Adam R. Aron

Inhibition and the right inferior frontal cortex

It is controversial whether different cognitive functions can be mapped to discrete regions of the prefrontal cortex (PFC). The localisationist tradition has associated one cognitive function - inhibition - by turns with dorsolateral prefrontal cortex (DLPFC), inferior frontal cortex (IFC), or orbital frontal cortex (OFC). Inhibition is postulated to be a mechanism by which PFC exerts its effects on subcortical and posterior-cortical regions to implement executive control. We review evidence concerning inhibition of responses and task-sets. Whereas neuroimaging implicates diverse PFC foci, advances in human lesion-mapping support the functional localization of such inhibition to right IFC alone. Future research should investigate the generality of this proposed inhibitory function to other task domains, and its interaction within a wider network.

Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans.

The precise localization of executive functions such as response inhibition within the prefrontal cortex (PFC), although theoretically crucial, has proven to be controversial and difficult. Functional neuroimaging has contributed importantly to this debate, but as human cortical lesions are seldom discrete, the literature still lacks definitive neuropsychological evidence that a specific region is necessary for task performance. We overcame this limitation by using a new observer-independent method to relate the degree of damage within a specific prefrontal region to performance on a stop-signal task that is sensitive to the neurodevelopmental aspects of stopping behavior and to attention-deficit/hyperactivity disorder (ADHD) as well as its amelioration by methylphenidate.

Cortical and Subcortical Contributions to Stop Signal Response Inhibition: Role of the Subthalamic Nucleus

Suppressing an already initiated manual response depends critically on the right inferior frontal cortex (IFC), yet it is unclear how this inhibitory function is implemented in the motor system. It has been suggested that the subthalamic nucleus (STN), which is a part of the basal ganglia, may play a role because it is well placed to suppress the “direct” fronto-striatal pathway that is activated by response initiation. In two experiments, we investigated this hypothesis with functional magnetic resonance imaging and a Stop-signal task. Subjects responded to Go signals and attempted to inhibit the initiated response to occasional Stop signals. In experiment 1, Going significantly activated frontal, striatal, pallidal, and motor cortical regions, consistent with the direct pathway, whereas Stopping significantly activated right IFC and STN. In addition, Stopping-related activation was significantly greater for fast inhibitors than slow ones in both IFC and STN, and activity in these regions was correlated across subjects. In experiment 2, high-resolution functional and structural imaging confirmed the location of Stopping activation within the vicinity of the STN. We propose that the role of the STN is to suppress thalamocortical output, thereby blocking Go response execution. These results provide convergent data for a role for the STN in Stop-signal response inhibition. They also suggest that the speed of Go and Stop processes could relate to the relative activation of different neural pathways. Future research is required to establish whether Stop-signal inhibition could be implemented via a direct functional neuroanatomic projection between IFC and STN (a “hyperdirect” pathway).

Triangulating a Cognitive Control Network Using Diffusion-Weighted Magnetic Resonance Imaging (MRI) and Functional MRI

The ability to stop motor responses depends critically on the right inferior frontal cortex (IFC) and also engages a midbrain region consistent with the subthalamic nucleus (STN). Here we used diffusion-weighted imaging (DWI) tractography to show that the IFC and the STN region are connected via a white matter tract, which could underlie a “hyperdirect” pathway for basal ganglia control. Using a novel method of “triangulation” analysis of tractography data, we also found that both the IFC and the STN region are connected with the presupplementary motor area (preSMA). We hypothesized that the preSMA could play a conflict detection/resolution role within a network between the preSMA, the IFC, and the STN region. A second experiment tested this idea with functional magnetic resonance imaging (fMRI) using a conditional stop-signal paradigm, enabling examination of behavioral and neural signatures of conflict-induced slowing. The preSMA, IFC, and STN region were significantly activated the greater the conflict-induced slowing. Activation corresponded strongly with spatial foci predicted by the DWI tract analysis, as well as with foci activated by complete response inhibition. The results illustrate how tractography can reveal connections that are verifiable with fMRI. The results also demonstrate a three-way functional–anatomical network in the right hemisphere that could either brake or completely stop responses.

Inhibition and the right inferior frontal cortex: one decade on

In our TICS Review in 2004, we proposed that a sector of the right inferior frontal cortex (rIFC) in humans is critical for inhibiting response tendencies. Here we survey new evidence, discuss ongoing controversies, and provide an updated theory. We propose that the rIFC (along with one or more fronto-basal-ganglia networks) is best characterized as a brake. This brake can be turned on in different modes (totally, to outright suppress a response; or partially, to pause), and in different contexts (externally, by stop or salient signals; or internally, by goals). We affirm inhibition as a central component of executive control that relies upon the rIFC and associated networks, and explain why rIFC disruption could generally underpin response control disorders.

The Neural Basis of Inhibition in Cognitive Control

The concept of “inhibition” is widely used in synaptic, circuit, and systems neuroscience, where it has a clear meaning because it is clearly observable. The concept is also ubiquitous in psychology. One common use is to connote an active/willed process underlying cognitive control. Many authors claim that subjects execute cognitive control over unwanted stimuli, task sets, responses, memories, and emotions by inhibiting them, and that frontal lobe damage induces distractibility, impulsivity, and perseveration because of damage to an inhibitory mechanism. However, with the exception of the motor domain, the notion of an active inhibitory process underlying cognitive control has been heavily challenged. Alternative explanations have been provided that explain cognitive control without recourse to inhibition as concept, mechanism, or theory. This article examines the role that neuroscience can play when examining whether the psychological concept of active inhibition can be meaningfully applied in cognitive control research. NEUROSCIENTIST 13(3):214—228, 2007.

From Reactive to Proactive and Selective Control: Developing a Richer Model for Stopping Inappropriate Responses

A better understanding of the neural systems underlying impulse control is important for psychiatry. Although most impulses are motivational or emotional rather than motoric per se, it is research into the neural architecture of motor response control that has made the greatest strides. This article reviews recent developments in the cognitive neuroscience of stopping responses. Most research of this kind has focused on reactive control-that is, how subjects stop a response outright when instructed by a signal. It is argued that reactive paradigms are limited as models of control relevant to psychiatry. Instead, a set of paradigms is advocated that begins to model proactive inhibitory control-that is, how a subject prepares to stop an upcoming response tendency. Proactive inhibitory control is generated according to the goals of the subject rather than by an external signal, and it can be selectively targeted at a particular response tendency. This may have wider validity than reactive control as an experimental model for stopping inappropriate responses.

The Cognitive Neuroscience of Response Inhibition: Relevance for Genetic Research in Attention-Deficit/Hyperactivity Disorder

Psychological functions that are behaviorally and neurally well specified may serve as endophenotypes for attention-deficit/hyperactivity disorder (ADHD) research. Such endophenotypes, which lie between genes and symptoms, may relate more directly to relevant genetic variability than does the clinical ADHD syndrome itself. Here we review evidence in favor of response inhibition as an endophenotype for ADHD research. We show that response inhibition--operationalized by Go/NoGo or Stop-signal tasks--requires the prefrontal cortex (PFC), in particular the right inferior frontal cortex (IFC); that patients with ADHD have significant response inhibition deficits and show altered functional activation and gray matter volumes in right IFC; and that a number of studies indicate that response inhibition performance is heritable. Additionally, we review evidence concerning the role of the basal ganglia in response inhibition, as well as the role of neuromodulatory systems. All things considered, a combined right IFC structure/function/response inhibition phenotype is a particularly good candidate for future heritability and association studies. Moreover, a dissection of response inhibition into more basic components such as rule maintenance, vigilance, and target detection may provide yet better targets for association with genes for neuromodulation and brain development.

Converging evidence for a fronto-basal-ganglia network for inhibitory control of action and cognition.

Imagine you are at an intersection, waiting for the traffic lights. They turn green, and you are about to press the gas pedal, when suddenly a cyclist swerves into your lane. Before your foot has actually moved, you have to rapidly prevent it from moving as planned. This example highlights the

Intracranial EEG Reveals a Time- and Frequency-Specific Role for the Right Inferior Frontal Gyrus and Primary Motor Cortex in Stopping Initiated Responses

Inappropriate response tendencies may be stopped via a specific fronto/basal ganglia/primary motor cortical network. We sought to characterize the functional role of two regions in this putative stopping network, the right inferior frontal gyrus (IFG) and the primary motor cortex (M1), using electocorticography from subdural electrodes in four patients while they performed a stop-signal task. On each trial, a motor response was initiated, and on a minority of trials a stop signal instructed the patient to try to stop the response. For each patient, there was a greater right IFG response in the beta frequency band (∼16 Hz) for successful versus unsuccessful stop trials. This finding adds to evidence for a functional network for stopping because changes in beta frequency activity have also been observed in the basal ganglia in association with behavioral stopping. In addition, the right IFG response occurred 100–250 ms after the stop signal, a time range consistent with a putative inhibitory control process rather than with stop-signal processing or feedback regarding success. A downstream target of inhibitory control is M1. In each patient, there was alpha/beta band desynchronization in M1 for stop trials. However, the degree of desynchronization in M1 was less for successfully than unsuccessfully stopped trials. This reduced desynchronization on successful stop trials could relate to increased GABA inhibition in M1. Together with other findings, the results suggest that behavioral stopping is implemented via synchronized activity in the beta frequency band in a right IFG/basal ganglia network, with downstream effects on M1.