Without an ability to inhibit behavior or action, it would be impossible to perform even the simplest of everyday tasks. During complex activities such as driving a car, behavior may be stopped, reviewed or changed, perhaps many times within a single minute. Behavior may need to be stopped because it is inappropriate in a particular situation (for example accelerating at traffic lights if the light is red), although the same response might be appropriate elsewhere (when the light turns green), or if there is competition with other possible actions in a set of programmed behaviors (for example accelerating versus braking).
In a broad sense, behavioral inhibition can be viewed as a critical executive-control mechanism that regulates a wide range of cognitive and motor processes with one unified outcome—to prevent the execution of an action. Although this concept of behavioral/motor, inhibition has attracted the interest of psychologists and neuroscientists for many years (reviewed in Aron, 2007
), it is only within the last decade that its neural basis has been studied in great detail, and the recent special issue of Neuroscience and Biobehavioral Reviews
(vol. 33(5), April 2009) on stopping brings this evidence together. This interest has, in part, been directed by clinical studies showing that pathological or maladaptive levels of inhibition failure are common to a number of neuropsychiatric conditions such as attention deficit and hyperactivity disorder (ADHD), Parkinson's disease, schizophrenia, obsessive-compulsive disorder (OCD), chronic substance abuse (e.g., cocaine, amphetamine, methamphetamine), and pathological gambling or shopping (Aron, 2007; Aron and Poldrack, 2005; Bellgrove et al., 2006; Durston et al., 2008; Fillmore and Rush, 2002; Fillmore et al., 2002, 2006; Gauggel et al., 2004; Monterosso et al., 2005; Nigg et al., 2004; Oosterlaan et al., 1998; Penades et al., 2006; Rubia et al., 1998, 2007, 2005; Schachar et al., 2007, 1995; van den Wildenberg et al., 2006
). Indeed, there is now a wealth of evidence to suggest that these behavioral impairments can also be useful markers of genetic risk factors for many of the disorders mentioned above (e.g., Aron and Poldrack, 2005; Congdon et al., 2008; Durston et al., 2008, 2006; LeMarquand et al., 1999; Menzies et al., 2007; Nigg et al., 2004
). For example, deficient motor inhibition has always been considered as one of the key executive function deficits within an integrative model of the ADHD spectrum (e.g., Castellanos et al., 2006
), and test batteries that include measures of inhibition (e.g., stop-signal, go/no-go and delay-discounting tasks) have been used with great success to assess this condition, both in children and adults (Boonstra et al., 2008; Rubia et al., 2007; Sergeant et al., 2003
further defined behavioral inhibition as the control of overt behavior such as motor inhibition, resisting temptation, delay of gratification and impulse control. In the context of neuropsychiatry, these features of behavioral inhibition are most commonly studied in terms of their failure. Suboptimal inhibition is considered to be a critical component of many psychiatric symptoms including impulsivity, compulsivity, perseveration, disinhibition, obsessions, aggression, attention deficits and mania (Aron, 2007
). Thus, while there is normally a balance between behavior and its inhibition that allows us to live and function well, the breakdown of behavioral inhibition mechanisms, in conditions such as those listed above, can result in behavior that is maladaptive or inappropriate. Of particular relevance to this review, behavioral inhibition failure may lead to actions that are ‘impulsive’ (rapid or without adequate planning or forethought, carried out without regard to the negative consequences of these actions), or that are ‘compulsive’ (where the repeated performance of a behavior continues despite adverse consequences, often as part of a ritual or addiction). Both of these forms of behavioral inhibition failure have been investigated extensively in rat studies.
In the clinic, complex test batteries have been designed to include a range of measures of behavioral inhibition. These simple tests, such as the go/no-go and stop-signal tasks, also have the advantage of being easily translated between human and rodent studies without the need for significant changes in experimental design. Therefore, these tests provide a strong framework for cross-talk between clinical and preclinical research during investigation of the neural basis and experimental therapeutics of particular disorders.
Often, these tests are used interchangeably and convergently to assess deficient behavioral inhibition in patients. However, within preclinical research, this unitary concept of behavioral inhibition has become outdated (Cardinal et al., 2004; Evenden, 1999; Winstanley et al., 2006
), following studies, such as that of Evenden (1999)
, which examined sub-types of behavioral inhibition in the context of impulsivity in particular. Indeed, impulsivity is often defined primarily as ‘a lack of behavioral inhibition’, including actions that are premature, mistimed, difficult to suppress and control, and also including impulsive choice, where actions are initiated without due deliberation of other possible options or outcomes (Dalley et al., 2007b
). Furthermore, Evenden (1999)
suggested that these subtypes of impulsivity, or inhibitory deficit, might arise from the dysfunction of different fundamental anatomical and neurochemical mechanisms. For example, different neural substrates may underlie the dichotomy of ‘impulsive action’ (the inability to inhibit a prepotent response) versus ‘impulsive choice’ (the selection of a small, immediate reward in favor of a larger, but delayed, reward) (Cardinal et al., 2004; Winstanley et al., 2006
In parallel, ‘impulsivity’ has been compared with other forms of behavioral inhibition failure, for example, ‘compulsivity’ (recent examples include: Arzeno Ferrao et al., 2006; Belin et al., 2008; Chamberlain et al., 2006a; Chudasama et al., 2003b; Grant and Potenza, 2006; Potenza, 2007
). The clinical relevance of this work is highlighted by addiction research that proposes a transition from impulsive to compulsive behavior during progression from recreactional drug use to addiction (Belin et al., 2009
Despite numerous lines of evidence to the contrary, many clinical studies still define a unitary concept of behavioral inhibition using a wide range of diagnostic tasks interchangeably in its evaluation. One aim of this review is to highlight the pitfalls of such a unitary approach strategy and the limitations that this approach brings to understanding the neural basis of behavioral inhibition mechanisms and their failure. For example, in many clinical studies, the stop-signal task is considered as an equivalent measure of motor inhibition to the go/no-go task, in particular when assessing impulsive action control. However, the stop-signal task measures the speed
at which an already-engaged
response is inhibited, whereas the go/no-go task measures the ability
to inhibit the initiation
of a response. Therefore, the go/no-go task may contain response-selection and ‘waiting’ elements that are absent from inhibition in the stop-signal task, and that are subserved by different neural mechanisms. Indeed, recent evidence has highlighted both anatomical and pharmacological differences between these inhibitory processes (Eagle et al., 2008b; Rubia et al., 2001
In this review we have re-examined aspects of the anatomical and pharmacological basis of behavioral inhibition in the rat in the context of two major new lines of evidence. Firstly, we integrated evidence from the recently developed stop-signal task for rats with existing models of impulsive action (5-choice serial reaction time (5-CSRT) task) and impulsive choice (delay-aversion/delay-discounting task) that have been used extensively in our laboratories (these tasks will be presented in greater detail in the following sections). The stop-signal task is a well-validated model of behavioral inhibition that has been used for many years in clinical studies, of ADHD in particular. As we have said, this task assesses the speed
of the process of inhibition (stop-signal reaction time, SSRT) of an ongoing action. SSRT is widely accepted within the psychological literature as a unique and indisputable form of motor inhibition (MacLeod et al., 2003
) that is increased/impaired in conditions that show symptomatic deficits in behavioral inhibition (Boonstra et al., 2005b; Logan, 1994; Logan and Cowan, 1984; Oosterlaan et al., 1998
). For example, recent reviews have indicated that SSRT is a critical and fundamental component of impulsive-action inhibition (Aron, 2007; Dalley et al., 2007b; Eagle et al., 2008b; Pattij and Vanderschuren, 2008
). However, there are aspects of its modulation within the brain that seriously bring to question the validity of impulsive action as a single construct.
Secondly, we have updated the frontal-basal-ganglia circuitry of behavioral inhibition to include recent evidence for the role of the subthalamic nucleus (STN). The STN is a small cerebral structure that has long been associated with motor processes, since its infarct is known to induce a hyperkinetic-like syndrome, or ‘ballism’ (Whittier, 1947
). More recently, the STN has been targeted surgically in the treatment of Parkinsonism (see Benabid, 2003
for review) and this has necessitated a better understanding of its functional involvement in behavioral control. The STN is conventionally thought of as an output structure of the basal ganglia, acting as part of the indirect, potentially inhibitory, cortico-striato-thalamic circuitry (DeLong, 1990
). Recently, an updated model of basal ganglia organization highlighted the direct connections between the cortex and the STN (the now so-called ‘hyperdirect pathway’), placing the latter in a position to share, with the striatum, the role of ‘major input structure’ to the basal ganglia from the cortex (Levy et al., 1997
) (). This model not only gives more functional importance to the STN, but has also contributed to the STN being seen as a key frontal-cortex target, which therefore should be involved in classical ‘frontal functions’ such as behavioral inhibition. Although a few previous reviews have connected the STN with behavioral inhibition, this structure usually remains missing from, or under-represented within, proposals of inhibitory circuitry (Cardinal, 2006; Dalley et al., 2007b; Robbins, 2002
Fig. 1 Schematic representation of the model of the basal ganglia proposed by Levy et al. (1997). Str: Striatum; Pf: parafascicular nucleus of the thalamus; GPe: External segment of the Globus Pallidus; GPi: Internal segment of the Globus Pallidus; SNpr: Substantia (more ...)
Recent anatomical and behavioral studies have proposed that the hyperdirect pathway, between the frontal cortex (possibly the right inferior frontal cortex in humans) and STN, represents a critical route through which information could be processed rapidly. This is supported by evidence that the STN is strongly implicated in the modulation of inhibition on the stop-signal task: a hyperdirect network could maintain the necessary speed of information-processing during this form of inhibition (see Chambers et al., 2009
). For example, STN activation correlated with faster stopping abilities (Aron and Poldrack, 2006
), and also correlated with activation of the right inferior frontal gyrus (RIFG), a region that has significant associations with stopping (Aron et al., 2003b
Therefore, from the integration of these new lines of evidence, we propose that regions within the frontal-basal-ganglia network might subserve a general mechanism for behavioral inhibition in the rat. Such a system in the human brain, comprising the RIFG, striatum and STN (or RIFG and STN via a hyperdirect pathway) has received considerable recent interest for its ability to perform rapid inhibition of behavioral responses (for review, see Chambers et al., 2009
). The existence of a comparable system in the rat would open up interesting possibilities for translational research into the mechanism of action of behavioral inhibition.