Adam R. Aron - US grants

How are we able to prevent ourselves from being distracted? How can we overcome our compulsions, tics and inappropriate urges? These are questions about cognitive control. A good understanding of the psychological and neural mechanisms underlying such control is of paramount importance for many aspects of everyday life as well as for basic science. A fruitful way to study cognitive control is to examine how people stop already initiated responses. Stopping an already initiated response could be an experimental model for the way in which we stop all kinds of urges in everyday life. Recent research suggests that stopping is achieved by several key "nodes" in the brain. It is likely that communication between the nodes occurs via long-range connections (white matter tracts). With support from the National Science Foundation, Dr. Adam Aron and his research team will test this idea of a network of long-range connections underlying stopping behavior. The approach is twofold: first, to use a form of neuroimaging to measure the strength of the connections in a sample of healthy young adults, and to examine how variations in the strength of the connections relates to individual differences in the behavioral ability to stop; second, to image the connections in patients with specific brain injuries. If particular connections are key for stopping, then damage to these connections will produce problems with stopping even when the key brain "nodes" themselves are intact. Overall, these studies will harness recently-developed methods for the analysis of brain connections to reveal novel information about how the network of connections between key brain regions underlies human control. They are in keeping with recent developments in cognitive neuroscience which emphasize the importance of connections rather than just brain regions themselves.

The funded work will complement activities in Dr. Aron's laboratory which already have an impact on science education at multiple stages, including outreach activities in San Diego area schools, hosting of minority students in the lab and undergraduate and graduate teaching. The work adds unique educational value by introducing new scientific components into Dr. Aron's lab and department: these include the study of patients with brain lesions and methods for analyzing brain connections. Overall, the planned experiments could yield information about the neural architecture of stopping that has implications for diverse domains such as human development, jurisprudence and neuropsychiatry. Alterations in brain connections, perhaps related to developmental delays, disease, or injury, could lead to deficits in inhibiting inappropriate actions. Various neuropsychiatric disorders, such as attention deficits, tic disorders, over-eating and substance abuse may relate to alterations in the brain connections underlying stopping.

ABSTRACT This proposal addresses the neural architecture underlying how people are able to use their goals to control inappropriate urges. This has large significance for a wide range of neuropsychiatric disorders characterized by impulsivity and perseveration. In the United States, the financial and societal cost of these disorders is staggering. Better understanding how people control themselves has come from the stop- signal paradigm, in which subjects must occasionally stop an initiated response. The neural architecture underlying the form of stopping in the standard stop-signal paradigm is already quite well understood. It is highly translatable across species and it has proven a very useful biomarker for cognitive control impairments in many neuropsychiatric disorders. However, the form of stopping measured in the standard stop-signal paradigm has some limitations as a model for real world control because it appears to have global effects on the motor system. Yet a person's ability to control an inappropriate urge requires selectivity of the control (i.e. to stop one tendency but not others). We have recently proposed a new behavioral method to study selective stopping. The first aim of this proposal is to study the neural mechanisms of selective stopping. We will use functional Magnetic Resonance Imaging (fMRI) in healthy volunteers to dissociate the fronto-basal-ganglia brain circuits for global stopping from those for selective stopping. We will use Transcranial Magnetic Stimulation (TMS) to examine the difference between global and selective stopping by identifying effects on motor representations in the primary motor cortex. We will use Electrocorticography (ECoG) in patients being evaluated for epilepsy to address how the functions of goal monitoring and response inhibition interact in the prefrontal cortex to allow a subject to stop selectively. ECoG provides unique spatiotemporal resolution to address this question in humans. Besides stopping, real-world control also requires a form of control that prevents responding without canceling it completely -something more akin to 'braking'. The second aim of this proposal is to study the neural mechanisms of braking and their relation with stopping. We will use all three methods of fMRI, TMS and ECoG. We anticipate that braking recruits the same brain systems as stopping, but without canceling motor output completely. Together, these studies will provide a novel neural-systems model for how selective stopping is possible and for how it relates to braking. This will enhance and expand understanding of cognitive control mechanisms, and is relevant for many diverse conditions including Obsessive Compulsive Disorder, Attention Deficit Hyperactivity Disorder, Tourette's syndrome, and substance abuse problems - all characterized by a loss of goal-driven control over particular response tendencies.

DESCRIPTION (provided by applicant): We all experience the sort of situation where, during a conversation, we are interrupted by a salient external signal (a 'novel'), e.g. a breaking window. We quickly orient to the novel, and then find that our train of thought, or more specifically our working memory (WM), has been interrupted. This proposal tests the theory that one reason for this WM decrement is because the salient stimulus activates the brain's motor stopping network, and this network has global effects on currently active motor and non-motor cortical contents. Based on our published and preliminary data we advance for the following neural systems model: a) novels act as stop signals, generating a rapid motor stop via the brain's global stopping network, b) this network is implemented via the subthalamic nucleus (STN) of the basal ganglia, c) activation of the STN leads to a widespread pulse of suppression on thalamocortical drive, d) as all motor and non-motor representations (including WM) are partly sustained by thalamocortical drive, there is a temporary interruption which manifests as a WM decrement. Validating this model has far-reaching significance for better understanding the relationship between stopping and WM in cognitive psychology; for better understanding the relation between the 'over-stopped' state in PD and cognitive inflexibility, and for advancing a new theory of distractibility, relevant for psychiatry. We test the model in PD patients and in healthy volunteers. In PD patients we will examine how stopping affects WM while we simultaneously record local field potentials from implanted STN electrodes and scalp EEG from the frontal cortex. We expect that stopping-induced activity in the STN will correspond with reductions in the cortical marker for WM, thus linking the putative global STN stop signal with a decrement in WM. In healthy volunteers we will use Transcranial Magnetic Stimulation of motor cortex as a surrogate probe of the global STN stop signal. We expect that the degree of global motor suppression measured by this method will correspond with the decrement in WM induced by stop signal as well as novels.

DESCRIPTION (provided by applicant): Everyday acts of self-control directed at, for example, cigarettes, food, and gambling, depend, in part, on the ability to stop action. While much is known about action stopping in humans, real world self-control, as in the above examples, has a strong valuational or motivational component. Yet there is scant research on how motor stopping interacts with value/motivation. Our core hypothesis, based on preliminary data, is that motor stopping can reduce value and motivation. We will test three possible mechanisms based on our work with three kinds of stopping systems. Our first aim is to test how rapid stopping concurrently reduces stimulus value. We hypothesize that rapid stopping recruits a global stopping system that inhibits all currently active representations, including value. Testing this requires measuring global inhibition (with Transcranial Magnetic Stimulation, TMS), imaging the stopping system and value representations (with fMRI and Electrocorticography) and, above all, showing that brain regions critical for stopping are causally important for reducing value (using a novel form of Direct Electrical Stimulation, in humans). Our second aim is to examine how motivational stimuli, which generate action tendencies, are suppressed. Our hypothesis is that this is done by the selective stopping system that is set up according to a subject's goals in working memory and which can be triggered by the motivational stimulus itself. We will test this by measuring the temporal dynamics of motor activation and suppression with TMS, and using fMRI to examine the putative underlying fronto-striatal system. Our third aim is to leverage automatic stopping to reduce stimulus value and motivation. We hypothesize that repeated stopping (via training) generates stimulus stop-tag, so that when that stimulus occurs in the future it reactivates the stopping system (automatically), which then reduces stimulus value and motivation.

PROJECT SUMMARY Research in several species shows that rapidly stopping action activates the subthalamic nucleus (STN) of the basal ganglia (BG) ? and that the STN may be recruited via a hyperdirect pathway (HDP) from prefrontal cortical stopping nodes. Human research also shows that unexpected events (such as a surprising tones) also recruit the stopping system (including the STN), and interrupt working memory (WM). At the core of this proposal is the idea that WM is maintained via a recurrent cortico-BG loop, and that this can be interrupted via HDP recruitment of the STN. The interruption is induced via stop signals and unexpected events, and could function to `clear cognition'. This is a radical new theory: that a fronto-BG circuit for stopping underlies cognitive interruptions. Validating this theory has broad implications for understanding the BG, for mechanisms of cognitive interruptions, and for potential cognitive under-and-over flexibility in Parkinson's disease (PD) and ADHD. Here we propose to systematically test this theory using parallel human-mouse studies, based on extensive preliminary data and using several novel approaches, including event-related Deep Brain Stimulation (eDBS). Aim 1 (motor stop) will use STN eDBS in humans and optogenetic stimulation in mice to test whether the STN is causally important for stopping action. Aim 2 (cognitive stop) will use eDBS and functional MRI in humans and optogenetics in mice to test whether the STN is causally important for decrementing WM. Aim 3 (HDP) will use combinatorial optogenetics in mice and novel combinations of transcranial magnetic stimulation with concurrent local field recordings in human STN to test whether motor and cognitive Stops are implemented via HDP inputs to STN from frontal cortex. Throughout the proposal we focus on designing complementary experiments across species, so that what is learned in mice can directly inform our understanding of human neural circuit function and behavior.

PROJECT SUMMARY Self-control refers to how we prevent inappropriate actions and thoughts. Poor self-control is manifest in symptoms of impulsivity, and is associated with numerous mental health problems. One proxy of real-world self-control is thought to involve rapid response inhibition. This metric, which is captured by the stop signal task, is embedded in the large-scale Adolescent Brain Cognitive Development study (ABCD). Indeed, the stop signal task is one of only three tasks for the fMRI part of ABCD. The researchers for ABCD will collect stop signal fMRI data in 12 000 adolescents repeatedly over 10 years. Stop signal metrics, especially the single subject aggregate measure of stop signal reaction time (SSRT) [how quickly people stop] will be correlated with fMRI activation and also with brain structure (gray and white matter). Individual differences in SSRT, and stop activation and structure, will then be correlated with a slew of personality and behavioral metrics. Meanwhile, recent developments in stop signal research, including by our group, suggest a potentially much richer dissection may be done of behavioral stopping than merely computing SSRT. The current proposal aims to test whether the dissected cognitive processes correspond to particular brain signatures (Aim 1 fMRI, Aim 2 EEG), and how well they account for variability in self-control for ?real world? self-report and other tests of impulsivity (Aim 3). We predict that these metrics will account for more variability in self-control than does SSRT itself, thus potentially putting the stop signal aspect of the ABCD endeavor, and others like it, on a firmer physiological footing

PROJECT SUMMARY Executive functions underlie our ability to control our behavior according to our goals. One element of executive function is top-down inhibitory control. Over the last funding periods we have distinguished two kinds of inhibitory control ? reactive and proactive. Reactive inhibitory control can have broad effects and is driven by stop signals. It is apparently implemented by prefrontal connections to the basal ganglia, which we suppose blocks thalamic drive to cortex. By contrast, proactive inhibitory control is set up in advance of any response and is apparently implemented by sensorimotor cortex, also with downstream effects on basal ganglia and thalamus. Here we leverage our knowledge of these reactive and proactive inhibitory systems to ask how we keep unwanted thoughts out of mind and what mental strategies can be used to reduce pain. Aim 1 tests whether prefrontally-driven reactive inhibitory control prevents thought intrusions. We use the so-called Think/NoThink paradigm in which, on NoThink trials, people have to try to prevent the intrusion of an unwanted memory. We have shown this relates to increased prefrontal beta band power. We do simultaneous EEG/fMRI to localize the prefrontal node that best corresponds with the requirement to Not Think, and we then use fMRI- guided repetitive Transcranial Magnetic Stimulation (TMS) to create a ?virtual lesion? of that prefrontal node to test its causal role in preventing intrusions of thought. Aim 2 moves away from reactive inhibitory control to test how proactive inhibitory control reduces subjective pain. We inculcate a proactive inhibitory state (which corresponds to increased sensorimotor beta power) and we then test if, during this state, a nociceptive pain stimulus is rated as less painful subjectively. We then do repetitive TMS to create a ?virtual lesion? of M1 (and circuitry) to test the causal role of sensorimotor beta oscillations in a ?suppressive? state pertinent to reducing pain ratings. Aim 3 tests whether inculcating a proactive suppression state can prevent thought intrusions. We will do this by embedding the Think/NoThink requirement in task-states characterized by increased beta oscillations. These states are generated either endogenously by the subject given a cue or by the use of beta band entrainment with rTMS.