Abstract
Background: Apathy is defined as diminished motivation free from altered consciousness, cognitive impairment or emotional distress. It is a prevalent syndrome in different disorders, which share brain system alterations despite very different underlying pathologies. However, to date, little research has be en devoted to the subject.
Aims: To review the concept of apathy and clarify its aetiology, structural and functional neural bases and treatment options.
Methods: Literature search and review, with “apathy” as a term, using all main databases (Medline, Psychinfo, Cochrane) included in our organization’s (RSMB; Osakidetza/Basque Health Service) Ovid search engine, together with a manual search of relevant papers.
Results: The literature reviewed shows that apathy is a multi-dimensional clinical construct with a current definition and validated diagnostic criteria. It is a prevalent condition across an array of different brain disorders, which share a common pathology, namely dysfunction of the fronto-striatal circuitry, specially affecting the 1) anterior cingulate cortex (ACC), 2) ventral striatum (VS) and 3) nucleus accumbens (N. Acc.). Different theories have emerged regarding the role of the ACC in the genesis of apathy. The neuromodulator dopamine is heavily implicated in 1- ACC, 2- VS, 3- in particulat the N. Acc., and 4- the genesis of apathy, although other neurotransmitters could also be involved to a lesser degree. There is a patent lack of RCTs on the efficiency of current therapeutic options.
Conclusion: Further research is needed to help understand the functional neuroanatomy, neuromodulators involved and possible treatment options of this clinical construct.
Keywords: Apathy, amotivation, lack of initiation, athymhormia, dopamine, frontostriatal circuitry.
Graphical Abstract
[2]
Krack P, Pagonabarraga J, Strafella AP, Kulisevsky J. Apathy: Who cares? Lancet Neurol 2015; 14: 465.
[3]
Fisher CM. Honored guest presentation: Abulia minor vs. agitated behavior. Neurosurgery 1984; 31(Suppl. 1): 9-31.
[4]
Marin RS. Differential diagnosis and classification o apathy. Am J Psychiatry 1990; 147(1): 22-30.
[6]
Berrios GE, Gili M. Abulia and impulsiveness revisited: a conceptual history. Acta Psychiatr Scand 1995; 92: 161-7.
[7]
Stuss DT, Van Reekum R, Murphy KJ. In Borod JC, Eds. The
Neuropsychology of Emotion. Oxford: Oxford University Press
2000; pp. 340-63.
[8]
Laplane D, Dubois B. Auto-activation deficit: a basal ganglia related syndrome. Mov Disord 2001; 16(5): 810-4.
[9]
Habib M. Athymhormia and disorders of motivation in basal ganglia disease. The J Neuropsychiatry Clin Neurosci 2004; 16: 509-24.
[10]
Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex 2006; 16: 916-28.
[11]
Starkstein SE, Leentjens AFG. The nosological position of apathy in clinical practice. J Neurol Neurosurg Psychiatry 2008; 79: 1088-92.
[12]
Le Heron C, Apps MAJ, Husain M. The anatomy of apathy: A neurocognitive framework for amotivated behaviour. Neuropsychologia 2018; 118: 54-67.
[13]
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology 1994; 44: 2308-14.
[14]
Sockeel P, Dujardin K, Devos D, Denève C, Destée A, Defebvre L. The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2006; 77: 579-84.
[15]
Robert P, Onyike CU, Leentjens AFG, et al. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. J Eur Psychiatry 2009; 24: 98-104.
[17]
Mulin E, Leone E, Dujardin K, Delliaux M, et al. Diagnostic criteria for apathy in clinical practice. Int J Geriatr Psychiatry 2011; 26: 158-65.
[18]
Levy ML, Cummings JL, Fairbanks LA, et al. Apathy is not depression. J Neuropsychiatry Clin Neurosci 1998; 10: 314-9.
[19]
García-Ramos R, Villanueva C, del Val J, Matías-Guíu J. Apatía en la enfermedad de Parkinson. Neurologia 2010; 25(1): 40-50.
[20]
Marin RS, Firinciogullari S, Biedrzycki RC. Group differences in the relationship between apathy and depression. J Nerv Ment Dis 1994; 182: 235-9.
[21]
Hama S, Yamashita H, Shigenobu M, et al. Depression or apathy and functional recovery after stroke. Int J Geriatr Psychiatry 2007; 22: 1046-51.
[22]
Van Reekum R, Stuss DT, Ostrander L. Apathy: Why care? J Neuropsychiatry Clin Neurosci 2005; 17(1): 7-19.
[23]
Tang WK, Caeiro L, Lau CG, et al. Apathy and suicide-related ideation 3 months after stroke: A cross-sectional study. BMC Neurology 2015; 15: 60.
[24]
Onoda K, Yamaguchi S. Dissociative contributions of the anterior cingulate cortex to apathy and depression: Topological evidence from resting-state functional MRI. Neuropsychologia 2015; 77: 10-8.
[25]
Robert PH, Clairet S, Benoit M, et al. The apathy inventory: assessment of apathy and awareness in Alzheimer’s disease, Parkinson’s disease and mils cognitive impairment. Int J Geriatr Psychiatry 2002; 17: 1099-105.
[26]
Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the Apathy Evaluation Scale. Psychiatry Res 1991; 38: 143-62.
[27]
Starkstein SE, Mayberg HS, Preziosi TJ, Andrerzejewswki P, Leiguarda R, Robinson RG. Reliability, validity and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci 1992; 4: 134-9.
[28]
Weiser M, Garibaldi G. Quantifying motivational deficits and apathy: A review of the literature. Eur Neuropsychopharmacol 2015; 25: 1060-81.
[29]
Lane-Brown AT, Tate RL. Measuring apathy after traumatic brain injury: Psychometric properties of the Apathy Evaluation Scale and the Frontal Systems Behavior Scale. Brain Inj 2009; 23(13-14): 999-1007.
[30]
Arnould A, Rochat L, Azouvi P, Van der Linden M. Apathetic symptom presentations in patients with severe traumatic brain injury: Assessment, heterogeneity and relationships with psychosocial functioning and caregivers’ burden. Brain Inj 2015; 29(13-14): 1597-603.
[31]
Arnould A, Rochat L, Azouvi P, Van der Linden M. A multidimensional approach to apathy after traumatic brain injury. Neuropsychol Rev 2013; 23: 210-33.
[32]
Bortolon C, Macgregor A, Capdevielle D, Raffard S. Apathy in schizophrenia: A review of neuropsychological and neuroanatomical studies Neuropsychologia 2018; 118(B): 22-33.
[33]
Brodaty H, Sachdev PS, Withall A, Altendorf A, Valenzuela MJ, Lorentz L. Frequency and clinical, neuropsychological and neuroimaging correlates of apathy following stroke - the Sydney Stroke Study. Psychol Med 2005; 35: 1707-16.
[34]
Caeiro L, Ferro JM, Figueira ML. Apathy in acute stroke patients. Eur J Neurol 2012; 19: 291-7.
[35]
Cipriani G, Lucetti C, Danti S, Nuti A. Apathy and dementia. Nosology, assessment and management. J Nerv Ment Dis 2014; 202(10): 718-24.
[36]
Jorge RE, Starkstein SE, Robinson RG. Apathy following stroke. Can J Psychiatry 2010; 55(6): 350-4.
[37]
Rao V, McCann U, Bergey A, Han D. Correlates of apathy during the first year after traumatic brain injury. Psychosomatics 2013; 54(4): 403-4.
[38]
Robert G, Le Jeune F, Lozachmeur C, et al. Apathy in patients with Parkinson’s disease without dementia or depression. A PET study. Neurology 2012; 79: 1155-60.
[39]
Tang WK, Chen YK, Liang HJ, et al. Location of infarcts and apathy in ischemic stroke. Cerebrovasc Dis 2013; 35: 566-71.
[40]
Van Dalen JW, Van Charante EPM, Nederkoorn PJ, Van Gool WA, Richard E. Poststroke apathy. Stroke 2013; 44: 851-60.
[41]
Starkstein SE, Fedoroff P, Price TR, Leiguarda R, Robinson RG. Apathy following cerebrovascular lesions. Stroke 1993; 24: 1625-30.
[42]
Yang S-R, Hua P, Shang X-Y, Hu R, Mo X-E, Pan X-P. Predictors of early post-ischemic stroke apathy and depression: A cross-sectional study. BMC Psychiatry 2013; 13: 164.
[43]
Caeiro L, Santos O, Ferro JM, Figueira ML. Neuropsychiatric disturbances in acute subarachnoid haemorrhage. Eur J Neurol 2011; 18: 857-64.
[44]
Caeiro L, Ferro JM, Costa J. Apathy secondary to stroke: A systematic review and meta-analysis. Cerebrovasc Dis 2013; 35: 23-39.
[45]
Mayo NE, Fellows LK, Scott SC, Cameron J, Wood-Dauphinee S. A longitudinal view of apathy and its impact after stroke. Stroke 2009; 40: 3299-307.
[46]
Starkstein SE, Petracca G, Chemerinski E, Kremer J. Syndromic validity of apathy in Alzheimer’s disease. Am J Psychiatry 2001; 158(6): 872-7.
[47]
Kuhlmei A, Walther B, Becker T, Müller U, Nikolaus T. Actigraphic daytime activity is reduced in patients with cognitive impairment and apathy. J Eur Psychiatr 2013; 28: 94-7.
[48]
Benito-León J, Cubo E, Coronell C. on behalf of the ANIMO Study Group. Impact of apathy on health-related quality of life in recently diagnosed Parkinson’s disease: The ANIMO study. Mov Disord 2012; 27(2): 211-8.
[49]
Tang WK, Lau CG, Mok V, Ungvari GS, Wong KS. Apathy and health-related quality of life in stroke. Arch Phys Med Rehabil 2014; 95: 857-61.
[50]
Njomboro P, Humphreys GW, Deb S. Exploring social cognition in patients with apathy following acquired brain damage. BMC Neurology 2014; 14: 18.
[51]
Berridge KC, Kringlebach ML. Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology 2008; 199: 457-80.
[52]
Chau DT, Roth RM, Green AI. The neural circuitry of reward and its relevance to psychiatric disorders. Curr Psychiatr Rep 2004; 6: 391-9.
[54]
Alexander GE, DeLong MR, Strick PR. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci 1986; 9: 357-81.
[55]
Alexander GE, Crutcher MD. Functional architecture of the basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990; 13: 266-71.
[56]
Alexander GE, Crutcher MD, DeLong MR. Basal ganglia-thalamo-cortical circuits: Parallel substrates for motor, oculomotor, “prefrontal” and “limbic” function. Prog Brain Res 1991; 85: 119-46.
[57]
Haber SN, Fudge JL, McFarland NR. Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J Neurosci 2000; 20(6): 2369-82.
[58]
Hong S, Hikosaka O. The globus pallidus sends reward-related signals to the lateral habenula. Neuron 2008; 60: 720-9.
[59]
Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995; 118: 279-306.
[60]
Nachev P, Kennard C, Husain M. Functional role of the supplementary and pre-supplementary motor areas. Nat Rev Neurosci 2008; 9: 856-69.
[61]
Bella R, Pennisi G, Cantone M, et al. Clinical presentation and outcome of geriatric depression in subcortical ischemic vascular disease. Gerontology 2010; 56(3): 298-302.
[62]
Concerto C, Lanza G, Cantone M, et al. Different patterns of cortical excitability in major depression and vascular depression: A transcranial magnetic stimulation study. BMC Psychiatry 2013; 13: 300.
[63]
Pennisi M, Lanza G, Cantone M, et al. Correlation between motor cortex excitability changes and cognitive impairment in vascular depression: Pathophysiological insights from a longitudinal TMS study. Neural Plast 2016; 2016Article ID: 8154969
[64]
Guerra A, Petrichella S, Vollero L, et al. Neurophysiological features of motor cortex excitability and plasticity in subcortical ischemic vascular dementia: A TMS mapping study. Clin Neurophysiol 2015; 126: 906-13.
[65]
Konstantakopoulos G, Ploumpidis D, Oulis P, et al. Apathy, cognitive deficits and functional impairment in schizophrenia. Schizophr Res 2011; 133: 193-8.
[66]
Grool AM, Geerlings MI, Sigurdsoon S, et al. Structural MRI correlates of apathy symptoms in older persons without dementia. The AGES-Reykjavik study. Neurology 2014; 82: 1628-35.
[67]
Mitchell RA, Herrmann N, Lanctôt KL. The role of dopamine in symptoms and treatment of apathy in Alzheimer’s disease. CNS Neurosci Ther 2011; 17: 411-27.
[68]
Stanton BR, Leigh PN, Howard RJ, Barker GJ, Brown RG. Behavioural and emotional symptoms of apathy are associated with distinct patterns of bran atrophy in neurodegenerative disorders. J Neurol 2013; 260: 2481-90.
[69]
Yuen GS, Gunning FM, Woods E, Klimstra SA, Hoptman MJ, Alexopoulos GS. Neuroanatomical correlates of apathy in late-life depression and antidepressant treatment response. J Affect Disord 2014; 166: 179-86.
[70]
Holroyd CB, Yeung N. Motivation of extended behaviors by anterior cingulate cortex. Trends Cogn Sci 2012; 16(2): 122-8.
[71]
Bartra O, McGuire JT, Kable JW. The valuation system: A coordinate-based meta-analysis of BOLD fMRI experiments examining neural correlates of subjective value. Neuroimage 2013; 76: 412-27.
[72]
Bonnelle V, Veromann K-R, Burnett Heyes S, Lo Sterzo E, Manohar S, Husain M. Characterization of reward and effort mechanisms in apathy. J Physiol Paris 2015; 109: 16-26.
[73]
Bonnelle V, Manohar S, Behrens T, Husain M. Individual differences in premotor brain systems underlie behavioural apathy. Cereb Cortex 2106(26): 807-19.
[74]
Holroyd CB, Umemoto A. The research domain criteria framework: The case for anterior cingulate cortex. Neurosci Biobehav Rev 2016; 71: 418-33.
[75]
Rowe JB, Hughes L, Nimmo-Smith I. Action selection: A race model for selected and non-selected actions distinguishes the contribution of premotor and prefrontal areas. Neuroimage 2010; 51: 888-96.
[76]
Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: Rewarding, aversive and alerting. Neuron 2010; 68: 815-34.
[77]
Collins AGE, Frank MJ. Surprise! Dopamine signals mix action, value and error. Nat Neurosci 2016; 19: 3-5.
[79]
Berridge KC. The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology 2007; 191: 391-431.
[80]
Syed ECJ, Grima LL, Magill PJ, Bogacz R, Brown P, Walton ME. Action initiation shapes mesolimbic dopamine encoding of future rewards. Nat Neurosci 2016; 19(1): 34-6.
[81]
Ivanov I, Liu X, Clerkin S, et al. Effects of motivation on reward and attentional networks: an fMRI study. Brain Behav 2012; 2(6): 741-53.
[82]
Westbrook A, Braver TS. Dopamine does double duty in motivating cognitive effort. Neuron 2016; 89: 695-710.
[83]
Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron 2012; 76: 470-85.
[84]
Hamid AA, Pettibone JR, Mabrouk OS, et al. Mesolimbic dopamine signals the value of work. Nat Neurosci 2016; 19(1): 117-26.
[85]
Chung SJ, Lee JJ, Ham JH, Lee PH, Sohn YH. Apathy and striatal dopamine defects in non-demented patients with Parkinson’s disease. Park Rel Dis 2016; 23: 62-5.
[86]
Dan R, Ruzicka F, Bezdicek O, et al. Separate neural representations of depression and apathy in Parkinson’s disease. Sci Rep 2017; 7: 12164.
[87]
Maillet A, Krack P, Lhommée E, et al. The prominent role of serotoninergic degeneration in apathy, anxiety and depression in de novo Parkinson’s disease. Brain 2016; 139: 2486-502.
[88]
Remy P, Doder M, Lees A, Turjansky N, Brooks D. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 2005; 128: 1314-22.
[89]
Adam R, Leff A, Sinha N, et al. Dopamine reverses reward insensitivity in apathy following globus pallidus lesions. Cortex 2013; 49: 1292-303.
[90]
Chong T-JT, Bonnelle V, Manohar S, et al. Dopamine enhances willingness to exert effort for reward in Parkinson’s disease. Cortex 2015; 69: 40-6.
[91]
Czernecki V, Pillon B, Houeto JL, Pochon JB, Levy R, Dubois B. Motivation, reward, and Parkinson’s disease: influence of dopatherapy. Neuropsychologia 2002; 40: 2257-67.
[92]
Muhammed K, Manohar S, Ben Yehuda M, et al. Reward sensitivity deficits modulated by dopamine are associated with apathy in Parkinson’s disease. Brain 2016; 139: 2706-21.
[93]
Rochat L, Van der Linden M, Renaud O, et al. Poor reward sensitivity and apathy after stroke. Neurology 2013; 81: 1674-80.
[94]
Roth RM, Flashman LA, McAllister TW. Apathy and its treatment. Curr Treat Options Neurol 2007; 9: 363-70.
[95]
Berman K, Brodaty H, Withall A, Seeher K. Pharmacologic treatment of apathy in dementia. Am J Geriatr Psychiatry 2012; 20(2): 104-22.
[96]
Antonini A, Bauer L, Dohin E, et al. Effects of rotigotine transdermal patch in patients with Parkinson’s disease presenting with non-motor symptoms - results of a double-blind, randomized, placebo-controlled trial. Eur J Neurol 2015; 22: 1400-7.
[97]
Hauser RA, Slawek J, Barone P, et al. Evaluation of rotigotine transdermal patch for the treatment of apathy and motor symptoms in Parkinson’s disease. BMC Neurology 2016; 16: 90.
[98]
Smith KM, Eyal E, Weintraub D. For the ADAGIO group. Combined rasagiline and anti-depressant use in Parkinson’s disease in the ADAGIO study. Effects on non-motor symptoms and tolerability. JAMA Neurol 2015; 72(1): 88-95.
[99]
Pérez-Pérez J, Pagonabarraga J, Martínez-Horta S, et al. Head-to-head comparison of the neuropsychiatric effect of dopamine agonists in Parkinson’s disease: A prospective, cross-sectional study in non-demented patients. Drugs Aging 2015; 32: 401-7.
[100]
Devos D, Moreau C, Maltête D, et al. Rivastigmine in apathetic but dementia and depressin free patients with Parkinson’s disease: A double-blind, placebo controlled, randomised clinical trial. J Neurol Neurosurg Psychiatry 2014; 85: 668-74.
[101]
Kohno N, Abe S, Toyoda G, Oguro H, Bokura H, Yamaguchi S. Successful treatment of post-stroke apathy by the dopamine receptor agonist ropinirole. J Clin Neurosci 2010; 17: 804-6.
[102]
Kohno N, Nabika Y, Toyoda G, Bokura H, Nagata T, Yamaguchi S. The effect of ropinirole on apathy and depression after herpes encephalitis. Cogn Behav Neurol 2012; 25(2): 98-102.
[103]
Monga V, Padala PR. Aripiprazole for treatment of apathy. Innov Clin Neur 2015; 12(9-10): 33-6.
[104]
Mikami K, Jorge RE, Moser DJ, et al. Prevention of post-stroke apathy using escitalopram or problem-solving therapy. Am J Geriatr Psychiatry 2013; 21(9): 855-62.
[105]
Blundo C, Gerace C. Dopamine agonists can improve pure apathy associated with lesions of the prefrontal-basal ganglia functional system. Ital J Neurol Sci 2015; 36: 1197-201.
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