Decision-making Cognition in Neurodegenerative Diseases

Ezequiel Gleichgerrcht; Agustín Ibáñez; María Roca; Teresa Torralva; Facundo Manes

Neuroanatomy of Decision-making

Human social interactions are extremely complex, and decisions can be influenced by factors such as adaptive strategies, personal preferences, reward evaluation, reinforcement learning, social cooperation, competition and control, as well as other parameters, including uncertainty, ambiguity and probability.^[20,48–50] Given the complexity of decision-making, the fact that no single convergent model has yet been proposed is, perhaps, not surprising. Nevertheless, a consensus has been reached concerning a number of fundamental aspects of decision-making. For example, normal decision-making is thought to require an extended neural network, mainly comprising the frontostriatal and limbic loops including serotonergic and dopaminergic pathways, the lateral, medial and orbitofrontal cortex, the striatum, amygdala, basal ganglia, and anterior cingulate cortex.^{[20,48,49,51]} Furthermore, the prefrontal cortex seems to have a critical role in reinforcement-guided decision-making.^[52–54]

Three main systems have been suggested to be involved in decision-making: a 'stimulus encoding system', an 'action selection system' and an 'expected reward system' (Figure 1). The stimulus encoding system is important during the evaluation stages of decision-making, and this initial stage seems to be strongly associated with activity in the ventromedial prefrontal cortex, striatum^[49] and orbitofrontal cortex,^[54,55] and in dopaminergic pathways involving the ventral tegmental area, nucleus accumbens, striatum, and frontal cortex.^[49]

(Enlarge Image)

Figure 1.

A neuroanatomical model of decision-making. Three main systems are thought to be involved in decision-making: a stimulus encoding system (orbitofrontal cortex shown in red), an action selection system (anterior cingulate cortex shown in green) and an expected reward system (basal ganglia and amygdala shown in blue). Other brain areas that are involved in decision-making include the ventromedial prefrontal cortex (stimulus encoding), the lateral prefrontal and parietal cortices (action selection), and the insula (expected reward).

The action selection system is involved in learning and subjective value encoding. Actions that follow a decision seem to be processed predominantly in the anterior cingulate cortex.^[55,56] Related processes, such as error perception, as well as exploratory actions and voluntary choices, are also processed in the anterior cingulate cortex.^[55] The lateral prefrontal cortex and lateral and medial intraparietal cotices are also activated during this stage of the decision-making process.^[49]

The expected reward system is associated with activity in the amygdala, insula cortex, basal ganglia—including the caudate nucleus, putamen and globus pallidus—and the orbitofrontal cortex.^[48,57] Reward-based decision-making can be affected by the brain reward system, which consists of the ventral tegmental area, ventral striatum, prefrontal cortex and amygdala.^[57] The amygdala also seems to have an important role in emotional learning, which can affect decision-making.^[51] The dopaminergic system is thought to modulate the expected reward system, as activity of this system relates to reward learning and prediction of errors.^[48,56] In fact, learning the subjective value of objects is critically dependent on midbrain dopamine levels.^[49,53]

In addition to these three components, other brain areas are thought to influence decision-making. For example, 'social' paradigms of decision-making—tasks that test an individual's ability to consider the preferences or choices of others—seem to require functioning of brain areas that are associated with theory of mind (ToM), such as the paracingulate cortex, in addition to the striatum, insula cortex, and orbitofrontal cortex.^[48,49] Moreover, 'special' forms of decision-making, such as moral decision-making, seem to be associated with activity in the orbitofrontal and dorsolateral prefrontal cortex, cingulate cortex, precuneus and temporoparietal junction.^[58] Furthermore, when complex decisions are being made, activity in the insula and posterior cingulate cortex is known to modulate the activity of the prefrontal cortex,^[54] and simple tasks involving human volition can engage presupplementary and parietal areas during decision-making.^[59] Notably, the numerous brain areas mentioned above interact during different processes. For example, the orbitofrontal cortex is involved not only in evaluation of stimuli but also in prediction of rewards.^[57] Similarly, brain areas not classically related to decision-making under ambiguity—the cingulate and parietal cortices—seem to be required for successful performance on the IGT.^[23,60] For instance, some patients with lesions in the anterior cingulate cortex might perform normally in the Stroop and Go/No-go tasks,^[26] which require action selection—participants must choose between competing stimuli—yet show impaired performance on tasks of decision-making. In summary, decision-making requires coordinated activity within a wide variety of brain areas and neural networks.

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Table 1. Summary of main studies of decision-making cognition in FTD
Study	Participants	Decision-making paradigm	Correlation with EF	Other multivariate comparison?	Brain and/or peripheral biomarker?	Main results
Rahman et al. (1999)⁶⁶	8 FTD, 8 controls	CGT	No	No	No	Deficit in risk adjustment and risk-taking behavior, and increased deliberation times in patient group
Rahman et al. (2005)⁶⁷	8 FTD	CGT	No	No	Yes: cardiovascular	Attenuation of risk-taking behavior following single dose (40 mg) of methylphenidate
Torralva et al. (2007)⁶⁸	20 FTD, 10 controls	IGT	No	Yes: no correlations	No	Poor performance on IGT independent of ToM deficits
Torralva et al. (2009)⁷²	35 FTD, 14 controls	IGT	Yes: impaired mental flexibility on WCST	Yes: no correlations	No	Poor performance on IGT
Manes et al. (2010)⁷⁴	FTD (1)	IGT	No	No	No	Genuine risk-taking behavior

Abbreviations: CGT, Cambridge Gambling Task; EF, executive functions; FTD, frontotemporal dementia; IGT, Iowa Gambling Task; ToM, Theory of Mind; WCST, Wisconsin Card Sorting Test.

Table 2. Summary of main studies on decision-making in AD
Study	Participants	Decision-making paradigm	Correlation with EF	Other multivariate comparison?	Brain and/or peripheral biomarker?	Main results
Torralva et al. (2000)⁷⁵	25 AD, 20 controls	IGT	Yes: impaired memory	Yes: no correlations	No	Patients with AD had impaired performance on IGT
Delazer et al. (2007)⁴³	19 AD, 25 controls	GDT	Yes: impaired set-shifting within the patient group	No	No	Patient group displayed no risky behavior or any evidence of strategic thinking
Sinz et al. (2008)³⁷	22 AD, 22 controls	IGT and PAG	Yes: deficient inhibitory control, deficits in motor programming in the patient group	No	No	Decision-making under ambiguity and decision-making under risk were impaired in patients with mild AD, characterized by a lack of advantageous strategies

Abbreviations: AD, Alzheimer disease; EF, executive functions; GDT, Game of Dice Task; IGT, Iowa Gambling Task; PAG, Probability-Associated Gambling.

Table 3. Summary of main studies of decision-making in PD
Study	Participants	Decision-making paradigm	Correlation with EF	Other multivariate comparison?	Brain and/or peripheral biomarker?	Main results
Czernecki et al. (2002)⁸⁷	23 PD, 28 controls	IGT	Yes: decreased "frontal score" in patient group	Yes: demographic variables	No	No benefit of levodopa administration on decision-making
Cools et al. (2003)⁸⁸	12 PD, 20 controls	CGT	No	No	No	Patients 'on' medication exhibited abnormal decision-making strategies
Thiel et al. (2003)⁶¹	5 PD, 5 controls	IGT	No	No	Yes: decreased activity in fronto-subcortical loops	No deficit on the IGT
Brand et al. (2004)⁴¹	20 PD, 20 controls	GDT	Yes: impaired mental flexibility and set-shifting on MCST in patient group	Yes: emotional feedback processing	No	Patients with PD preferred selecting cards from the disadvantageous decks
Perreta et al. (2005)⁸⁹	16 early PD, 16 late PD, 19 controls	IGT	No	Yes: BDI total score in early PD	No	Both PD groups presented with learning impairments
Mimura et al. (2006)⁹⁰	18 PD, 40 controls	IGT	No	Yes: affective component of ToM	No	Patients with PD had deficits in decision-making, which correlated with affective ToM
Pagonabarraga et al. (2007)⁹⁵	35 PD, 31 controls	IGT	No	Yes: memory and GCP	No	More-severe deficits on the IGT associated with better general cognitive performance
Kobayakawa et al. (2007)⁹⁶	34 PD, 22 controls	IGT	No	Yes: emotional responses and SCR	Yes: decreased SCRs	Patients with PD selected more disadvantageous decks on the IGT and their SCR was lower than controls
Ibarretxe-Bilbao et al. (2009)⁹⁸	24 early PD, 24 controls	IGT	No	Yes: Ekman total score and RDS	Yes: gray matter loss in the right amygdala and in the OFC	Patients with PD had impaired decision-making on the IGT; volume in left lateral orbitofrontal cortex showed a slight correlation with IGT scores in the patient group
Euteneuer et al. (2009)⁹⁹	21 PD, 23 controls	IGT, GDT	Yes: impaired EFs with GDT but not IGT	No	Yes: impaired EDRs	Patients with PD were significantly impaired on the GDT, but not on the IGT
Delazer et al. (2009)¹⁰⁰	20 PD, 19 PDD, 20 controls	IGT, PAG	Yes: deficits in several EFs in the PD group	No	No	Both PD and PPD groups demonstrated impaired decision-making under ambiguity; but only the PDD group was impaired on the PAG
Poletti et al. (2010)¹⁰¹	30 PD, 25 controls	IGT	No	No	No	Patients with PD were unimpaired on the IGT

Abbreviations: BDI, Beck Depression Inventory; CGT, Cambridge Gambling Task; EDRs, electrodermal responses; EF, executive functions; GCP, global cognitive performance; GDT, Game of Dice Task; IGT, Iowa Gambling Task; MCST, Modified Card Sorting Test; OFC, orbitofrontal cortex; PAG, Probability-Associated Gambling; PD, Parkinson disease; PDD, Parkinson disease with dementia; RDS, reverse digit span; SCR, skin conductance response; ToM, Theory of Mind.

Table 4. Summary of main studies of decision-making in HD
Study	Participants	Decision-making paradigm	Correlation with EF reported?	Other multivariate comparison?	Brain and/or peripheral biomarker?	Main results
Watkins et al. (2000)¹⁰³	20 HD, 25 controls	CGT	Yes: impaired visuospatial planning	Yes: activities of daily living scores	No	Unimpaired decision-making in patients with HD
Stout et al. (2001)¹⁰⁶	14 HD, 20 PD, 31 controls	IGT	No	Yes: MDRS	No	Decision-making deficits in HD group owing to learning and memory deficits
Busemeyer & Stout (2002)¹⁰⁷	14 HD, 20 PD, 31 controls	IGT	No	No	No	Altered decision-making in HD group owing to deficits in working memory
Campbell et al. (2004)¹⁰⁸	15 HD, 16 controls	IGT	No	No	Yes: decreased skin conductance response in patients with HD	Altered decision-making in patients with HD owing to learning and memory deficits

Abbreviations: CGT, Cambridge Gambling Task; EF, executive functions; HD, Huntington disease; IGT, Iowa Gambling Task; MDRS, Mattis Dementia Rating Scale; PD, Parkinson disease.

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Decision-making Cognition in Neurodegenerative Diseases

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