine numbers in area 9 and the CA1 field: relationship with the progression of Alzheimer's disease. . Neurobiol. Aging 2008; 29: 1296-1307.
Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, McEwen BS, Morrison JH, Wearne SL, Hof PR. Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J. Comp. Neurol 2008; 507: 1141-1150.
Hof PR, Van der Gucht E. The structure of the cerebral cortex of the humpback whale, Megaptera novaeangliae (Cetacea, Mysticeti, Balaenopteridae). Anat. Rec 2007; 290: 1-31.
Rodriguez A, Ehlenberger DB, Hof PR, Wearne SL. Rayburst sampling, an algorithm for automated three-dimensional shape analysis from laser scanning microscopy images.. Nature Protocols 2006; 1: 2152-2161.
Hof PR, Morrison JH. The aging brain: morphomolecular senescence of cortical circuits. Trends Neurosci 2004; 27: 607-613.
Bussiere T, Giannakopoulos P, Bouras C, Perl DP, Morrison JH, Hof PR. Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer's disease: a stereologic analysis of prefrontal cortex area 9. J. Comp. Neurol 2003; 463: 281-302.
Bussière T, Giannakopoulos P, Bouras C, Perl DP, Morrison JH, Hof PR. Progressive degeneration of nonphosphorylated neurofilament protein-enriched pyramidal neurons predicts cognitive impairment in Alzheimer's disease: stereologic analysis of prefrontal cortex area 9. The Journal of comparative neurology 2003 Aug; 463(3).
Duan H, Wearne SL, Rocher AB, Macedo A, Morrison JH, Hof PR. Age-related dendritic and spine changes in corticocortically projecting neurons in macaque monkeys. Cerebral cortex (New York, N.Y. : 1991) 2003 Sep; 13(9).
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