Toward Precision Medicine for Smoking Cessation: Developing a Neuroimaging-Based Classification Algorithm to Identify Smokers at Higher Risk for Relapse.

INTRODUCTION: By improving our understanding of the neurobiological mechanisms underlying addiction, neuroimaging research is helping to identify new targets for personalized treatment interventions. When trying to quit, smokers with larger electrophysiological responses to cigarette-related, compared with pleasant, stimuli ("C > P") are more likely to relapse than smokers with the opposite brain reactivity profile ("P > C"). AIM AND METHOD: The goal was to (1) build a classification algorithm to identify smokers characterized by P > C or C > P neuroaffective profiles and (2) validate the algorithm's classification outcomes in an independent data set where we assessed both smokers' electrophysiological responses at baseline and smoking abstinence during a quit attempt. We built the classification algorithm applying discriminant function analysis on the event-related potentials evoked by emotional images in 180 smokers. RESULTS: The predictive validity of the classifier showed promise in an independent data set that included new data from 177 smokers interested in quitting; the algorithm classified 111 smokers as P > C and 66 as C > P. The overall abstinence rate was low; 15 individuals (8.5% of the sample) achieved CO-verified 12-month abstinence. Although individuals classified as P > C were nearly 2.5 times more likely to be abstinent than smokers classified as C > P (12 vs. 3, or 11% vs. 4.5%), this result was nonsignificant, preliminary, and in need of confirmation in larger trials. CONCLUSION: These results suggest that psychophysiological techniques have the potential to advance our knowledge of the neurobiological underpinnings of nicotine addiction and improve clinical applications. However, larger sample sizes are necessary to reliably assess the predictive ability of our algorithm. IMPLICATIONS: We assessed the clinical relevance of a neuroimaging-based classification algorithm on an independent sample of smokers enrolled in a smoking cessation trial and found those with the tendency to attribute more relevance to rewards than cues were nearly 2.5 times more likely to be abstinent than smokers with the opposite brain reactivity profile (11% vs. 4.5%). Although this result was not statistically significant, it suggests our neuroimaging-based classification algorithm can potentially contribute to the development of new precision medicine interventions aimed at treating substance use disorders. Regardless, these findings are still preliminary and in need of confirmation in larger trials.

Directional interconnectivity of the human amygdala, fusiform gyrus, and orbitofrontal cortex in emotional scene perception.

The perception of emotionally arousing scenes modulates neural activity in ventral visual areas via reentrant signals from the amygdala. The orbitofrontal cortex (OFC) shares dense interconnections with amygdala and has been strongly implicated in emotional stimulus processing in primates, but our understanding of the functional contribution of this region to emotional perception in humans is poorly defined. In this study we acquired targeted rapid functional imaging from lateral OFC, amygdala, and fusiform gyrus (FG) over multiple scanning sessions (resulting in over 1,000 trials per participant) in an effort to define the activation amplitude and directional connectivity among these regions during naturalistic scene perception. All regions of interest showed enhanced activation during emotionally arousing, compared with neutral scenes. In addition, we identified bidirectional connectivity between amygdala, FG, and OFC in the great majority of individual subjects, suggesting that human emotional perception is implemented in part via nonhierarchical causal interactions across these three regions.NEW & NOTEWORTHY Due to the practical limitations of noninvasive recording methodologies, there is a scarcity of data regarding the interactions of human amygdala and orbitofrontal cortex (OFC). Using rapid functional MRI sampling and directional connectivity, we found that the human amygdala influences emotional perception via distinct interactions with late-stage ventral visual cortex and OFC, in addition to distinct interactions between OFC and fusiform gyrus. Future efforts may leverage these patterns of directional connectivity to noninvasively distinguish clinical groups from controls with respect to network causal hierarchy.

A neurophysiological measure of reward sensitivity and its association with anhedonia in psychiatrically healthy adolescents and young adults.

Anhedonia (i.e., the attenuated ability to enjoy pleasurable stimuli) characterizes multiple mood disorders, but its neurophysiological underpinnings are not yet clear. Here, we measured event-related potentials in 116 adolescents and young adults engaged in an asymmetric reinforcement procedure designed to objectively characterize the anhedonic phenotype. In line with previous studies, the behavioral results showed that approximately 35% of the sample did not develop a response bias towards the more frequently rewarded stimuli (a sign of low hedonic capacity). The event-related potentials (ERPs) evoked by the reward feedback stimuli delivered during the task showed that individuals that did not develop a response bias had less cortical positivity at Fz from 224 ms to 316 ms post feedback onset compared to those that developed a response bias during the task. However, further analyses showed that this between groups difference was relatively weak, as it disappeared when we controlled for response-locked ERPs. Furthermore, the response bias observed in the asymmetric reinforcement procedure was not strongly associated with self-reported ratings of hedonic capacity. We conclude that even though the asymmetric reinforcement procedure may be used as a reward sensitivity measure in neurotypical adolescents and young adults, this task may only be able to detect clinically significant levels of anhedonia in this particular population.

Assessing the Primacy of Human Amygdala-Inferotemporal Emotional Scene Discrimination with Rapid Whole-Brain fMRI.

The comparative roles of the human amygdala and orbitofrontal cortex in emotional processing are under substantial debate, supported prominently by invasive primate studies. Noninvasive studies in humans are restricted by the limitations of electro- and magneto-encephalographic methods, which are hampered by the closed-field architecture and deep location of these structures. Here we employ whole-brain functional magnetic resonance imaging at an effective sampling rate of 300 ms to define the latency of enhanced blood oxygen level dependent (BOLD) contrast within structures activated by emotionally evocative relative to neutral scenes, in an effort to assess the hypothesized primacy of amygdala-inferotemporal co-activity in human emotional perception, relative to orbitofrontal cortex. Consistent with much prior work, we identified heightened BOLD signal during pleasant and unpleasant scene presentations in extrastriate occipital, ventral temporal, and posterior parietal visual system, as well as enhanced activation in cortical regions including the dorsal frontoparietal network, insula, and orbitofrontal cortex. Subcortical structures including the amygdala, locus coeruleus, and basal forebrain also showed reliably increased activity during emotional scene perception. The latency at which emotional BOLD signal enhancement varied considerably across structures, ranging from 2 to 6 seconds after scene onset. Though coarse, the spatiotemporal pattern of emotion-enhanced activity identified here is consistent with the idea that the amygdala and inferior temporal fusiform gyrus are the first regions to discriminate scene emotionality, which may then distribute this categorical information to other cortical and subcortical structures.

Hemodynamic and electrocortical reactivity to specific scene contents in emotional perception.

Emotional scene perception is characterized by enhanced neural activity across broad regions of visual cortex, the frontoparietal network, and anterior corticolimbic structures. In human fMRI and electrocortical experiments, activation enhancement is strongly related to self-reported emotional arousal evoked by scene stimuli. However, an additional bias in reaction to pleasant scenes has been reported in a subset of emotion-enhanced brain regions. Human fMRI and primate electrophysiological studies show biased frontoparietal network activity in response to rewarding cues. In addition, activation in lateral occipital regions may show a bias in pleasant scene perception, as shown in fMRI and in the early posterior negativity (EPN) ERP component. To define this potential pleasure bias, we presented a balanced set of naturalistic scenes to participants during separate fMRI and ERP recording sessions. Consistent with past work, the amplitude of the slow-wave late positive potential (LPP), as well as hemodynamic activity in fusiform gyrus and amygdala, showed equivalent enhancement across highly arousing pleasant and unpleasant, relative to neutral scenes. In addition to this emotional enhancement, the EPN component, as well as hemodynamic activity in lateral occipital cortex and frontoparietal network, showed greater reactivity during highly arousing pleasant relative to unpleasant scenes, consistent with a pleasure bias. The interpretation of this pattern of reactivity is discussed with respect to selective and evolved attention mechanisms.

The reality of "food porn": Larger brain responses to food-related cues than to erotic images predict cue-induced eating.

While some individuals can defy the lure of temptation, many others find appetizing food irresistible. The goal of this study was to investigate the neuropsychological mechanisms that increase individuals' vulnerability to cue-induced eating. Using ERPs, a direct measure of brain activity, we showed that individuals with larger late positive potentials in response to food-related cues than to erotic images are more susceptible to cue-induced eating and, in the presence of a palatable food option, eat more than twice as much as individuals with the opposite brain reactivity profile. By highlighting the presence of individual brain reactivity profiles associated with susceptibility to cue-induced eating, these findings contribute to the understanding of the neurobiological basis of vulnerability to obesity.

Primate Visual Perception: Motivated Attention in Naturalistic Scenes.

Research has consistently revealed enhanced neural activation corresponding to attended cues coupled with suppression to unattended cues. This attention effect depends both on the spatial features of stimuli and internal task goals. However, a large majority of research supporting this effect involves circumscribed tasks that possess few ecologically relevant characteristics. By comparison, natural scenes have the potential to engage an evolved attention system, which may be characterized by supplemental neural processing and integration compared to mechanisms engaged during reduced experimental paradigms. Here, we describe recent animal and human studies of naturalistic scene viewing to highlight the specific impact of social and affective processes on the neural mechanisms of attention modulation.

Reduced medial prefrontal-subcortical connectivity in dysphoria: Granger causality analyses of rapid functional magnetic resonance imaging.

A cortico-limbic network consisting of the amygdala, medial prefrontal cortex (mPFC), and ventral striatum (vSTR) has been associated with altered function in emotional disorders. Here we used rapidly sampled functional magnetic resonance imaging and Granger causality analyses to assess the directional connectivity between these brain structures in a sample of healthy and age-matched participants endorsing moderate to severe depressive symptomatology as they viewed a series of natural scene stimuli varying systematically in pleasantness and arousal. Specifically during pleasant scene perception, dysphoric participants showed reduced activity in mPFC and vSTR, relative to healthy participants. In contrast, amygdala activity was enhanced to pleasant as well as unpleasant arousing scenes in both participant groups. Granger causality estimates of influence between mPFC and vSTR were significantly reduced in dysphoric relative to control participants during all picture contents. These findings provide direct evidence that during visual perception of evocative emotional stimuli, reduced reward-related activity in dysphoria is associated with dysfunctional causal connectivity between mPFC, amygdala, and vSTR.

Human thalamic and amygdala modulation in emotional scene perception.

Emotional scene perception is associated with enhanced activity in ventral occipitotemporal cortex and amygdala. While a growing body of research supports the perspective that emotional perception is organized via amygdala feedback to rostral ventral visual cortex, the contributions of high-order thalamic structures strongly associated with visual attention, specifically the mediodorsal nucleus and pulvinar, have not been well investigated. Here we sample the activity of amygdala, MDN, pulvinar, and extrastriate ventral visual regions with fMRI as a group of participants view a mixed series of pleasant, neutral, and unpleasant natural scenes, balanced for basic perceptual characteristics. The results demonstrate that all regions showed enhanced activity during emotionally arousing relative to neutral scene perception. Consistent with recent research, the latency of emotional discrimination across subcortical and visual cortical regions suggests a role for the amygdala in the early evaluation of scene emotion. These data support the perspective that higher order visual thalamic structures are sensitive to the emotional value of complex scene stimuli, and may serve in concert with amygdala and fusiform gyrus to modulate visual attention toward motivationally relevant cues.

Emotional perception: correspondence of early and late event-related potentials with cortical and subcortical functional MRI.

This research examines the relationship between brain activity recorded with functional magnetic resonance imaging (fMRI) and event related potentials (ERP) as these responses varied over a series of emotionally evocative and neutral pictures. We investigate the relationship of early occipitotemporal and later centroparietal emotion-modulated ERPs in one sample to fMRI estimates of neural activity in another sample in a replicated experiment. Using this approach, we aimed to link effects found in time-resolved electrocortical measures to specific neural structures across individual emotional and nonemotional picture stimuli. The centroparietal late positive potential (LPP) showed covariation with emotion-modulated regions of hemodynamic activation across multiple dorsal and ventral visual cortical structures, while the early occipitotemporal potential was not reliably associated. Subcortical and corticolimbic structures involved in the perception of motivationally relevant stimuli also related to modulation of the LPP, and were modestly associated to the amplitude of the early occipitotemporal potential. These data suggest that early occipitotemporal potentials may reflect multiple sources of modulation including motivational relevance, and supports the perspective that the slow-wave LPP represents aggregate cortical and subcortical structures involved in emotional discrimination.

P3a from white noise.

P3a and P3b event-related brain potentials (ERPs) were elicited with an auditory three-stimulus (target, distracter, and standard) discrimination task in which subjects responded only to the target. Distracter stimuli consisted of white noise or novel sounds with stimulus characteristics perceptually matched. Target/standard discrimination difficulty was manipulated by varying target/standard pitch differences to produce relatively easy, medium, and hard tasks. Error rate and response time increased with increases in task difficulty. P3a was larger for the white noise compared to novel sounds, maximum over the central/parietal recording sites, and did not differ in size across difficulty levels. P3b was unaffected by distracter type, decreased as task difficulty increased, and maximum over the parietal recording sites. The findings indicate that P3a from white noise is robust and should be useful for applied studies as it removes stimulus novelty variability. Theoretical perspectives are discussed.

Stimulus-driven reorienting in the ventral frontoparietal attention network: the role of emotional content.

Activity in the human temporoparietal junction (TPJ) and inferior frontal gyrus (IFG) is hypothesized to underlie stimulus-driven, or "bottom-up" attention reorienting. Demanding tasks require focused attention, and as task difficulty increases, activity suppression in the ventral network correlates positively with task performance, an effect thought to reflect the gating of irrelevant cues. However, activation in these structures is elicited by a range of stimulus features and task demands that vary across multiple characteristics, complicating the interpretation of the functional role of this pathway. Consideration of several current studies suggests that, in addition to task difficulty, the motivational relevance or emotional intensity of distractor stimuli may supersede ongoing task priority, and evoke ventral network activation. Support for this possibility is offered from a review of recent reports, and the import of this perspective for models of attention reorienting is discussed.

Time-dependent effects of dim light at night on re-entrainment and masking of hamster activity rhythms.

Bright light has been established as the most ubiquitous environmental cue that entrains circadian timing systems under natural conditions. Light equivalent in intensity to moonlight (<1 lux), however, also strongly modulates circadian function in a number of entrainment paradigms. For example, compared to completely dark nights, dim nighttime illumination accelerated re-entrainment of hamster activity rhythms to 4-hour phase advances and delays of an otherwise standard laboratory photocycle. The purpose of this study was to determine if a sensitive period existed in the night during which dim illumination had a robust influence on speed of re-entrainment. Male Siberian hamsters were either exposed to dim light throughout the night, for half of the night, or not at all. Compared to dark nights, dim illumination throughout the entire night decreased by 29% the time for the midpoint of the active phase to re-entrain to a 4-hour phase advance and by 26% for a 4-hour delay. Acceleration of advances and delays were also achieved with 5 hours of dim light per night, but effects depended on whether dim light was present in the first half, second half, or first and last quarters of the night. Both during phase shifting and steady-state entrainment, partially lit nights also produced strong positive and negative masking effects, as well as entrainment aftereffects in constant darkness. Thus, even in the presence of a strong zeitgeber, light that might be encountered under a natural nighttime sky potently modulates the circadian timing system of hamsters.