Neural correlates of apathy in patients with neurodegenerative disorders: an activation likelihood estimation (ALE) meta-analysis

  • Simona Raimo
  • Gabriella Santangelo
  • Alfonsina D’Iorio
  • Luigi Trojano
  • Dario Grossi
Review Article


Apathy is commonly reported in Alzheimer’s Disease (AD), Fronto-Temporal Dementia (FTD) and Parkinson’s Disease (PD). In our meta-analysis we analysed a total of 41 studies to identify brain patterns associated with apathy. For these purposes we used activation likelihood estimation meta-analyses. Our main overall analysis showed that apathy is associated to hypometabolism and a decreased gray matter volume in the left inferior frontal gyrus (BA 45, 46). Disorder-specific analyses, not performed by means of meta-analysis, because of the small number of studies, but by means a label-based review, revealed an altered brain perfusion and decreased gray matter volume in anterior cingulate cortex (BA 24, 32) in AD patients and a decreased gray matter volume in inferior frontal gyrus (BA 44, 45) and parietal cortex (BA 40) in FTD patients. These findings suggest that apathy is mainly associated with a cortical dysfunction of areas involved in executive-cognitive processing (i.e. action planning) and emotional regulation (auto-activation and reward processing). Knowledge about the neural underpinnings of apathy is crucial for understanding its clinical characteristics in neurodegenerative diseases and for developing novel strategies of treatment in clinical practice.


Apathy Neural correlates Meta-analysis Alzheimer disease Dementia Parkinson disease 

Supplementary material

11682_2018_9959_MOESM1_ESM.docx (19 kb)
ESM 1 (DOCX 19 kb)
11682_2018_9959_MOESM2_ESM.docx (44 kb)
ESM 2 (DOCX 43 kb)


  1. Agüera-Ortiz, L., Hernandez-Tamames, J. A., Martinez-Martin, P., Cruz-Orduña, I., Pajares, G., López-Alvarez, J., et al. (2017). Structural correlates of apathy in Alzheimer's disease: a multimodal MRI study. International Journal of Geriatric Psychiatry, 32(8), 922–930.PubMedCrossRefGoogle Scholar
  2. Alzahrani, H., Antonini, A., & Venneri, A. (2016). Apathy in mild Parkinson's disease: neuropsychological and neuroimaging evidence. Journal of Parkinson's Disease, 6(4), 821–832.PubMedCrossRefGoogle Scholar
  3. Apostolova, L. G., Akopyan, G. G., Partiali, N., Steiner, C. A., Dutton, R. A., Hayashi, K. M., et al. (2007). Structural correlates of apathy in Alzheimer's disease. Dementia and Geriatric Cognitive Disorders, 24(2), 91–97.PubMedCrossRefPubMedCentralGoogle Scholar
  4. Arikuni, T., & Kubota, K. (1986). The organization of prefrontocaudate projections and their laminar origin in the macaque monkey: a retrograde study using HRP-gel. The Journal of Comparative Neurology, 244(4), 492–510.PubMedCrossRefPubMedCentralGoogle Scholar
  5. Auffret, M., Le Jeune, F., Maurus, A., Drapier, S., Houvenaghel, J. F., & Robert, G. H. (2017). Apomorphine pump in advanced Parkinson's disease: effects on motor and nonmotor symptoms with brain metabolism correlations. Journal of the Neurological Sciences, 372, 279–287.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Baggio, H. C., Segura, B., Garrido-Millan, J. L., Marti, M. J., Compta, Y., & Valldeoriola, F. (2015). Resting-state frontostriatal functional connectivity in Parkinson's disease-related apathy. Movement Disorders, 30(5), 671–679.PubMedCrossRefPubMedCentralGoogle Scholar
  7. Ballarini, T., Iaccarino, L., Magnani, G., Ayakta, N., Miller, B. L., & Jagust, W. J. (2016). Neuropsychiatric subsyndromes and brain metabolic network dysfunctions in early onset Alzheimer's disease. Human Brain Mapping, 37(12), 4234–4247.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Benoit, M. (2015). What is the position of apathy in Parkinson's disease? European Journal of Neurology, 22(2), 221–222.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Benoit, M., Koulibaly, P. M., Migneco, O., Darcourt, J., Pringuey, D. J., & Robert, P. H. (2002). Brain perfusion in Alzheimer’s disease with and without apathy: a SPECT study with statistical parametric mapping analysis. Psychiatry Research: Neuroimaging, 114(2), 103–111.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Benoit, M., Clairet, S., Koulibaly, P. M., Darcourt, J., & Robert, P. H. (2015). Brain perfusion correlates of the apathy inventory dimensions of Alzheimer’s disease. International Journal of Geriatric Psychiatry, 19(9), 864–869.CrossRefGoogle Scholar
  11. Bertoux, M., Volle, E., Funkiewiez, A., de Souza, L.C., Leclercq, D., Dubois, B. (2012). Social cognition and emotional assessment (SEA) is a marker of medial and orbital frontal functions: a voxel-based morphometry study in behavioral variant of frontotemporal degeneration. Journal of the International Neuropsychological Society, 18(6),972–985.PubMedCrossRefGoogle Scholar
  12. Blumenfeld, R. S., Nomura, E. M., Gratton, C., & D'Esposito, M. (2013). Lateral prefrontal cortex is organized into parallel dorsal and ventral streams along the rostro-caudal axis. Cerebral Cortex, 23(10), 2457–2466.PubMedCrossRefGoogle Scholar
  13. Bonelli, R. M., & Cummings, J. L. (2007). Frontal-subcortical circuitry and behavior. Dialogues in Clinical Neuroscience, 9(2), 141–151.PubMedPubMedCentralGoogle Scholar
  14. Boorman, E., Behrens, T., Woolrich, M., & Rushworth, M. (2009). How green is the grass on the other side? Frontopolar cortex and the evidence in favor of alternative courses of action. Neuron, 62(5), 733–743.PubMedCrossRefGoogle Scholar
  15. Borroni, B., Grassi, M., Premi, E., Gazzina, S., Alberici, A., Cosseddu, M., et al. (2012). Neuroanatomical correlates of behavioural phenotypes in behavioural variant of frontotemporal dementia. Behavioural Brain Research, 235(2), 124–129.PubMedCrossRefGoogle Scholar
  16. Bruen, P. D., McGeown, W. J., Shanks, M. F., & Venneri, A. (2008). Neuroanatomical correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain, 131(pt 9), 2455–2463.PubMedCrossRefGoogle Scholar
  17. Chow, T. W. (2005). Treatment approaches to symptoms associated with frontotemporal degeneration. Current Psychiatry Reports, 7(5), 376–380.PubMedCrossRefGoogle Scholar
  18. Chow, T. W., Binns, M. A., Cummings, J. L., Lam, I., Black, S. E., Miller, B. L., et al. (2009). Apathy symptom profile and behavioral associations in frontotemporal dementia vs dementia of Alzheimer type. Archives of Neurology, 66(7), 888–893.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Christoff, K., & Gabrieli, J. D. E. (2000). The frontopolar cortex and human cognition: Evidence for a rostrocaudal hierarchical organization within the human prefrontal cortex. Psychobiology, 28(2), 168–186.Google Scholar
  20. Clarke, D. E., Ko, J. Y., Kuhl, E. A., van Reekum, R., Salvador, R., & Marin, R. S. (2011). Are the available apathy measures reliable and valid? A review of the psychometric evidence. Journal of Psychosomatic Research, 70(1), 73–97.PubMedCrossRefGoogle Scholar
  21. Craig, A. H., Cummings, J. L., Fairbanks, L., Itti, L., Miller, B. L., Li, J., et al. (1996). Cerebral blood flow correlates of apathy in Alzheimer disease. Archives of Neurology, 53(11), 1116–1120.PubMedCrossRefGoogle Scholar
  22. Day, G. S., Farb, N. A., Tang-Wai, D. F., Masellis, M., Black, S. E., Freedman, M., et al. (2013). Salience network resting-state activity: prediction of frontotemporal dementia progression. JAMA Neurology, 70(10), 1249–1253.PubMedGoogle Scholar
  23. Delrieu, J., Desmidt, T., Camus, V., Sourdet, S., Boutoleau-Bretonnière, C., Mullin, E., et al. (2015). Alzheimer's disease neuroimaging initiative. Apathy as a feature of prodromal Alzheimer's disease: an FDG-PET ADNI study. International Journal of Geriatric Psychiatry, 30(5), 470–477.PubMedCrossRefGoogle Scholar
  24. Eickhoff, S. B., Bzdok, D. (2013). Meta-analyses in basic and clinical neuroscience: State of the art and perspective. fMRI. Springer, 77–87.Google Scholar
  25. Eickhoff, S. B., Laird, A. R., Grefkes, C., Wang, L. E., Zilles, K., & Fox, P. T. (2009). Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: a random-effects approach based on empirical estimates of spatial uncertainty. Human Brain Mapping, 30(9), 2907–2926.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Eickhoff, S. B., Bzdok, D., Laird, A. R., Kurth, F., & Fox, P. T. (2012). Activation likelihood estimation meta-analysis revisited. Neuroimage, 59(3), 2349–2361.PubMedCrossRefGoogle Scholar
  27. Eickhoff, S. B., Nichols, T. E., Laird, A. R., Hoffstaedter, F., Amunts, K., Fox, P. T., et al. (2017). Behavior, sensitivity, and power of activation likelihood estimation characterized by massive empirical simulation. Neuroimage, 137, 70–85.CrossRefGoogle Scholar
  28. Elliott, R., Newman, J. L., Longe, O. A., & Deakin, J. F. W. (2003). Differential response patterns in the striatum and orbitofrontal cortex to financial reward in humans: a parametric functional magnetic resonance imaging study. Journal of Neuroscience, 23(1), 303–307.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Eslinger, P. J., Moore, P., Antani, S., Anderson, C., & Grossman, M. (2012). Apathy in frontotemporal dementia: behavioral and neuroimaging correlates. Behavioural Neurology, 25(2), 127–136.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Fan, L., Li, H., Zhuo, J., Zhang, Y., Wang, J., Chen, L., et al. (2016). The human Brainnetome atlas: a new brain atlas based on connectional architecture. Cerebral Cortex, 26(8), 3508–3526.PubMedCrossRefGoogle Scholar
  31. Farb, N. A., Grady, C. L., Strother, S., Tang-Wai, D. F., Masellis, M., Black, S., et al. (2013). Abnormal network connectivity in frontotemporal dementia: evidence for prefrontal isolation. Cortex, 49(7), 1856–1873.PubMedCrossRefPubMedCentralGoogle Scholar
  32. Fernández-Matarrubia, M., Matías-Guiu, J. A., Cabrera-Martín, M. N., Moreno-Ramos, T., Valles-Salgado, M., Carreras, J. L., et al. (2018). Different apathy clinical profile and neural correlates in behavioral variant frontotemporal dementia and Alzheimer's disease. International Journal of Geriatric Psychiatry, 33(1), 141–150.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Franceschi, M., Anchisi, D., Pelati, O., Zuffi, M., Matarrese, M., Moresco, R. M., et al. (2005). Glucose metabolism and serotonin receptors in the frontotemporal lobe degeneration. Annals of Neurology, 57(2), 216–225.PubMedCrossRefPubMedCentralGoogle Scholar
  34. Gesquière-Dando, A., Guedj, E., Loundou, A., Carron, R., Witjas, T., Fluchère, F., et al. (2015). A preoperative metabolic marker of parkinsonian apathy following subthalamic nucleus stimulation. Movement Disorders, 30(13), 1767–1776.PubMedCrossRefPubMedCentralGoogle Scholar
  35. Habas, C., Kamdar, N., Nguyen, D., Prater, K., Beckmann, C. F., Menon, V., et al. (2009). Distinct cerebellar contributions to intrinsic connectivity networks. Journal of Neuroscience, 29(26), 8586–8594.PubMedCrossRefPubMedCentralGoogle Scholar
  36. Hahn, C., Lim, H. K., Won, W. Y., Ahn, K. J., Jung, W. S., & Lee, C. U. (2013). Apathy and white matter integrity in Alzheimer's disease: a whole brain analysis with tract-based spatial statistics. PLoS One, 8(1).PubMedPubMedCentralCrossRefGoogle Scholar
  37. Hayata, T. T., Bergo, F. P., Rezende, T. J., Damasceno, A., Damasceno, B. P., & Cendes, F. (2015). Cortical correlates of affective syndrome in dementia due to Alzheimer's disease. Arquivos de Neuro-Psiquiatria, 73(7), 553–560.PubMedCrossRefPubMedCentralGoogle Scholar
  38. Hollocks, M. J., Lawrence, A. J., Brookes, R. L., Barrick, T. R., Morris, R. G., Husain, M., & Markus, H. S. (2015). Differential relationships between apathy and depression with white matter microstructural changes and functional outcomes. Brain, 138(12), 3803–3815.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Holthoff, V. A., Beuthien-Baumann, B., Kalbe, E., Lüdecke, S., Lenz, O., Zündorf, G., et al. (2005). Regional cerebral metabolism in early Alzheimer's disease with clinically significant apathy or depression. Biological Psychiatry, 57(4), 412–421.PubMedCrossRefGoogle Scholar
  40. Huang, C., Ravdin, L. D., Nirenberg, M. J., Piboolnurak, P., Severt, L., & Maniscalco, J. S. (2013). Neuroimaging markers of motor and nonmotor features of Parkinson's disease: an 18f fluorodeoxyglucose positron emission computed tomography study. Dementia and Geriatric Cognitive Disorders, 35(3–4), 183–196.PubMedCrossRefGoogle Scholar
  41. Jahanshahi, M., & Frith, C. D. (1998). Willed action and its impairments. Cognitive Neuropsychology 15, 483–533.PubMedCrossRefGoogle Scholar
  42. Jonsson, M., Edman, A., Lind, K., Rolstad, S., Sjogren, M., & Wallin, A. (2010). Apathy is a prominent neuropsychiatric feature of radiological white-matter changes in patients with dementia. International Journal of Geriatric Psychiatry, 25, 588–595.PubMedGoogle Scholar
  43. Kang, J. Y., Lee, J. S., Kang, H., Lee, H. W., Kim, Y. K., Jeon, H. J., et al. (2012). Regional cerebral blood flow abnormalities associated with apathy and depression in Alzheimer disease. Alzheimer Disease and Associated Disorders, 26(3), 217–224.PubMedCrossRefGoogle Scholar
  44. Kos, C., van Tol, M. J., Marsman, J. B., Knegtering, H., & Aleman, A. (2016). Neural correlates of apathy in patients with neurodegenerative disorders, acquired brain injury, and psychiatric disorders. Neuroscience and Biobehavioral Reviews, 69, 381–401.PubMedCrossRefGoogle Scholar
  45. Kos, C., Klaasen, N.G., Marsman, J.C., Opmeer, E.M., Knegtering, H., Aleman, A. & van Tol, M.J. (2017). Neural basis of self-initiative in relation to apathy in a student sample. Science Reports, 7(1), 3264.Google Scholar
  46. Kringelbach, M. L. (2005). The human orbitofrontal cortex: linking reward to hedonic experience. Nat. Reviews in the Neurosciences, 6, 691–702.Google Scholar
  47. Kumfor, F., Zhen, A., Hodges, J. R., Piguet, O., & Irish, M. (2018). Apathy in Alzheimer's disease and frontotemporal dementia: distinct clinical profiles and neural correlates. Cortex, 103, 350–359.PubMedCrossRefGoogle Scholar
  48. Laird, A. R., Fox, P. M., Price, C. J., Glahn, D. C., Uecker, A. M., Lancaster, J. L., et al. (2005). ALE meta-analysis: controlling the false discovery rate and performing statistical contrasts. Human Brain Mapping, 25(1), 155–164.PubMedCrossRefGoogle Scholar
  49. Lamsma, J., Mackay, C., & Fazel, S. (2017). Structural brain correlates of interpersonal violence: systematic review and voxel-based meta-analysis of neuroimaging studies. Psychiatry Research: Neuroimaging, 267, 69–73.PubMedCrossRefGoogle Scholar
  50. Lanctôt, K. L., Moosa, S., Herrmann, N., Leibovitch, F. S., Rothenburg, L., Cotter, A., et al. (2007). A SPECT study of apathy in Alzheimer's disease. Dementia and Geriatric Cognitive Disorders, 24(1), 65–72.PubMedCrossRefGoogle Scholar
  51. Landes, A. M., Sperry, S. D., Strauss, M. E., & Geldmacher, D. S. (2001). Apathy in Alzheimer's disease. Journal of the American Geriatrics Society, 49(12), 1700–1707.PubMedCrossRefGoogle Scholar
  52. Lavretsky, H., Zheng, L., Weiner, M. W., Mungas, D., Reed, B., Kramer, J. H., et al. (2008). The MRI brain correlates of depressed mood, anhedonia, apathy, and anergia in older adults with and without cognitive impairment or dementia. International Journal of Geriatric Psychiatry, 23, 1040–1050. Scholar
  53. Le Heron, C., Apps, M. A. J., & Husain, M. (2017). The anatomy of apathy: A neurocognitive framework for amotivated behaviour. Neuropsychologia, S0028-3932(17), 30250–30256.Google Scholar
  54. Le Jeune, F., Drapier, D., Bourguignon, A., Péron, J., Mesbah, H., Drapier, S., et al. (2009). Subthalamic nucleus stimulation in Parkinson disease induces apathy: a PET study. Neurology, 73(21), 1746–1751.PubMedCrossRefGoogle Scholar
  55. Levy, R., & Dubois, B. (2006). Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cerebral Cortex, 16(7), 916–928.PubMedCrossRefGoogle Scholar
  56. Levy, M. L., Miller, B. L., Cummings, J. L., Fairbanks, L. A., & Craig, A. (1996). Alzheimer disease and frontotemporal dementias. Behavioral distinctions. Archives of Neurology, 53(7), 687–690.PubMedCrossRefGoogle Scholar
  57. Levy, M. L., Cummings, J. L., Fairbanks, L. A., Masterman, D., Miller, B. L., Craig, A. H., et al. (1998). Apathy is not depression. The Journal of Neuropsychiatry and Clinical Neurosciences, 10(3), 314–319.PubMedCrossRefGoogle Scholar
  58. Lohner, V., Brookes, R. L., Hollocks, M. J., Morris, R. G., & Markus, H. S. (2017). Apathy, but not depression, is associated with executive dysfunction in cerebral small vessel disease. PLoS One, 12(5), e0176943.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Marin, R. S. (1991). Apathy: a neuropsychiatric syndrome. The Journal of Neuropsychiatry and Clinical Neurosciences, 3(3), 243–254.PubMedCrossRefGoogle Scholar
  60. Marshall, G. A., Monserratt, L., Harwood, D., Mandelkern, M., Cummings, J. L., & Sultzer, D. L. (2007). Positron emission tomography metabolic correlates of apathy in Alzheimer disease. Archives of Neurology, 64(7), 1015–1020.PubMedCrossRefPubMedCentralGoogle Scholar
  61. Massimo, L., Powers, C., Moore, P., Vesely, L., Avants, B., & Gee, J. (2009). Neuroanatomy of apathy and disinhibition in frontotemporal lobar degeneration. Dementia & Geriatric Cognitive Disorders, 27(1), 96–104.CrossRefGoogle Scholar
  62. McPherson, S., Fairbanks, L., Tiken, S., Cummings, J. L., & Back-Madruga, C. (2002). Apathy and executive function in Alzheimer's disease. Journal of the International Neuropsychological Society, 8(3), 373–381.PubMedCrossRefPubMedCentralGoogle Scholar
  63. Meyer, A., Zimmermann, R., Gschwandtner, U., Hatz, F., Bousleiman, H., Schwarz, N., et al. (2014). Apathy in Parkinson's disease is related to executive function, gender and age but not to depression. Frontiers in Aging Neuroscience, 6, 350.PubMedPubMedCentralGoogle Scholar
  64. Migneco, O., Benoit, M., Koulibaly, P. M., Dygai, I., Bertogliati, C., Desvignes, P., et al. (2001). Perfusion brain SPECT and statistical parametric mapping analysis indicate that apathy is a cingulate syndrome: a study in Alzheimer's disease and nondemented patients. Neuroimage, 13(5), 896–902.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Moayedi, M., Salomons, T. V., Dunlop, K. A. M., Downar, J., & Davis, K. D. (2015). Connectivity-based parcellation of the human frontal polar cortex. Brain Structure & Function, 220(5), 2603–2616.CrossRefGoogle Scholar
  66. Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & PRISMA Group. (2009). Preferred reporting for systematic reviews and meta-analyses: the PRISMA statement. Annals of Internal Medicine, 151(4), 264–269.PubMedCrossRefGoogle Scholar
  67. Moon, Y., Moon, W. J., Kim, H., & Han, S. H. (2014). Regional atrophy of the insular cortex is associated with neuropsychiatric symptoms in Alzheimer's disease patients. European Neurology, 71(5–6), 223–229.PubMedCrossRefGoogle Scholar
  68. Morbelli, S., Ferrara, M., Fiz, F., Dessi, B., Arnaldi, D., & Picco, A. (2016). Mapping brain morphological and functional conversion patterns in predementia late-onset bvFTD. European Journal of Nuclear Medicine and Molecular Imaging, 43, 1337–1347.PubMedCrossRefGoogle Scholar
  69. Müller, V. I., Cieslik, E. C., Laird, A. R., Fox, P. T., Radua, J., Mataix-Cols, D., et al. (2018). Ten simple rules for neuroimaging meta-analysis. Neuroscience and Biobehavioral Reviews, 84, 151–161.PubMedCrossRefGoogle Scholar
  70. O'Doherty, J., Kringelbach, M. L., Rolls, E. T., Hornak, J., & Andrews, C. (2001). Abstract reward and punishment representations in the human orbitofrontal cortex. Nature Neuroscience, 4(1), 95–102.PubMedCrossRefGoogle Scholar
  71. Ota, M., Sato, N., Nakata, Y., Arima, K., & Uno, M. (2012). Relationship between apathy and diffusion tensor imaging metrics of the brain in Alzheimer's disease. International Journal of Geriatric Psychiatry, 27(7), 722–726.PubMedCrossRefGoogle Scholar
  72. Ott, B. R., Noto, R. B., & Fogel, B. S. (1996). Apathy and loss of insight in Alzheimer's disease: a SPECT imaging study. The Journal of Neuropsychiatry and Clinical Neurosciences, 8(1), 41–46.PubMedCrossRefGoogle Scholar
  73. Pedersen, K. F., Larsen, J. P., Alves, G., & Aarsland, D. (2009). Prevalence and clinical correlates of apathy in Parkinson's disease: a community-based study. Parkinsonism & Related Disorders, 15(4), 295–299.CrossRefGoogle Scholar
  74. Peters, F., Perani, D., Herholz, K., Holthoff, V., Beuthien-Baumann, B., Sorbi, S., et al. (2006). Orbitofrontal dysfunction related to both apathy and disinhibition in frontotemporal dementia. Dementia and Geriatric Cognitive Disorders, 21(5–6), 373–379.PubMedCrossRefGoogle Scholar
  75. Pochon, J. B., Levy, R., Fossati, P., Lehericy, S., Poline, J. B., & Pillon, B. (2002). The neural system that bridges reward and cognition in humans: an fMRI study. Proceedings of the National Academy of Sciences of the United States of America, 99(8), 5669–5674.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Powers, J. P., Massimo, L., McMillan, C. T., Yushkevich, P. A., Zhang, H., Gee, J. C., et al. (2014). White matter disease contributes to apathy and disinhibition in behavioral variant frontotemporal dementia. Cognitive and Behavioral Neurology, 27(4), 206–214.PubMedPubMedCentralCrossRefGoogle Scholar
  77. Radua, J., & Mataix-Cols, D. (2012). Meta-analytic methods for neuroimaging data explained. Biology of Mood & Anxiety Disorders, 2, 6.CrossRefGoogle Scholar
  78. Raimo, S., Trojano, L., Spitaleri, D., Petretta, V., Grossi, D., & Santangelo, G. (2016). The relationships between apathy and executive dysfunction in multiple sclerosis. Neuropsychology, 30(6), 767–774.PubMedCrossRefPubMedCentralGoogle Scholar
  79. Ray, K., Zald, D., Bludau, S., Riedel, M., Bzdok, D., & Yanes, J. (2015). Co-activation based parcellation of the human frontal pole. NeuroImage, 123, 200–211.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Reijnders, J. S., Scholtissen, B., Weber, W. E., Aalten, P., Verhey, F. R., & Leentjens, A. F. (2010). Neuroanatomical correlates of apathy in Parkinson's disease: a magnetic resonance imaging study using voxel-based morphometry. Movement Disorders, 25(14), 2318–2325.PubMedCrossRefGoogle Scholar
  81. Remy, P., Doder, M., Lees, A., Turjanski, N., & Brooks, D. (2005). Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain, 128(6), 1314–1322.PubMedCrossRefGoogle Scholar
  82. Robert, P. H., Darcourt, G., Koulibaly, M.P., Clairet, S., Benoit, M., Garcia, R., et al. (2006). Lack of initiative and interest in Alzheimer's disease: a single photon emission computed tomography study. European Journal of Neurology, 13(7), 729–735.PubMedCrossRefGoogle Scholar
  83. Robert, P., Onyike, C. U., Leentjens, A. F., Dujardin, K., Aalten, P., Starkstein, S., et al. (2009). Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. European Psychiatry, 24(2), 98–104.PubMedCrossRefGoogle Scholar
  84. Robert, G., Le Jeune, F., Lozachmeur, C., Drapier, S., Dondaine, T., Péron, J., et al. (2012). Apathy in patients with Parkinson disease without dementia or depression: a PET study. Neurology, 79(11), 1155–60.PubMedCrossRefGoogle Scholar
  85. Robert, G., Le Jeune, F., Dondaine, T., Drapier, S., Péron, J., Lozachmeur, C., et al. (2014a). Apathy and impaired emotional facial recognition networks overlap in Parkinson’s disease: a PET study with conjunction analyses. Journal of Neurology, Neurosurgery, and Psychiatry, 85(10), 1153–1158.PubMedCrossRefGoogle Scholar
  86. Robert, G.H., Le Jeune, F., Lozachmeur, C., Drapier, S., Dondaine, T., Péron, J., et al. (2014b) Preoperative factors of apathy in subthalamic stimulated Parkinson disease: a PET study. Neurology, 83(18),1620–1626.PubMedCrossRefGoogle Scholar
  87. Rosen, H. J., Allison, S. C., Schauer, G. F., Gorno-Tempini, M. L., Weiner, M. W., & Miller, B. L. (2005). Neuroanatomical correlates of behavioural disorders in dementia. Brain, 128(Pt 11), 2612–2625.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Santangelo, G., Trojano, L., Barone, P., Errico, D., Grossi, D., & Vitale, C. (2013). Apathy in Parkinson's disease: diagnosis, neuropsychological correlates, pathophysiology and treatment. Behavioural Neurology, 27(4), 501–513.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Santangelo, G., Vitale, C., Trojano, L., Picillo, M., Moccia, M., Pisano, G., et al. (2015). Relationship between apathy and cognitive dysfunctions in de novo untreated Parkinson's disease: a prospective longitudinal study. European Journal of Neurology, 22(2), 253–260.PubMedCrossRefGoogle Scholar
  90. Schroeter, M. L., Vogt, B., Frisch, S., Becker, G., Seese, A., Barthel, G., et al. (2011). Dissociating behavioral disorders in early dementia-an FDG-PET study. Psychiatry Research: Neuroimaging, 194, 235–244.PubMedCrossRefPubMedCentralGoogle Scholar
  91. Selemon, L. D., & Goldman-Rakic, P. S. (1985). Longitudinal topography and interdigitation of corticostriatal projections in the rhesus monkey. The Journal of Neuroscience, 5(3), 776–794.PubMedCrossRefGoogle Scholar
  92. Shen, Y. T., Li, J. Y., Yuan, Y. S., Wang, X. X., Wang, M., Wang, J. W., et al. (2018). Disrupted amplitude of low-frequency fluctuations and causal connectivity in Parkinson's disease with apathy. Neuroscience Letters, 683, 75–81.PubMedCrossRefGoogle Scholar
  93. Shin, J. H., Shin, S. A., Lee, J. Y., Nam, H., Lim, J. S., & Kim, Y. K. (2017). Precuneus degeneration and isolated apathy in patients with Parkinson's disease. Neuroscience Letters, 653, 250–257.PubMedCrossRefGoogle Scholar
  94. Skidmore, F. M., Yang, M., Baxter, L., von Deneen, K., Collingwood, J., He, G., et al. (2013). Apathy, depression, and motor symptoms have distinct and separable resting activity patterns in idiopathic Parkinson disease. Neuroimage, 1(81), 484–495.CrossRefGoogle Scholar
  95. Stadler, C., Sterzer, P., Schmeck, K., Krebs, A., Kleinschmidt, A., & Poustka, F. (2007). Reduced anterior cingulate activation in aggressive children and adolescents during affective stimulation: association with temperament traits. Journal of Psychiatric Research, 41, 410–417.PubMedCrossRefGoogle Scholar
  96. Stanton, B. R., Leigh, P. N., Howard, R. J., Barker, G. J., & Brown, R. G. (2013). Behavioural and emotional symptoms of apathy are associated with distinct patterns of brain atrophy in neurodegenerative disorders. Journal of Neurology, 260(10), 2481–2490.PubMedCrossRefGoogle Scholar
  97. Starkstein, S. E., Mayberg, H. S., Preziosi, T. J., Andrezejewski, P., Leiguarda, R., & Robinson, R. G. (1992). Reliability, validity, and clinical correlates of apathy in Parkinson's disease. The Journal of Neuropsychiatry and Clinical Neurosciences, 4(2), 134–139.PubMedCrossRefGoogle Scholar
  98. Starkstein, S. E., Mizrahi, R., Capizzano, A. A., Acion, L., Brockman, S., & Power, B. D. (2009). Neuroimaging correlates of apathy and depression in Alzheimer's disease. Journal of Neuropsychiatry and Clinical Neurosciences, 21(3), 259–265.PubMedCrossRefGoogle Scholar
  99. Sterzer, P., Stadler, C., Krebs, A., Kleinschmidt, A., & Poustka, F. (2005). Abnormal neural responses to emotional visual stimuli in adolescents with conduct disorder. Biological Psychiatry, 57, 7–15.PubMedCrossRefGoogle Scholar
  100. Tekin, S., & Cummings, J. L. (2002). Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. Journal of Psychosomatic Research, 53(2), 647–654.PubMedCrossRefPubMedCentralGoogle Scholar
  101. Terada, T., Miyata, J., Obi, T., Kubota, M., Yoshizumi, M., & Murai, T. (2018). Reduced gray matter volume is correlated with frontal cognitive and behavioral impairments in Parkinson's disease. Journal of the Neurological Sciences, 390, 231–238.PubMedCrossRefPubMedCentralGoogle Scholar
  102. Thobois, S., Ardouin, C., Lhommee, E., Klinger, H., Lagrange, C., Xie, J., et al. (2010). Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation. Brain, 133(4), 1111–1127.PubMedCrossRefGoogle Scholar
  103. Tunnard, C., Whitehead, D., Hurt, C., Wahlund, L. O., Mecocci, P., Tsolaki, M., et al. (2011). Apathy and cortical atrophy in Alzheimer's disease. International Journal of Geriatric Psychiatry, 26(7), 741–748.PubMedCrossRefGoogle Scholar
  104. Turkeltaub, P. E., Eden, G. F., Jones, K. M., & Zeffiro, T. A. (2002). Meta-analysis of the functional neuroanatomy of single-word reading: method and validation. Neuroimage, 16(3 pt 1), 765–780.PubMedCrossRefGoogle Scholar
  105. Van Reekum, R., Stuss, D. T., & Ostrander, L. (2005). Apathy: Why care? The Journal of Neuropsychiatry and Clinical Neuroscience, 17(1), 7–19.CrossRefGoogle Scholar
  106. Wallis, J. D. (2007). Orbitofrontal cortex and its contribution to decision-making. Annual Review of Neuroscience (Palo Alto, CA), 30, 31–56.CrossRefGoogle Scholar
  107. Wu, X., Li, Q., Yu, X., Chen, K., Fleisher, A. S., Guo, X., et al. (2016). A triple network connectivity study of large-scale brain systems in cognitively normal APOE4 carriers. Frontiers in Aging Neuroscience, 8, 231.PubMedPubMedCentralGoogle Scholar
  108. Yuen, G. S., Gunning-Dixon, F. M., Hoptman, M. J., AbdelMalak, B., McGovern, A. R., Seirup, J. K., et al. (2014). The salience network in the apathy of late-life depression. International Journal of Geriatric Psychiatry, 29(11), 1116–1124.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Zamboni, G., Huey, E. D., Krueger, F., Nichelli, P. F., & Grafman, J. (2008). Apathy and disinhibition in frontotemporal dementia: insights into their neural correlates. Neurology, 71(10), 736–742.PubMedPubMedCentralCrossRefGoogle Scholar
  110. Zold, C. L., Larramendy, C., Riquelme, L. A., & Murer, M. G. (2007). Distinct changes in evoked and resting globus pallidus activity in early and late Parkinson's disease experimental models. The European Journal of Neuroscience, 26, 1267–1279.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Simona Raimo
    • 1
    • 2
  • Gabriella Santangelo
    • 2
  • Alfonsina D’Iorio
    • 2
  • Luigi Trojano
    • 2
    • 3
  • Dario Grossi
    • 2
  1. 1.Department of Medical and Surgical SciencesUniversity of “Magna Graecia”CatanzaroItaly
  2. 2.Department of PsychologyUniversity of Campania “Luigi Vanvitelli”CasertaItaly
  3. 3.Salvatore Maugeri FoundationScientific Institute of Telese TermeTelese TermeItaly

Personalised recommendations