Apathy Following Stroke
Ricardo E Jorge, MD^; Sergio E Starkstein, MD^; Robert G Robinson,
Objective: We will review the available evidence on the frequency, clinical correlates, mechanism, and
treatment of apathy following stroke.
Methods: We have explored relevant databases (that is, PubMed, MEDLINE, and PsyclNFO) using the
following key words and their combinations: apathy, motivation, abulia, stroke, cerebrovascular disease,
basal ganglia, prefrontal cortex, anterior cerebral infarction, and thalamus.
Results: The frequency of apathy following stroke has been consistently estimated between 20% and 25%.
It appears to be associated with the presence of cognitive impairment, a chronic course characterized by
progressive functional decline, and with disruption of neural networks connecting the anteriorcingulate
gyrus, the dorsomedial frontal cortex, and the frontal pole with the ventral aspects of the caudate nucleus,
the anterior and ventral globus pallidus, and the dorsomedian and intralaminar thalamic nuclei. Published
treatment studies have been mostly limited to anecdotal case reports, generally using dopamine agonists
or stimulant medications. Cholinesterase inhibitors and nefiracetam may significantly reduce apathetic
symptoms. However, their efficacy was examined in relatively small clinical trials that require replication.
Conclusion: Apathy is a frequent neuropsychiatrie complication of stroke that, although often associated
with depression and cognitive impairment, may occur independently of both. Its presence has been
consistently associated with greater functional decline. However, there is no conclusive evidence about
which is the best treatment for this condition.
Can J Psychiatry. 2010;55(6):350-354.
• Although apathy is a frequent and debilitating condition following stroke, there is a paucity of controlled
clinical trials on the efficacy of current therapeutic options, such as dopaminergic agents, stimulants,
or cholinesterase inhibitors.
• Other drugs with the potential of modulating neurotransmission in multiple projection systems should
also be rigorously tested.
• We have restricted our search to published English-language studies that were included in the
Key Words: apathy, motivation, abulia, stroke, cerebrovascular disease
the harmful influence of passions. However, during the
nineteenth century, at the inception of modem psychiatric
nosology, apathy turned to be regarded as a morbid negative
state affecting free will, intellectual capacity, and emotional
responsiveness.' In 1991, Marin formulated apathy as an
independent neuropsychiatrie syndrome. He described the
phenomenological aspects of apathy around the concepts of
reduced goal-directed behaviour (as manifested by lack of
effort, initiative, and productivity), reduced goal-directed
cognition (as manifested by decreased interests, lack of plans
pathy was initially conceptualized by stoic philosophers
as a desirable and virtuous state of the soul, free from
and goals, and lack of concern about one's own health or
functional status), and reduced emotional concomitants of
goal-directed behaviours (as manifested by flat affect, emo-
tional indifference, and restricted responses to important life
events). However, it is unclear if changes in emotional
experience and emotional expression should be considered
an essential component of apathy or if this can occur inde-
pendently of anhedonia and blunted emotional reactivity. Other
investigators have questioned whether the psychological
concept of motivation is appropriate to describe the behav-
ioural changes observed after brain damage.^ These investi-
gators emphasize that the lack of spontaneity observed
La Revue canadienne de psychiatrie, voi 55, no 6, juin 2010
Apathy Following Stroke
among apathetic patients can be reverted by external cues.^ In
this sense, constructs such as the auto-activation deficit^ and
athymhormia'' describe pathological states in which patients
are incapable of self-initiating goal-directed activities but
respond normally to behavioural prompting.
There are different instruments to assess the presence of
apathy. In the early 1990s, Marin and colleagues^'^ developed
the Apathy Evaluation Scale, an 18-item scale that can be
administered as a self-rated scale, as a caregiver
paper-and-pencil test, or as a clinician-administered test. The
scale provided a conceptual framework for the diagnosis of
apathy and a reliable measure of its severity. In the following
years, although other instruments were designed to assess the
frequency and severity of apathetic symptoms,^"'" there was
not a clear formulation of specific diagnostic criteria.
Starkstein et al" have recently proposed a set of criteria along
with a structured interview to diagnose apathy in dementia.
The structured interview includes questions assessing the lack
of motivation domains relative to a person's previous level of
ñmctioning, lack of effort to perform ADL, dependency on
others to structure activity, lack of interest in learning new
things or in new experiences, lack of concem about one's per-
sonal problems, unchanging or flat affect, and lack of emo-
tional response to positive or negative personal events (Table
1). However, as we gradually move into the DSM-V nomen-
clature, there is a need for ñirther discussion and consensus on
the denning characteristics of apathy as a syndrome.
Apathy is more frequent among people with sonie degree of
cognitive impairment, such as inay be observed among
patients with stroke, Alzheimer disease, or Parkinson
disease.'"'^''^ Consistently, most studies assessirig apathy in
various neurological disorders reported relatively low MMSE
scores for patients with apathy,'"* Compared with those ,\yho
are not apathetic. •
However, cognitive deficits are not sufficient to produce
apathy, given that a significant proportion of people with
JTioderate or severe dementia do not show apathy.'^''^
Similarly, although apathy is more frequent among patients
with depressive disorders, particularly major depression, t:hey
should be considered as distinct syndromes with diffei-ent
clinical features as well<as prognostic and treatment iniplica-
tions. " Further, apathy and disinhibition could alternate iri the
same person. In fact, several studies demonstrated a significaht
Abbreviations used in this article
AAD auto-activation deficit
ADL activities of daiiy living
FiM Functional independence iVIeasure
MMSE Mini-Mentai State Examination
. NAA-Gr N-acetyläspartate-creatine fatio -
rCBF regionai cerebrai biood fipw '
association between apathy and disinhibition in patients with
This review will focus on apathetic syndromes observed
following stroke. We have explored relevant databases (that
is, PubMed, MEDLINE, and PsycINFO) using the following
key words and their combinations: apathy, motivation,
abulia, stroke, cerebrovascular disease, basal ganglia,
prefrontal cortex, anterior cerebral infarction, and thalamus.
In addition, we have explored the references cited in the arti-
cles retrieved by our original search.
Apathy in Stroke
Apathy has been consistently described among patients with
cerebrovascular disease. Starkstein et al'^ examined the fre-
quency and correlates of apathy in a series of 80 patients with
stroke. Using a cut-off score of 12 on the Apathy Scale (an
abridged version of the Apathy Evaluation Scale), Starkstein
et al'^ found that 18 of 80 consecutive patients (22.5%) admit-
ted to hospital with an acute cerebroyascular lesion met this
criterion for apathy. Among the 18 patients with apathy, 9
(50%) had associated major or minor depression. Poststroke
apathy was also significantly associated with older age, cogni-
tive impairnient; and impairnient in ADL; as well as lesions of
the posterior limb of the internal capsule.'^
Angelellj et aP" administered the Neuropsychiatrie Inventory to
a group of 124 stroke patients, divided jnto 3 groups on the basis
of time from stroke (2, 6, and 12 mcinths) and to 61 healthy
subjects. Apathy was significantly more frequent arnong
stroke patients. It was diagnosed in'33 patients (27%), and
depressive disorder was diagnosed in 76 patients (61 %).^*' In
this series, apathy was more frequent in the chronic phase
(that is, àt 6 and 12 months) than ih the subaCute stage. There
were no significarit associations with the severity of impainnent
and stroke location.'^"
Brodaty et aP' compared the frequency and correlates of apathy
ahiong 135 patients with ischémie stroke and 109 control
subjects rriatched for sex and age. Patiients were assessed 3 to
6 months after their stroke. Apathy was diagnosed in 26.7%
of stroke patients, compared to 5.4% of control subjects.
Consistent with previous results, apathetic stroke patients
were older, more functionally dependent, and more
cognitively impaired than those without apathy. There was
not significant correlation betweeri apathy and depression as
diagnosed by al clinical interview.^ Apathy was riot related to
the type, location, volume; or severity of stroke. However,
apathetic patients were more likely to present right frontal
Hama et aP^ used the Neuropsychiatrie Inventory to assess
the frequency of depression and apathy among 237 Japanese
stroke patients. Depression was observed in 88 patients
(40.2%) and apathy in 42 (19.2%). In addition, they exam-
iried whether severity of depressive or apathetic symptoms
had a negative impact on ADL recovery measured by the
The Canadian Journal of Psychiatry, Voi 55, No'6, June 2010
FIM. Multiple regression analysis revealed that, in this sam-
ple of stroke patients, the severity of apathetic symptoms but
not the severity of depressive symptoms was inversely corre-
lated with improvement in FIM.^^ These investigators also ana-
lyzed the relation between the presence of apathy and
depression and the location of stroke. The severity of
depressive symptoms was associated with left frontal lobe
(but not basal ganglia) damage, while the severity of apathetic
symptoms was related to damage to the bilateral basal ganglia
(but not to the frontal ^^
Santa et aP examined the frequency of apathy among 67 stroke
patients within 3 months after their first ischémie or hemor-
rhagic stroke, excluding those with dementia or significant
aphasia. From the Apathy Scale, 14 patients (21%) were diag-
nosed as being apathetic. The apathetic patients were older and
more cognitively impaired than patients without apathy. In
addition, following rehabilitation therapy, apathetic patients
showed less improvement in physical disability and ftxnctional
independence than nonapathetic patients.^''
In summary, the frequency of apathy following stroke has
been consistently estimated between 20% and 25%. It appears
to be associated with the presence of cognitive impairment, a
chronic course characterized by progressive functional
decline, and with disruption of basal ganglia circuits.
Previous studies suggest an association between apathy
following stroke and damage to frontal-subcortical networks.
For instance, Starkstein and Manes^^ reported that apathy was
associated with the presence of internal capsule lesions
involving the pallidal and nigral output to the thalamus. In a
classic paper, Bhatia and Marsden^* reviewed the behavioural
and movement disorders reported in 240 patients with lesions
affecting the caudate nucleus, putamen, and the globus
pallidus. They found that apathy (abulia) was observed in
30 patients (13%). Lesions of the caudate nucleus were more
likely to cause significant apathetic symptoms. These were
observed among 18 of 64 (28%) patients with caudate lesions,
15 of which were unilateral. Conversely, apathy was not
observed with lesions of the putamen, suggesting that lesions
of the motor loop do not produce significant motivational
Ischémie lesions of the anterior cerebral artery territory
have been also associated with apathy.^^ A recent study^* of a
100 patients with anterior cerebral artery infarction found that
43 patients presented with hypobulic syndromes. Apathy was
related to lesions located in the fontal pole, cingulate gyrus,
and superior medial frontal gyrus. It also occurred more
frequently in patients with bilateral lesions, followed by
left-sided lesions.^* In addition, apathy may be a prominent
feature of thalamic strokes, particularly those involving the
territory of the paramedian arteries, including the
dorsomedian and intralaminar thalamic nuclei.^'
Table 1 Diagnostic criteria for apathy
(adapted from Marin^")
A. Lack of motivation relative to the patient's previous level of
functioning or the standards of his or her age and culture as
indicated either by subjective account or observation by
B. Presence, while with lack of motivation, of at least
1 symptom belonging to each of the following 3 domains:
1. Diminished goal-directed behaviour
• Lack of effort
• Dependency on others to structure activity
2. Diminished goal-directed cognition
• Lack of interest in learning new things, or in new ex-
• Lack of concern about one's personal problems
3. Diminished concomitants of goal-directed behaviour
• Unchanging affect
• Lack of emotional response to positive or negative
C. The symptoms cause clinically significant distress or
impairment in social, occupational, or other important areas
D. The symptoms are not due to diminished level of
consciousness or the direct physiological effects of a
substance (for example, a drug of abuse, a medication).
Overall, these findings suggest that apathy is related to the
disruption of neural networks connecting the anterior
cingulate gyrus, the dorsomedial frontal cortex, and the frontal
pole with the ventral aspects of the caudate nucleus, the anterior
and ventral globus pallidus, and the dorsomedian and
intralaminar thalamic nuclei. However, functional studies
probing the integrity of these circuits in apathetic stroke
patients have been rare and showed contradictory results. For
instance, Okada et aP° examined the relation between rCBF
and severity of apathetic symptoms in 40 elderly stroke
patients (mean age, 71.4 years), one-half of whom showed
apathy. The apathetic group showed a significantly reduced
rCBF in the right dorsolateral frontal and left frontotemporal
regions. Moreover, apathy scores were negatively correlated
with rCBF in the same regions.^" In addition, a recent study^'
used single voxel proton magnetic resonance spectroscopy to
compare frontal lobe NAA-Cr ratios between 31 patients
with ischémie stroke that did not involve the frontal lobes and
20 healthy subjects. Among the 31 patients, 13 (42%) presented
an apathetic syndrome. NAA-Cr ratios were significantly
reduced in the right frontal lobes of apathetic patients with
left-sided brain lesions, suggesting a laterality effect.^'
Another study^^ examined novelty processing in a group of
stroke patients with and without apathy. Processing of novel
events was quantitated by the latency and amplitude of
brain-evoked potentials elicited by task-irrelevant novel
• La Revue canadienne de psychiatrie, vol 55, no 6, juin 2010
Apathy Foiiowing Stroke
Stimuli (novelty P3). The apathetic group was more
eognitively impaired and showed significantly prolonged and
reduced novelty-related potentials over the frontal lobe,
suggesting that P3 is a useful physiological measure for apathy
following stroke.^^ Finally, Schmidt el al" studied graded
motor responses from 13 patients with bilateral basal ganglia
lesions and AAD and 13 patients with Parkinson disease in
their off state. They developed a behavioural paradigm con-
trasting the force levels elicited to squeeze a hand grip as a
result of externally driven cues to the force levels generated
through a self-driven task based on the expectation of different
monetary rewards. Patients with AAD did not differ from
patients with Parkinson disease in motor responses to external
instructions or affective response to monetary incentives
assessed by skin conductance tests. However, unlike the
changes observed in patients with Parkinson disease, they
failed to vary their grip force according to the different mone-
tary incentives. The authors concluded that although AAD
patients had preserved motor control and normal affective
appraisal of positive rewards, they were unable to integrate
their expected value into their motor output." Interestingly,
this impairment appears to be unrelated to dopaminergic
Despite a growing interest in apathy, published treatment
studies-''*'" have been mostly limited to anecdotal case
reports, generally using dopamine agonists or stimulant
medications. For instance, a patient with prominent apathy
secondary to multiple subcortical infarcts was treated suc-
cessfully with methylphenidate.^* Single photon emission
computed tomography and reaction time testing showed
selective improvement of frontal system function.^*
Whyte et aF' examined the effect of acetylcholinesterase
inhibitors on functional recovery from ischémie stroke. Par-
ticipants received galantamine (maximum dose, 24 mg/day)
or donepezil (maximum dose, 10 mg/day) for 12 weeks.
Donepezil-treated participants experienced a 14-point greater
improvement in the FIM motor score, compared with either
galantamine-treated participants or an historical comparator
group. Change in apathy, but not in cognition, was also associated
with change in the FIM motor ^^
Nefiracetam is a novel cyclic gamma-aminobutyric com-
pound that has been demonstrated in animal studies to
enhance aminergic, glutamatergic, and cholinergic
neurotransmission by stimulating alpha-4, beta-2 type
neuronal nicotinic acetylcholine receptors.'"'^' In addition,
nefiracetam increased brain-derived neurotrophic factor
expression as well as rCBF and glucose use after sustained
cerebral ischemia in rats.'**'*^ Robinson et al"*^ have conducted
a 12-week randomized double-blind, placebo-controlled trial
assessing the efficacy of nefiracetam for treatment of
poststroke depression". Within 3 months of an index stroke,
159 patients with major depression were randomly assigned to
receive placebo, 600 or 900 mg nefiracetam, and evaluated at 4,
9, and 12 weeks using the 17-item version of the Hamilton
Depression Rating Scale"*' as the primary outcome measure.
Robinson et al"*^ found that nefiracetam was not more effica-
cious than placebo in treating depressive disorder."*^ This was
largely due to a high placebo response in this group of stroke
patients. However, Robinson et al"*^ performed a secondary
analysis of this trial focusing on the efficacy of nefiracetam,
compared with placebo, in treating apathy following stroke.
Among the 137 patients who had at least 4 weeks of treat-
ment, 70 patients (51.1%) met diagnostic criteria for apathy
as well as major depression owing to stroke. Robinson et al"*^
found that poststroke apathy associated with major depres-
sion was significantly improved using 900 mg/day of
nefiracetam, compared with a lower dose of nefiracetam
(600 mg) or placebo. Further studies should assess
whether apathy without depression may also respond to this
In summary, although apathy is a frequent and debilitating
condition following stroke, there is a paucity of controlled
clinical trials on the efficacy of current therapeutic options
such as dopaminergic agents, stimulants, or cholinesterase
inhibitors. Other drugs with the potential of modulating
neurotransmission in multiple projection systems should also
be rigorously tested.
The Canadian Psychiatric Association proudly supports the In
Review series by providing an honorarium to the authors.
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Manuscript received and accepted September 2009.
' Associate Professor, Departtnent of Psychiatry, Carver College of Medicine,
The University of Iowa, Iowa City, Iowa.
^ Professor, School of Psychiatry and Clinical Neurosciences, The
University of Western Australia, Perth, Australia, and Fretnantle
Hospital, Fremantle, Australia
' Paul W Penningroth Chair, Professor and Head, Department of
Psychiatry, Carver College of Medicine, The University of Iowa, Iowa
Address for correspondence: Dr RE Jorge, Department of Psychiatry,
The University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242;
Résume: L'apathie consécutive à un accident vascuiaire cérébrai
Objectif : Nous examinerons les preuves disponibles sur la fréquence, les corrélats cliniques, le mécanisme, et le traitement
de l'apathie consécutive à un accident vascuiaire cérébral (AVC).
Méthodes : Nous avons exploré les bases de données pertinentes (c'est-à-dire, PubMed, MEDLINE, et PsycINFO) à l'aide
des mots clés suivants et des combinaisons de ceux-ci : apathie, motivation, aboulie, accident vascuiaire cérébral, maladie
vascuiaire cérébrale, noyaux gris centraux, cortex préfrontal, infarctus cérébral antérieur, et thalamus.
Résultats : La fréquence de l'apathie consécutive à un AVC est habituellement estimée entre 20 % et 25 %. Elle semble être
associée à la présence d'une déficience cognitive, une évolution chronique caractérisée par un déclin fonctionnel progressif, et
à une perturbation des réseaux neuronaux reliant le gyrus du cingulum antérieur, le cortex frontal dorsomédial, et le pôle
frontal avec les aspects ventraux du noyau caudé, le pallidum antérieur et ventral, et le noyau thalamique dorsomedian et
intralaminaire. Les études de traitements publiées se limitent pour la plupart à des exposés de cas anecdotiques, utilisant
généralement des agonistes de la dopamine ou des psychostimulants. Les inhibiteurs de la cholinestérase et le nefiracetam
peuvent réduire significativement les symptômes de l'apathie. Cependant, leur efficacité a été examinée dans des essais
cliniques relativement restreints qui exigent une répétition.
Conclusion : L'apathie est une complication neuropsychiatrique fréquente de l'AVC qui, bien que souvent associée à la
dépression et à la déficience cognitive, peut survenir indépendamment de ces deux dernières. Sa présence est régulièrement
associée à un déclin fonctionnel accru. Toutefois, il n'y a pas de données probantes concluantes à propos de ce qui constitue
le meilleur traitement de cette affection.
La Revue canadienne de psychiatrie, vol 55, no 6, juin 2010
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