Antoine Bechara - US grants

DESCRIPTION: (Applicant's Abstract) The long term goal of this project is to understand the cognitive and neural mechanisms underlying substance abuse. Neurological patients with bilateral ventromedial (VM) lesions of the prefrontal cortex and substance abusers present with similar behavioral characteristics in that 1) they often deny, or they are not aware that they have a problem; 2) they often make the wrong decisions, i.e. when faced with the choice to pursue a course of action that has some immediate reward, at the risk of incurring future negative consequences, including the loss of reputation, job, home, and family, they choose the immediate reward and ignore the future consequences. We hypothesize that substance abusers suffer from a decision-making impairment similar to that of patients with VM lesions. Using a decision-making instrument known as the "Gambling Task", we have made a significant progress in characterizing this impairment in VM patients at the (1 ) behavioral; (2) psychophysiological; and (3) cognitive levels. Here, we plan to apply the experimental strategies we used in the studies of VM patients to study substance abusers. We believe that knowledge about the mechanisms underlying this impairment in VM patients may help us to learn about the cognitive and neural mechanisms underlying substance abuse. Our research approach is promising because 1) the experimental strategies we plan to use have been developed and tested in patients with focal brain lesions; 2) comparing the profiles of the decision-making impairment in patients with focal brain lesions to substance abusers will enable us to link some aspects of the addiction disorder to specific anatomical and cognitive mechanisms. The proposed studies are feasible because 1) preliminary evidence from researchers at NIDA suggests that cocaine abusers show poor performance on the Gambling Task, just like VM patients do; 2) functional neuroimaging studies of human substance abusers show abnormal activity in brain regions that include the VM cortex. In future studies, we will investigate the pharmacological substrates that subserve and influence decision-making in normal individuals and substance abusers. Thus, this research is a beginning that may guide the future development of pharmacotherapeutic strategies that help improve the methods of treatment and prevention of substance abuse.

DESCRIPTION (adapted from applicants abstract): The long term goal of this project is elucidation of the pharmacological basis of decision making, a term which is often referred to in the psychological literature as "executive functions," and the application of the derived knowledge to the treatment and prevention of substance abuse. Both substance abusers and patients with ventromedial prefrontal frontal lobe lesions suffer from impairments in decision-making. Here we plan to study frontal patients and extend the findings to substance abusers. The proposal is guided by a theoretical framework designed to account for the defects in reasoning and decision-making that are so salient in frontal patients. The hypothesis posits that those decision-making defects, specifically those which involve personal and social behavior, are the results of defective activation of somatic markers that normally function as covert or overt signposts for helping with the process of making choices which are advantageous to the organism. In the past few years, we investigated the anatomical, physiological, and cognitive aspects of the neural network presumed to underlie decision-making and somatic marker activation. We found that the failure to enact somatic states results from dysfunction in a neural system in which the ventromedial (VM) prefrontal cortex is one critical region. However, other neural regions, including the amygdala and somatosensory cortices (SI, SII, and insula) are also hypothesized to be components of that same neural system. The operation of this system is thought to be influenced by non-specific neurotransmitter systems through direct or indirect anatomical connections. However, the nature of these neurotransmitter systems, has not been elucidated. Using experimental strategies which we perfected in the study of these patients, here we propose to carry out specific neurotransmitter manipulations and investigate their effects on decision-making in normals and in patients with frontal lobe lesions. In addition, we plan to investigate how another frontal lobe function, namely working memory, is affected by the same manipulations, relative to decision-making. Recent evidence has established that substance abusers suffer from decision-making impairments as revealed by the same laboratory tests which we used to study frontal patients. Ongoing investigations are probing further the link between decision-making, the frontal lobe, and substance abuse. Therefore, the results from this project will help the development of pharmacological therapies that assist in the rehabilitation of 1) substance abusers; and 2) many patients who suffer from disturbances of executive function caused by head injury, stroke, and surgical ablation of tumors.

The overall aim of this project is the investigation of the neurobiological basis of reasoning and decision-making, guided by a specific theoretical framework, the "somatic marker hypothesis". The hypothesis posits that decision-making defects in the personal and social realms are the result of defective engagement of emotion related signals ("somatic markers") that normally operate, covertly or overtly, to facilitate the process of making advantageous choices. In the current funding period, we have investigate anatomical, physiological, and cognitive aspects of a neural network presumed to underlie somatic marker activation and decision making. We confirmed that dysfunction in the ventromedial (VM) prefrontal cortex leads to a failure to enact somatic states and to decision-making defects. However, lesions in other neural regions, including the amygdala and the somatosensory cortices (SII, SI, and insula) also compromise somatic state activation and decision-making, suggesting that these several regions are part of a neural system involved in decision-making. Guided by the results obtained so far, the new studies we propose aim at defining the functional roles played by these components, and by others we propose here. The studies call for the testing of several hypotheses of several hypotheses using the lesion approached in cognitive and psychophysiological experiments. Disorders of decision-making are A prominent feature of the "dysexecutive syndrome" seen in stroke, head injury, and brain tumors. Such disorders are also prevalent in drug addiction, psychopathy, and borderline personality disorder. Our results will contribute to the understanding of normal and pathological mechanisms of decision- making and lead to the development of novel behavioral and pharmacological management strategies.

Project Summary/ Abstract A network of neural structures crucial for the cognitive and behavioral processes of drug addiction, including nicotine, includes the orbitofrontal cortex, anterior cingulate, insular cortices, the amygdala, and the striatum. However, no work has addressed how damage to different components of this neural network in humans may impact the maintenance of addiction to drugs. Under the tenure of an R21 awarded through CEBRA (Cutting- Edge Basic Research Awards), we began addressing this important issue in patients addicted to cigarette smoking and who had suffered a stroke that included any of these areas. It was found that although lesions of the ventromedial prefrontal cortex (VMPFC) were associated with a marked impairment of cue-induced urge in the laboratory, they were not associated with an increased likelihood of quitting smoking. In fact, lesions of the insular cortex were associated with an ability to quit smoking easily, immediately, without relapses and without a lasting urge to smoke. Although preliminary, these results suggest that, while VMPFC lesions may disrupt cue-induced urges, they do not disrupt smoking addiction. However, the insula, which also plays a key role in urges, seems most critical for maintaining smoking addiction and driving smoking behavior. The results also suggest that the insula functions in psychological processes that may contribute to the difficulty of quitting smoking. Encouraged by these intriguing, but preliminary, results, our primary aims are to (1) expand and confirm these findings in a larger sample, using more precise anatomical analyses to characterize the size and placement of lesions; (2) examine whether there are gender differences in terms of the ease to quit smoking after a lesion; and (3) conduct prospective studies on smokers who suffer strokes and monitor their smoking behavior for several years after the lesion onset. The proposed research is a beginning of a novel approach with potential for developing more effective therapies for breaking the vicious cycle of addiction. Specifically, one therapeutic approach called up by the proposed research would be to directly modulate the function of the insula. Project Narrative A prune-sized region deep in the brain called the insula is intimately involved in smoking addiction, and damage to this structure can completely erase the body's urge to smoke. Obviously brain damage is not a treatment option for nicotine addiction, but if confirmed, these results may offer leads for therapies to help smokers kick the habit, or for monitoring smokers' progress while using existing therapies.

This proposal focuses the neural systems involved in emotions and biases and their role in human decision-making. Neural systems that subserve human biases and emotions have evolved for survival purposes. The automatic biases and emotions triggered by a given situation help the normal decision-making process by narrowing down the options for action, either by discarding those that are dangerous or endorsing those that are advantageous. Biases and emotions serve an adaptive role speeding up the decision-making process. However, there are circumstances in which a naturally occurring bias or emotional response must be inhibited, so that a deliberate and potentially wiser decision can be made. Although recent research in neuroscience and psychology has highlighted the positive roles played by biases and emotions in decision-making, there are many instances where there is a negative side to biases and emotions in decision-making. Depending on the circumstances, biases, moods, and emotions can play useful as well as disruptive roles in the process of making advantageous decisions. Thus it is not a simple issue of trusting biases and emotions as the necessary arbiter of good and bad decisions. It is a matter of discovering the circumstances in which biases and emotions can be useful or disruptive, and using the reasoned coupling of circumstances and biases and emotions as a guide to human behavior.

This project will:
(1) Explore some of the circumstances in which biases and emotions influence decisions one way or another, and examine whether there are some personality and/or cognitive characteristics that render an individual more or less susceptible to a specific form of bias.
(2) Examine the functional organization of the CEO of the brain, the prefrontal cortex, and understand how this structure manages complex information, assign values to information, and ultimately execute decisions.
(3) Test a model of human intelligence that is based on how the CEO of the brain is functionally organized. The idea is that one individual will assume the function of one group of cells or sub-region of the prefrontal cortex, instead of the whole region. A group of individuals, with each one processing a separate stream of information in parallel, will then merge together, thus simulating the function of the prefrontal cortex of a human brain.

environmental exposure; substance abuse related behavior; craving; smoking; nicotine; neuropsychology; drug addiction; tobacco abuse; cingulate gyrus; amygdala; frontal lobe /cortex; behavioral /social science research tag; patient /disease registry; clinical research;

DESCRIPTION (provided by applicant): The overall aim of this project is to assess the neurocognitive mechanisms of judgment and decision-making that may be impaired in recreational MDMA ("Ecstasy") users, and the relationship of these defective mechanisms to the complex strategical and tactical decision-making operations needed to safely drive a motor vehicle. The widespread use of ecstasy by young people causes concern, especially due to its associated risk of traffic accidents. Epidemiological research and case studies have shown that impaired judgment and higher risk taking are the most likely contributors to ecstasy-related traffic accidents. Research also shows that there is a link between recreational ecstasy use, possible serotonin neurotoxicity, decline in decision-making, impulse control, and other mechanisms of executive functions, and a potential impact on driving behavior. These problems seem to remain long after the recreational use of Ecstasy has ceased, suggesting that the neuropharmacological damage may be long lasting or permanent. Although the residual cognitive effects of ecstasy have been studied extensively in drug free ecstasy users, these studies have focused primarily on mechanisms of memory, divided attention, semantic recognition, verbal reasoning and learning. Very little is known about how ecstasy impacts directly the mechanisms of judgment/decision-making, working memory, and impulse control, in abstinent users. Therefore, we will test a series of hypotheses on cognition and driving behavior in ecstasy users. Our overall hypothesis is that recreational use of MDMA, and to a lesser extent other drugs (e.g. cannabis), will produce residual cognitive effects that in turn result in errors in judgment during the driving task. These errors in judgment are directly related to decline in specific executive functions as measured by neuropsychological tests of frontal lobe functions. Elucidation of the residual effects of ecstasy on judgment, decision-making, and impulse control has several important practical consequences, in addition to its obvious value in advancing fundamental knowledge in cognitive neuroscience. On the medical front, it will help determine the conditions under which substance abuse leads to a decline in frontal lobe functions. On the social front, the study helps shed more light on how to identify individuals who may present a risk to others and to themselves on the road.

PROJECT 2: ANATOMICAL BASIS OF DECISION-MAKING The overall aim of this project is the continued investigation of the neurobiogical basis of decision-making, guided by a systems-level neuroanatomical and cognitive framework for decision-making. This framework posits that decision-making defects in the personal and social realms are the result of a defective engagement of emotion-related signals that normally operate, covertly or overtly, to facilitate the process of making advantageous choices. In the current funding period, we provided new evidence in support of the notion that: (1) the neural systems subserving decision-making and social functioning overlap with those subserving emotions and feelings;(2) the vagus nerves are possible conduits for the emotion-related, signals that play a critical role in decision-making;(3) the right ventromedial prefrontal cortex may be more critical than the left for social conduct, decision-making, and emotional processing;and that (4) emotions may have a disruptive role in certain kinds of decisions. Guided by these results, the new studies we propose aim at (1) exploring the neural substrates supporting different types of decisions, and investigating the role of emotions in each type;(2) addressing the possible gender-related differences in decision-making; and (3) addressing new challenges to the interpretation of our past experiments on decision-making. The studies call for the testing of several hypotheses using the lesion approach in cognitive and psychophysiological experiments. Public health relevance: Disorders of decision-making are a prominent feature of the "dysexecutive syndrome" seen in stroke, head injury, and brain tumors. Such disorders are also prevalent in drug addiction, psychopathy, and borderline personality disorder. Our results will contribute to the understanding of pathological mechanisms of decision-making and lead to the development of novel therapeutic and management strategies for these disorders. In addition to these benefits to public health, our results are likely to contribute to the emerging field of neuroeconomics, a promising hybrid combining the neural investigation of decision-making with behavioral economics. Few areas of the life sciences are as exciting, and even fewer offer the same potential for understanding human nature while also making an impact in medicine.

DESCRIPTION (provided by applicant): This project seeks to identify key neural pathways responsible for one's loss of ability to self-control and exert willpower when faced with tempting choices such as drugs. However, given the impracticality of using drugs in a population of adolescents, we will use food cues as a model to examine how calorie-rich food impacts activity within these neural systems. Three key neural systems are hypothesized to contribute to the loss of willpower to resist food, and these same neural systems have been implicated in the willpower to resist drugs: (1) a hyperactive amygdala-striatal (dopamine-dependent) neural system, which promotes cue-induced habitual behaviors; (2) a hypoactive prefrontal cortex neural system, which subserves decision-making and impulse control capacities; and (3) an altered insular cortex function, which responds to homeostatic and interoceptive signals triggered by states of deprivation, or by exposure to environmental cues that elicit craving. The insula translates these interoceptive signals into what subjectively become experienced as an urge, which in turn acts to (1) exacerbate the hypersensivity of the amygdala-striatal system, and (2) weaken the inhibitory function of the prefrontal system. Using BOLD functional magnetic resonance imaging techniques, we will test the hypothesis that high behavioral measures of consumption of foods that are high in fat and sugar, as measured by the Youth/Adolescent Questionnaire (YAQ), will correlate with (1) increased activity in an amygdala-striatal neural system that promotes habitual and impulsive behaviors, and (2) decreased activity in a prefrontal cortex system for decision-making and inhibitory control. We will also test the hypothesis that food deprivation induces an increased activation of the insular cortex with the consequence of exacerbating activity of the habit system, and weakening activity of the prefrontal system. The proposed research is of high public health significance as it advances knowledge for creating novel intervention strategies that are transferrable to the prevention of substance abuse. In particular, the current project is also relevant to cancer prevention as it advances knowledge that promotes healthier eating, avert compulsive eating, and reduce cancer risk behaviors.