There is emerging evidence that individuals with drug addiction have dysfunctions in brain systems that are important for interoceptive processing, which include, among others, the insular and the anterior cingulate cortices. These individuals may not be expending sufficient neural resources to process perturbations of the interoceptive state but may exert over-activation of these systems when processing drug-related stimuli. As a consequence, insufficient detection and processing of interoceptive state changes may result in inadequate anticipation and preparation to adapt to environmental challenges, e.g., adapt to abstinence in the presence of withdrawal symptoms. Here, we integrate interoceptive dysfunction in drug-addicted individuals, with the neural basis for meditation and exercise to develop a heuristic to target the interoceptive system as potential treatments for drug addiction. First, it is suggested that mindfulness-based approaches can modulate both interoceptive function and insular activation patterns. Second, there is an emerging literature showing that the regulation of physical exercise in the brain involves the insula and anterior cingulate cortex and that intense physical exercise is associated with a insula changes that may provide a window to attenuate the increased interoceptive response to drug-related stimuli. It is concluded that the conceptual framework of interoceptive dysfunctions in drug addiction and the experimental findings in meditation and exercise provide a useful approach to develop new interventions for drug addiction.
addiction; interoception; exercise; meditation; insula
Touch is a fundamental, but complex, element of everyday interaction that impacts one’s sensory and affective experience via interoceptive processing. The insular cortex is an integral component of the neural processes involved in interoception, i.e. the generation of an “emotional moment in time” through the sensing of the internal body state (Craig, 2002). Here, we examine the contribution of different parts of the insular cortex in the representation of both affective and sensory aspects of touch. To that end, subjects were administered a cued application of touch during functional MRI. We find that stimulus-related activation occurs in the mid-to-posterior insula, whereas anticipatory related activation is seen mostly in anterior insula. Moreover, the degree of activation in anterior insula during anticipation is correlated with the degree of activation in the posterior insula and caudate during stimulus processing. Finally, the degree of activation in the anterior insula during anticipation is also correlated with experienced intensity of the touch. Taken together, these results are consistent with the hypothesis that the anterior insula is preparing for the sensory and affective impact of touch. This preparatory function has important implications for the understanding of both anxiety and addictive disorders because dysfunctions in anticipatory processing are a fundamental part of the psychopathology.
Cognitive and affective processing has been the central focus of brain-related functions in psychology and psychiatry for many years. Much less attention has been paid to, what could be considered the primary function of the brain, to regulate the function of the body. Recent developments, which include the conceptualization of interoception as a process consisting of integrating the information coming from the inside of the body in the central nervous system (CNS) and the appreciation that complex emotional processes are fundamentally affected by the processing and regulation of somatic states, have profoundly changed the view of the function and dysfunction of the brain. This review focuses on the relationship between breathing and anxiety. Several anxiety disorders have been associated with altered breathing, perception of breathing and response to manipulations of breathing. Both clinical and experimental research studies are reviewed that relate breathing dysfunctions to anxiety. Altered breathing may be useful as a physiological marker of anxiety as well as a treatment target using interoceptive interventions.
Decisions under risk and with outcomes that are delayed in time are ubiquitous in real life and can have a significant impact on the health and wealth of the decision-maker. Despite its potential relevance for real-world choices, the degree of aberrant risky and intertemporal decision-making in patients suffering from major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) has received little attention to date.
We used a case-control design to compare decision-making in healthy control subjects (N=16) versus untreated depressed subjects in a current major depressive episode (N=20). In order to examine how major depressive disorder (MDD) may impact decision-making, subjects made decisions over (1) risky outcomes and (2) delayed outcomes in the domain of gains and losses using choice paradigms from neuroeconomics. In a pre-planned analysis, depressed subjects were subdivided into those with primary PTSD along with comorbid MDD (MDD+PTSD) versus those with primary MDD without PTSD (MDD-only). Choice behavior was modeled via a standard econometric model of intertemporal choice, a quasi-hyperbolic temporal discounting function, which was estimated for each subject group separately.
Under conditions of potential gain, depressed subjects demonstrated greater discounting for gains across all time frames compared to controls. In the realm of losses, both subgroups of depressed subjects discounted more steeply than controls for short time frames. However, for delayed losses ranging from >1-10 years, MDD+PTSD subjects showed shallower discounting rates relative to MDD-only subjects, who continued to discount future losses steeply. Risk attitudes did not contribute to differences in intertemporal choice.
Depressed patients make choices that minimize current pain and maximize current reward, despite severe later consequences or lost opportunities. Anxiety associated with PTSD may serve as a partially protective factor in decision-making about long-term potential losses compared to MDD patients without PTSD.
Combat-related PTSD has been associated with reduced gray matter volume in regions of the prefrontal and temporal cortex, hippocampus, insula, and amygdala. However, the relationship between gray matter volume and specific deployment and post-deployment experiences has not been investigated. The aim of this study was to delineate how such experiences may contribute to structural brain changes for combat veterans.
Operation Iraqi Freedom/Operation Enduring Freedom veterans (N = 32) completed magnetic resonance imaging, the Deployment Risk and Resilience Inventory, Alcohol Use Disorders Identification Test, and Clinical Administered PTSD Scale. Voxel-wise Huber robust multiple regressions were used to quantify the relationship between gray matter volume and deployment experiences (combat experiences, military social support) and post-deployment symptoms (PTSD, alcohol use).
There was an interaction between severity of combat experiences and military social support for orbitofrontal gyrus gray matter volume. Specifically, individuals with more orbitofrontal gyrus gray matter volume reported less combat experiences and higher unit support. Individuals with more severe PTSD symptoms showed reduced gray matter volume within a large temporal region (inferior temporal and parahippocampal gyrus).
The identified association between unit support and orbitofrontal gyrus volume supports two potential resilience mechanisms to be delineated with future longitudinal studies. First, individuals with larger orbitofrontal gyrus may engage in greater quality of social interactions and thus experience combat as less stressful. Second, individuals who experience greater unit support may preserve a larger orbitofrontal gyrus, serving to “protect” them from aversive consequences of combat.
A low level of response (LR) to alcohol is an important endophenotype associated with an increased risk for alcoholism. However, little is known about how neural functioning may differ between individuals with low and high LRs to alcohol. This study examined whether LR group effects on neural activity varied as a function of acute alcohol consumption.
30 matched high- and low-LR pairs (N=60 healthy young adults) were recruited from the University of California, San Diego and administered a structured diagnostic interview and laboratory alcohol challenge followed by two fMRI sessions under placebo and alcohol conditions, in randomized order. Task performance and BOLD response contrast to high relative to low working memory load in an event-related visual working memory (VWM) task was examined across 120 fMRI sessions.
Both LR groups performed similarly on the VWM task across conditions. A significant LR group by condition interaction effect was observed in inferior frontal and cingulate regions, such that alcohol attenuated the LR group differences found under placebo (p<.05). The LR group by condition effect remained even after controlling for cerebral blood flow, age, and typical drinking quantity.
Alcohol had differential effects on brain activation for low and high LR individuals within frontal and cingulate regions. These findings represent an additional step in the search for physiological correlates of a low LR, and identify brain regions that may be associated with the low LR response.
Level of response; fMRI; visual working memory; cerebral blood flow
Emotion processing and decision-making are integral aspects of daily life. However, our understanding of the interaction between these constructs is limited. In this review, we summarize theoretical approaches to the link between emotion and decision-making, and focus on research with anxious or depressed individuals that reveals how emotions can interfere with decision-making. We integrate the emotional framework based on valence and arousal with a Bayesian approach to decision-making in terms of probability and value processing. We then discuss how studies of individuals with emotional dysfunctions provide evidence that alterations of decision-making can be viewed in terms of altered probability and value computation. We argue that the probabilistic representation of belief states in the context of partially observable Markov decision processes provides a useful approach to examine alterations in probability and value representation in individuals with anxiety and depression and outline the broader implications of this approach.
Pregabalin, an anticonvulsant and anxiolytic compound that binds to α2-δ auxiliary subunit Types 1 and 2 of voltage-gated calcium channels, has been shown to reduce excitatory neurotransmission partially through modulation of glutamatergic signaling. Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating impacted by disruption of the glutamatergic system and is reduced in schizophrenia patients. Dysregulation of the glutamatergic system has also been implicated in the pathophysiology of schizophrenia. Here we tested the hypothesis that pregabalin may ameliorate PPI in a model of deficient gating in humans and mice. In study 1, 14 healthy human subjects participated in a within subjects, cross-over study with placebo, 50 mg or 200 mg pregabalin treatment prior to undergoing a PPI task. In study 2, 24 C57BL/6 mice underwent a similar procedure with vehicle, 30 and 100 mg/kg dose treatments. In both studies, subjects were assigned to a “Low” or “High” gating group using a median split procedure based on their PPI performance during placebo/vehicle. Drug effects were then examined across these groups. In humans, pregabalin treatment significantly increased PPI performance in the “low gating” group. In mice, pregabalin treatment significantly increased PPI in the low gating group but reduced PPI in the high gating group. Across species, pregabalin treatment improves PPI in subjects with low gating. These data support further exploration of pregabalin as a potential treatment for disorders characterized by sensorimotor gating deficits and glutamatergic hypersignaling, such as schizophrenia.
Schizophrenia; Pre-pulse inhibition; Glutamate; Pregabalin; Startle; Sensorimotor gating
Psychostimulants like cocaine and amphetamine are commonly abused by young adults who often state that they take these drugs to increase social or cognitive performance. The current study tested the hypothesis that individuals at early stages of occasional stimulant use show subtle executive dysfunctions such as verbal fluency deficits. 155 young (age 18-25), non-dependent occasional users of stimulants and 49 stimulant naïve comparison subjects performed the Delis-Kaplan Verbal Fluency test. Correlation and median split analyses were conducted to account for stimulant history and co-drug use. Compared to stimulant naïve subjects, occasional stimulant users generated significantly more responses on an over-learned verbal fluency task (Category Fluency), but at the expense of increased error rates (Set Loss and Repetition Errors). These performance differences were not related to lifetime uses of stimulants or marijuana. Taken together, these results support the hypothesis that individuals who are using stimulants occasionally exhibit subtle executive dysfunctions when required to generate verbal sets under time pressure. In particular, occasional stimulant users apply quickly but inaccurately verbal rules, which may represent a mix of diminished cognitive flexibility along with increased rigidity and impulsivity. This specific executive dysfunction may help to identify individuals at risk for stimulant use or dependence.
stimulant; cocaine; amphetamine; executive function; verbal fluency
Ineffective emotion regulation and abnormal amygdala activation have each been found in adolescent-onset major depressive disorder. However, amygdala activation during emotion regulation has not been studied in adolescent-onset major depressive disorder.
Fourteen unmedicated adolescents diagnosed with current depression without comorbid psychiatric disorders and fourteen well-matched controls ages 13 to 17 years underwent an emotional regulation task during functional magnetic resonance imaging. During this task, participants viewed negatively-valence images and were asked to notice how they were feeling without trying to change it and maintain their emotional reaction (“Maintain”) or to interpret the image in such a way as minimize their emotional response (“Reduce”).
Imaging analyses demonstrated that adolescents with depression showed: (1) greater right amygdala activation during the maintain condition relative to controls, (2) less connectivity during the maintain condition between the amygdala and both the insula and medial prefrontal cortex than controls, and (3) a significant positive correlation between amygdala-seeded connectivity during maintenance of emotion and psychosocial functioning.
The current study is cross-sectional comparison and longitudinal investigations with larger sample sizes are needed to examine the association between amygdala reactivity and emotion regulation over time in adolescent MDD.
During the maintain condition, adolescents with depression showed a heightened amygdala response and less reciprocal activation in brain regions that may modulate the amygdala. A poorly modulated, overreactive amygdala may contribute to poor emotion regulation.
Major Depression; Functional MRI; Insula; Reappraisal; Prefrontal Cortex
Stimulants are used increasingly to enhance social (cocaine) or cognitive performance (stimulants normally prescribed, prescription stimulants, e.g. methylphenidate, amphetamines). Chronic use, on the other hand, has been associated with significant verbal memory and learning deficits. This study sought to determine whether subtle learning and memory problems characterize individuals who exhibit occasional but not chronic use of stimulants.
154 young (age 18–25) occasional, non-dependent stimulant users and 48 stimulant naïve comparison subjects performed the California Verbal Learning test (CVLT-II). Lifetime uses of stimulants and co-use of marijuana were considered in correlation and median split analyses.
Compared to stimulant naïve subjects, occasional stimulant users showed significant performance deficits, most pronounced in the verbal recall and recognition domains. Lifetime uses of stimulants and marijuana did not affect CVLT-II performance. The type of stimulant used, however, was of major relevance: users of cocaine only were less impaired, while cumulative use of prescription stimulants was associated with impaired verbal learning and memory capacities.
These results support the hypothesis of subtle and possibly pre-existing neurocognitive deficiencies in occasional users of stimulants, which may be related to the motivation of using these drugs. More importantly, despite beneficial short-term effects, cumulative use, particularly of prescription amphetamines and methylphenidate, intensifies these deficits.
Stimulant; cocaine; amphetamine; executive function; verbal learning; verbal memory
Sensation seeking has been linked to increased risk taking and is therefore crucial in influencing behavioral outcomes of risk-taking behavior. Using functional magnetic resonance imaging (fMRI), the neural underpinnings of risk appraisal were studied in a large subject sample (n=188), stratified according to thrill and adventure seeking (TAS) ratings. As defined by a median split of the sample, low and high TAS groups were compared on a simple decision-making task completed during fMRI. The task was designed such that risk (i.e., magnitude of outcome) and gains (i.e., direction of outcome) could be mapped independently. Behavioral analysis indicated that high TAS individuals are more sensitive to rewards but less discriminating between risk with and without punishment and that low TAS individuals are less sensitive to rewards but quite sensitive to receiving punishments in risky situations. Imaging results on the group differences for the interaction between level of risk and level of gain showed differences in the right superior frontal gyrus (BA6), left insula (BA21), right nucleus accumbens, left lentiform nucleus, and left precuneus (BA7). The presented data suggest a neural model of risk processing in sensation seeking individuals such that the positive response to reward outweighs the impact of equivalent loss. This imbalance in approach/avoidance is evident in differences in the underlying neural substrates in TAS individuals and leads to greater risk behavior in the face of potential loss.
sensation seeking; fMRI; SFG; neural correlates; decision making; risk taking
A low level of response (i.e., a low LR) to alcohol is a genetically influenced phenotype that predicts later alcoholism. While the low LR reflects, at least in part, a low brain response to alcohol, the physiological underpinnings of the low LR have only recently been addressed.
Forty-nine drinking but not yet alcoholic matched pairs of 18-25-year-old subjects (N = 98; 53% female) with low and high LRs as established in separate alcohol challenges were evaluated in two event-related functional magnetic resonance imaging (fMRI) sessions (placebo and ~ 0.7 ml/kg of alcohol) while performing a validated stop signal task. The high and low LR groups had identical blood alcohol levels during the alcohol session.
Significant high versus low LR group and LR group × condition effects were observed in blood oxygen level dependent (BOLD) signal during error and inhibitory processing, despite similar LR-group performance on the task. In most clusters with significant (corrected p<.05, clusters >1344 μl) LR group × alcohol/placebo condition interactions, the low LR group demonstrated relatively less, whereas the high LR group demonstrated more, error and inhibition-related activation after alcohol compared to placebo.
This is one of the first fMRI studies to demonstrate significant differences between healthy groups with different risks for a future life threatening disorder. The results may suggest a brain mechanism that contributes to how a low LR might enhance the risk for future heavy drinking and alcohol dependence.
alcohol; reaction; risk; fMRI
The influence of emotion on higher-order cognitive functions, such as attention allocation, planning, and decision-making, is a growing area of research with important clinical applications. In this review, we provide a computational framework to conceptualize emotional influences on inhibitory control, an important building block of executive functioning. We first summarize current neuro-cognitive models of inhibitory control and show how Bayesian ideal observer models can help reframe inhibitory control as a dynamic decision-making process. Finally, we propose a Bayesian framework to study emotional influences on inhibitory control, providing several hypotheses that may be useful to conceptualize inhibitory control biases in mental illness such as depression and anxiety. To do so, we consider the neurocognitive literature pertaining to how affective states can bias inhibitory control, with particular attention to how valence and arousal may independently impact inhibitory control by biasing probabilistic representations of information (i.e., beliefs) and valuation processes (e.g., speed-error tradeoffs).
emotion; inhibitory control; Bayesian modeling; ideal observer model
Problems inhibiting non-adaptive behaviors have been linked to an increased risk for substance use and other risk taking behaviors in adolescence. This study examines the hypothesis that abnormalities in neural activation during inhibition in early adolescence may predict subsequent substance involvement.
Thirty eight adolescents from local area middle schools, ages 12–14, with very limited histories of substance use, underwent functional magnetic resonance imaging (fMRI) as they performed a go/no-go task of response inhibition and response selection. Adolescents and their parents were then followed annually with interviews covering substance use and other behaviors. Based on follow-up data, youth were classified as transitioning to heavy use of alcohol (TU; n=21), or as healthy controls (CON; n=17).
At baseline, prior to the onset of use, youth who later transitioned into heavy use of alcohol showed significantly less activation than those who went on to remain non to minimal users throughout adolescence. Activation reductions in TU at baseline were seen on no-go trials in 12 brain regions, including right inferior frontal gyrus, left dorsal and medial frontal areas, bilateral motor cortex, cingulate gyrus, left putamen, bilateral middle temporal gyri, and bilateral inferior parietal lobules (corrected p < .01, each cluster ≥ 32 contiguous voxels).
These results support the hypothesis that less neural activity during response inhibition demands predicts future involvement with problem behaviors such as alcohol and other substance use.
alcohol; adolescence; fMRI; inhibition; go/no-go
Animal approach-avoidance conflict paradigms have been used extensively to characterize effects of anxiolytic agents and probe neural circuitry related to anxiety. However, there are few behavioral approaches to measure conflict in human populations, limiting the translation of findings from animal conflict tasks to human clinical research. We developed a novel approach-avoidance conflict (AAC) paradigm involving situations in which the same decision is associated with “reward” (points) and “punishment” (negative affective stimuli). The AAC task was completed by 95 young adults (56 female) with varying levels of self-reported trait anxiety. As expected, conflict-related approach behavior correlated with self-reported motivation to approach reward and avoid punishment and greater reward level increased approach behavior. Additionally, females exhibited less approach behavior than males. Anxiety Sensitivity Index (Physical subscale) scores related negatively to approach behavior for males, while Behavioral Activation Scale (BAS, Fun Seeking subscale) scores related positively to approach behavior for females. Results support the utility of the AAC task as a behavioral test that has strong reverse translational features. Findings indicate that approach drives and anxiety sensitivity may be important in determining conflict behavior for females and males respectively. The approach-avoidance conflict task offers a novel, translational measure to probe neural systems underlying conflict behavior, motivational processes, and anxiety disorders.
Conflict; Reward; Anxiety; Avoidance; Decision making; Translational research
This review presents a novel conceptualization of addiction, integrating the concepts of interoception (i.e., the CNS representation of visceral feelings) and alliesthesia (i.e., that rewarding properties of stimuli are dependent on the internal state of the individual) with existing theories. It is argued that the body state, as defined by the integration of interoceptive information, is a crucial arbiter of the risk for initiation of and transition to compulsive use of addictive compounds. Overall, individuals at risk for drug dependence are characterized by an altered internal bodily state that leads to a change in hedonic and incentive motivational properties of addictive drugs. Specifically, drug dependent individuals experience alliesthesia of interoceptive processing, leading to increased incentive motivational properties of the drug over time and thereby increasing the probability of subsequent use. This extension of previous theories of addiction to include interoception and alliesthesia is based upon a clearly delineated set of neural substrates mediating interoception, key elements of which also recently have been implicated in drug addiction. The model thereby provides new potential targets for interventions that are aimed at changing the internal state that puts the individual at risk for continued substance use.
Addiction; Insula; Interoception; Alliesthesia; Reward
Prior neuroimaging studies support the hypothesis that anticipation, an important component of anxiety, may be mediated by activation within the insular and medial prefrontal cortices including the anterior cingulate cortex. However, there is an insufficient understanding of how affective anticipation differs across anxiety groups in emotional brain loci and networks. We examined 14 anxiety positive (AP) and 14 anxiety normative (AN) individuals completing an affective picture anticipation task during functional magnetic resonance imaging (fMRI). Brain activation was examined across groups for cued anticipation (to aversive or pleasant stimuli). Both groups showed greater activation in the bilateral anterior insula during cued differential anticipation (i.e., aversive vs. pleasant) and activation on the right was significantly higher in AP compared to AN subjects. Functional connectivity showed that the left anterior insula was involved in a similar network during pleasant anticipation in both groups. The left anterior insula during aversive and the right anterior insula during all anticipation conditions co-activated with a cortical network consisting of frontal and parietal lobes in the AP group to a greater degree. These results are consistent with the hypothesis that anxiety is related to greater anticipatory reactivity in the brain and that there may be functional asymmetries in the brain that interact with psychiatric traits.
In this review, we survey the state of the field of functional magnetic resonance imaging (fMRI) as it relates to drug discovery and drug development. We highlight the advantages and limitations of fMRI for this purpose and suggest ways to improve the use of fMRI for developing new therapeutics, with emphasis on treatments for anxiety disorders. Fundamentally, pharmacological studies with standard psychiatric treatments using standardized behavioral probes during fMRI will need to be carried out to determine characteristic brain signatures that could be used to predict whether novel compounds are likely to have specific therapeutic effects.
Aims: Alcohol acutely reduces agitation and is widely used in social situations, but the neural substrates of emotion processing during its intoxication are not well understood. We examine whether alcohol's social stress dampening effect may be via reduced activity in the cortical systems that subserve awareness of bodily sensations, and are associated with affective distress. Methods: Blood oxygen level-dependent activation was measured through 24 functional magnetic resonance imaging sessions in 12 healthy volunteers during an emotional face-processing task following ingestion of a moderate dose of alcohol and a placebo beverage. Results: Results revealed that bilateral anterior insula response to emotional faces was significantly attenuated following consumption of alcohol, when compared with placebo (clusters >1472 μl; corrected P < 0.05). Conclusion: Attenuated response in the anterior insula after alcohol intake may explain some of the decreased interoceptive awareness described during intoxication.
The purpose of this review is to highlight some of the issues that need to be addressed in order to optimally utilize functional neuroimaging as a clinical tool to predict outcomes in substance use disorders. First, the importance of recognizing the clinical heterogeneity of substance use disorders population is highlighted. We also emphasize that empirical and theoretical analyses support the idea that the courses of substance use disorders are relatively independent of the types of substance being used. Second, various approaches to the measurement and characterization of the longitudinal courses of substance use disorders are summarized. Third, predictors of outcomes are reviewed and their limitations are discussed. Within this context, we describe aspects of our work that focus on using functional magnetic resonance imaging (fMRI) to predict outcomes. Fourth, we discuss future directions, critical experiments and the utility of functional neuroimaging as a clinical tool.
Addiction; Stimulants; Outcomes; Prediction; fMRI; Neuroimaging
Several studies provide empirical evidence for the association between impulsivity and time perception. However, little is known about the neural substrates underlying this function. This investigation examined the influence of impulsivity on neural activation patterns during the encoding and reproduction of intervals with durations of 3, 9 and 18 seconds using event-related functional magnetic resonance imaging (fMRI). Twenty-seven subjects participated in this study, including 15 high impulsive subjects that were classified based on their self-rating. FMRI activation during the duration reproduction task was correlated with measures of two self-report questionnaires related to the concept of impulsivity (Barratt Impulsiveness Scale, BIS; Zimbardo Time Perspective Inventory, ZTPI). Behaviorally, those individuals who under-reproduced temporal intervals also showed lower scores on the ZTPI future perspective subscale and higher scores on the BIS. FMRI activation revealed an accumulating pattern of neural activity peaking at the end of the 9- and 18-s interval within right posterior insula. Activations of brain regions during the reproduction phase of the timing task, such as those related to motor execution as well as to the ‘core control network’ – encompassing the inferior frontal and medial frontal cortex, the anterior insula as well as the inferior parietal cortex – were significantly correlated with reproduced duration, as well as with BIS and ZTPI subscales. In particular, the greater activation in these regions the shorter were the reproduced intervals, the more impulsive was an individual and the less pronounced the future perspective. Activation in the core control network, thus, may form a biological marker for cognitive time management and for impulsiveness.
time perception; duration reproduction; impulsivity; time perspective; fMRI
Pregabalin (PGB) has shown potential as an anxiolytic for treatment of generalized and social anxiety disorder. PGB binds to voltage-dependent calcium channels, leading to upregulation of GABA inhibitory activity and reduction in the release of various neurotransmitters. Previous functional magnetic resonance imaging (fMRI) studies indicate that selective serotonin reuptake inhibitors and benzodiazepines attenuate amygdala, insula, and medial prefrontal cortex activation during anticipation and emotional processing in healthy controls. The aim of this study was to examine whether acute PGB administration would attenuate activation in these regions during emotional anticipation. In this double-blind, placebo-controlled, randomized crossover study, 16 healthy controls completed a paradigm involving anticipation of negative and positive affective images during fMRI approximately 1 h after administration of placebo, 50, or 200 mg PGB. Linear mixed model analysis revealed that PGB was associated with (1) decreases in left amygdala and anterior insula activation and (2) increases in anterior cingulate (ACC) activation, during anticipation of positive and negative stimuli. There was also a region of the anterior amygdala in which PGB dose was associated with increased activation during anticipation of negative and decreased activation during anticipation of positive stimuli. Attenuation of amygdala and insula activation during anticipatory or emotional processing may represent a common regional brain mechanism for anxiolytics across drug classes. PGB induced increases in ACC activation could be a unique effect related to top–down modulation of affective processing. These results provide further support for the viability of using pharmaco-fMRI to determine the anxiolytic potential of pharmacologic agents.
pregabalin; neuroimaging; insula; amygdala; anticipation; psychopharmacology; neuropharmacology; psychopharmacology; mood/anxiety/stress disorders; imaging; clinical or preclinical; pregabalin; anxiety; insula; prefrontal cortex; amygdala
Although there are multiple indications that alcohol can alter many physiological brain functions, including cerebral blood flow (CBF), studies of the latter have generally used small or modest sized samples. Few investigations have yet evaluated how CBF changes after alcohol relate to subsets of subjects with elevated alcoholism risks, such as those with lower levels of response (LR) to alcohol. This study used arterial spin labeling (ASL) after alcohol administration to evaluate a large sample of healthy young men and women with low and high alcohol responses, and, thus, varying risks for alcohol use disorders (AUD).
Healthy young adult social drinkers with low and high LR (N=88, 50% female) matched on demography and drinking histories were imaged with whole brain resting ASL ~1 hour after ingesting ~3 drinks of ethanol and after a placebo beverage (i.e., 178 ASL sessions). The relationships of CBF changes from placebo to alcohol for subjects with low and high LR were evaluated.
CBF increased after alcohol as compared to placebo in five frontal brain regions. Despite identical BACs, these increases with alcohol were less prominent in individuals who required more drinks to experience alcohol-related effects (i.e., had a lower LR to alcohol). The LR group differences remained significant after covarying for recent drinking quantities.
The results confirm that alcohol intake is associated with acute increases in CBF, particularly in frontal regions. Less intense CBF changes were seen in subjects with a genetically influenced characteristic, a low LR to alcohol, that relates to the future risk of heavy drinking and alcohol problems.
alcohol; arterial spin labeling; level of response to alcohol; alcoholism risk
Personality and alcohol expectancies have been examined as risk factors for the initiation and maintenance of alcohol use in adolescents and young adults. Differences in processing appetitive stimuli are seen as a mechanism for personality's influence on behavior, and that mechanism predisposes individuals to form more positive expectancies for alcohol. The go/no-go task has been used to show how personality differences influence responding to appetitive stimuli in adolescents and adults, and functional magnetic resonance imaging (fMRI) has been used to examine the relation of go/no-go responding to personality in adult males. However, no study to date has examined the relation between fMRI responding, personality and alcohol expectancies in adolescents.
Forty-six adolescents (ages 12−14 years; 61% male) with minimal substance use histories completed measures of neuroticism, extraversion, and alcohol expectancies, and performed a go/no-go task during fMRI acquisition.
Greater blood oxygen level-dependent (BOLD) response to inhibition predicted fewer expectancies of cognitive and motor improvements but more expectancies of cognitive and motor impairment from alcohol. In addition, extraverted youths reported more positive alcohol expectancies. However, BOLD response did not predict neuroticism or extraversion.
These preliminary results suggest that decreased inhibitory neural processing may contribute to more positive and less negative expectancies, which can eventually lead to problem drinking. Further, extraversion may also yield more positive expectancies and could underlie a vulnerability to disordered alcohol use.