Research report Dopamine reverses reward insensitivity in apathy following globus pallidus lesions Robert Adam a,b , Alexander Leff a,b , Nihal Sinha a,b, *, Christopher Turner b , Paul Bays b , Bogdan Draganski c,d and Masud Husain a,b a UCL Institute of Cognitive Neuroscience, London, UK b UCL Institute of Neurology, London, UK c LREN, Department des neurosciences cliniques - CHUV, Universite de Lausanne, Switzerland d Max-Planck Institute for Human Cognitive and Brain Sciences article info Article history: Received 17 December 2011 Reviewed 3 February 2012 Revised 28 February 2012 Accepted 19 April 2012 Action editor Angela Sirigu Published online 17 May 2012 Keywords: Basal ganglia Motivation Effort Stroke abstract Apathy is a complex, behavioural disorder associated with reduced spontaneous initiation of actions. Although present in mild forms in some healthy people, it is a pathological state in conditions such as Alzheimer’s and Parkinson’s disease where it can have profoundly devastating effects. Understanding the mechanisms underlying apathy is therefore of urgent concern but this has proven difficult because widespread brain changes in neuro- degenerative diseases make interpretation difficult and there is no good animal model. Here we present a very rare case with profound apathy following bilateral, focal lesions of the basal ganglia, with globus pallidus regions that connect with orbitofrontal (OFC) and ventromedial prefrontal cortex (VMPFC) particularly affected. Using two measures of oculo- motor decision-making we show that apathy in this individual was associated with reward insensitivity. However, reward sensitivity could be established partially with levodopa and more effectively with a dopamine receptor agonist. Concomitantly, there was an improvement in the patient’s clinical state, with reduced apathy, greater motivation and increased social interactions. These findings provide a model system to study a key neuropsychiatric disorder. They demonstrate that reward insensitivity associated with basal ganglia dysfunction might be an important component of apathy that can be reversed by dopaminergic modulation. ª 2012 Elsevier Ltd. All rights reserved. 1. Introduction Apathy is widespread in mild forms in many people. Recently it has become clear that it can be a severe behavioural condition in disorders such as Alzheimer’s and Parkinson’s disease (Marin, 1991; Starkstein and Leentjens, 2008). Defined as a state of impassivity associated with a lack of interest, concern or enthusiasm, apathy is dissociable from depres- sion (Marin, 1991). But despite increasing awareness of the condition, we lack a good biological model. This is partly because attempts to understand underlying mechanisms in neurodegenerative diseases are difficult because of wide- spread brain changes. In addition it is now appreciated that apathy is unlikely to be a unitary construct but is more likely to be a syndrome that might result from dysfunction in several different component decision-making mechanisms (Levy and Dubois, 2006). Here, we investigate the possibility that one component of apathy might be relative insensitivity * Corresponding author. UCL Institute of Cognitive Neuroscience, 17 Queen Square, London WC1N 3AR, UK. E-mail address: [email protected](N. Sinha). Available online at www.sciencedirect.com Journal homepage: www.elsevier.com/locate/cortex cortex 49 (2013) 1292 e1303 0010-9452/$ e see front matter ª 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.cortex.2012.04.013
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c o r t e x 4 9 ( 2 0 1 3 ) 1 2 9 2e1 3 0 3
Available online at
Journal homepage: www.elsevier.com/locate/cortex
Research report
Dopamine reverses reward insensitivity in apathy followingglobus pallidus lesions
Robert Adama,b, Alexander Leff a,b, Nihal Sinha a,b,*, Christopher Turner b, Paul Bays b,Bogdan Draganski c,d and Masud Husain a,b
aUCL Institute of Cognitive Neuroscience, London, UKbUCL Institute of Neurology, London, UKc LREN, Department des neurosciences cliniques - CHUV, Universite de Lausanne, SwitzerlanddMax-Planck Institute for Human Cognitive and Brain Sciences
a r t i c l e i n f o
Article history:
Received 17 December 2011
Reviewed 3 February 2012
Revised 28 February 2012
Accepted 19 April 2012
Action editor Angela Sirigu
Published online 17 May 2012
Keywords:
Basal ganglia
Motivation
Effort
Stroke
* Corresponding author. UCL Institute of CogE-mail address: [email protected] (N
0010-9452/$ e see front matter ª 2012 Elsevdoi:10.1016/j.cortex.2012.04.013
a b s t r a c t
Apathy is a complex, behavioural disorder associated with reduced spontaneous initiation
of actions. Although present in mild forms in some healthy people, it is a pathological state
in conditions such as Alzheimer’s and Parkinson’s disease where it can have profoundly
devastating effects. Understanding the mechanisms underlying apathy is therefore of
urgent concern but this has proven difficult because widespread brain changes in neuro-
degenerative diseases make interpretation difficult and there is no good animal model.
Here we present a very rare case with profound apathy following bilateral, focal lesions of
the basal ganglia, with globus pallidus regions that connect with orbitofrontal (OFC) and
ventromedial prefrontal cortex (VMPFC) particularly affected. Using two measures of oculo-
motor decision-making we show that apathy in this individual was associated with reward
insensitivity. However, reward sensitivity could be established partially with levodopa and
apathy in this case is associated with lack of motivation to
obtain rewards. Animal learning theory has proposed that
rewards might in fact constitute the basic goals of voluntary
behaviour (Dickinson and Balleine, 1994). From this perspec-
tive, the absence of sensitivity to rewards would be expected to
have devastating consequences for goal-directed action, just as
one observes in apathy. But note that although this viewmight
account for behaviour in our particular case, apathy is most
likely to be a syndrome that is multidimensional (Cummings,
1993; Levy and Dubois, 2006). In different clinical contexts, it
could potentially result from deficits in other cognitive
components of the decision-making process. Further studies
are required to delineate these components and which specific
deficits occur in different clinical conditions. Our study repre-
sents progress towards understanding one component of
apathy e namely, relative reward insensitivity.
Although cases such as KD with bilateral GPi lesions are
rare, apathy is common in Parkinson’s disease (Oguru et al.,
2010; Pedersen, et al., 2009; Starkstein, 2009), as well as in
other neurodegenerative disorders, including Huntington’s
and Alzheimer’s disease (Bonelli and Cummings, 2008; Chow
et al., 2009; Starkstein et al., 2006; Marin, 1991). These condi-
tions often involve disruption of cortico-striato-thalamo-
cortical loops (Alexander et al., 1986) but the mechanisms
underlying apathy when there is widespread neuro-
degeneration has been difficult to study. Focal lesion cases
such as KD provide important information about the neural
substrates underlying apathy and modulation of this behav-
ioural state with neuropharmacological intervention.
Acknowledgements
This research was supported by The Wellcome Trust and
NIHR BRC at UCLH/UCL. We thank KD for his participation in
these studies.
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