Mary M. Heitzeg

Variations in the Human Pain Stress Experience Mediated by Ventral and Dorsal Basal Ganglia Dopamine Activity

In addition to its involvement in motor control and in encoding reward value, increasing evidence also implicates basal ganglia dopaminergic mechanisms in responses to stress and aversive stimuli. Basal ganglia dopamine (DA) neurotransmission may then respond to environmental events depending on their saliency, orienting the subsequent responses of the organism to both positive and negative stimuli. Here we examined the involvement of DA neurotransmission in the human response to pain, a robust physical and emotional stressor across species. Positron emission tomography with the DA D2 receptor antagonist radiotracer [11C]raclopride detected significant activation of DA release in dorsal and ventral regions of the basal ganglia of healthy volunteers. Activation of nigrostriatal (dorsal nucleus caudate and putamen) DA D2 receptor-mediated neurotransmission was positively associated with individual variations in subjective ratings of sensory and affective qualities of the pain. In contrast, mesolimbic (nucleus accumbens) DA activation, which may impact on both D2 and D3 receptors, was exclusively associated with variations in the emotional responses of the individual during the pain challenge (increases in negative affect and fear ratings). These data demonstrate that basal ganglia dopamine D2 receptor-mediated neurotransmission is involved in responses to pain and that it contributes to individual variations in the pain experience at the levels of physical and emotional elements, albeit with different neuroanatomical substrates.

Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism

Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory γ-amino butyric acid α2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI). In a sample of 173 families (449 subjects), 129 of whom had at least one member diagnosed with alcohol dependence or abuse, carriers for the G allele in two single-nucleotide polymorphisms (SNPs) and haplotypes were more likely to have alcohol dependence symptoms (rs279858, P=0.01; rs279826, P=0.05; haplotype, P=0.02) and higher NEO Personality Inventory-Revised (NEO-PI-R) Impulsiveness scores (rs279858, P=0.016; rs279826, P=0.012; haplotype, P=0.032) with a stronger effect in women (rs279858, P=0.011; rs279826, P=0.002; haplotype, P=0.006), all P-values are corrected for family history and age. A subset of offspring from these families (n=44, 20 females), genotyped for GABRA2, participated in an fMRI study using a monetary incentive delay task. Increased insula activation during reward (r2=0.4; P=0.026) and loss (r2=0.38; P=0.039) anticipation was correlated with NEO-PI-R Impulsiveness and further associated with the GG genotype for both SNPs (Ps<0.04). Our results suggest that GABRA2 genetic variation is associated with Impulsiveness through variation of insula activity responses, here evidenced during anticipatory responses.

Affective circuitry and risk for alcoholism in late adolescence: Differences in frontostriatal responses between vulnerable and resilient children of alcoholic parents

BACKGROUND Children of alcoholics (COAs) are at elevated risk for alcohol use disorders (AUD), yet not all COAs will develop AUD. The 2 primary aims of this study were to identify neural activation mechanisms that may mark protection or vulnerability to AUD in COAs and to map the same activation patterns in relation to risk behavior (externalizing or internalizing behavior). METHODS Twenty-two adolescent COAs were recruited from an ongoing community longitudinal study of alcoholic and matched control families. They were categorized as either vulnerable (n = 11) or resilient (n = 11) based on the level of problem drinking over the course of adolescence. Six other adolescents with no parental history of alcoholism, and no evidence of their own problem drinking were recruited from the same study and labeled as low-risk controls. Valenced words were presented to the participants in a passive viewing task during functional magnetic resonance imaging. Activation to negative versus neutral words and positive versus neutral words were compared between groups. Behavior problems were assessed with the Youth Self-Report (YSR). RESULTS The resilient COA group had more activation of the orbital frontal gyrus (OFG), bilaterally, and left insula/putamen than the control and vulnerable groups, in response to emotional stimuli. In contrast, the vulnerable group had more activation of the dorsomedial prefrontal cortex and less activation of the ventral striatum and extended amygdala, bilaterally, to emotional stimuli than the control and resilient groups. The vulnerable group had more externalizing behaviors which correlated with increased dorsomedial prefrontal activation and decreased ventral striatal and extended amygdala activation. CONCLUSIONS These results are consistent with dissociable patterns of neural activation underlying risk and resiliency in COAs. We propose that the pattern observed in the resilient COAs represents an active emotional monitoring function, which may be a protective factor in this group. On the other hand, the vulnerable group displayed a pattern consistent with active suppression of affective responses, perhaps resulting in the inability to engage adaptively with emotional stimuli.

Executive function in chronic pain patients and healthy controls: different cortical activation during response inhibition in fibromyalgia.

UNLABELLED The primary symptom of fibromyalgia (FM) is chronic, widespread pain; however, patients report additional symptoms including decreased concentration and memory. Performance-based deficits are seen mainly in tests of working memory and executive function. Neural correlates of executive function were investigated in 18 FM patients and 14 age-matched healthy controls during a simple Go/No-Go task (response inhibition) while they underwent functional magnetic resonance imaging (fMRI). Performance was not different between FM and healthy control, in either reaction time or accuracy. However, fMRI revealed that FM patients had lower activation in the right premotor cortex, supplementary motor area, midcingulate cortex, putamen and, after controlling for anxiety, in the right insular cortex and right inferior frontal gyrus. A hyperactivation in FM patients was seen in the right inferior temporal gyrus/fusiform gyrus. Despite the same reaction times and accuracy, FM patients show less brain activation in cortical structures in the inhibition network (specifically in areas involved in response selection/motor preparation) and the attention network along with increased activation in brain areas not normally part of the inhibition network. We hypothesize that response inhibition and pain perception may rely on partially overlapping networks, and that in chronic pain patients, resources taken up by pain processing may not be available for executive functioning tasks such as response inhibition. Compensatory cortical plasticity may be required to achieve performance on a par with control groups. PERSPECTIVE Neural activation (fMRI) during response inhibition was measured in fibromyalgia patients and controls. FM patients show lower activation in the inhibition and attention networks and increased activation in other areas. Inhibition and pain perception may use overlapping networks: resources taken up by pain processing may be unavailable for other processes.

Emotion processing, major depression, and functional genetic variation of neuropeptide Y.

CONTEXT Despite recent progress in describing the common neural circuitry of emotion and stress processing, the bases of individual variation are less well understood. Genetic variants that underlie psychiatric disease have proven particularly difficult to elucidate. Functional genetic variation of neuropeptide Y (NPY) was recently identified as a source of individual differences in emotion. Low NPY levels have been reported in major depressive disorder (MDD). OBJECTIVE To determine whether low-expression NPY genotypes are associated with negative emotional processing at 3 levels of analysis. DESIGN Cross-sectional, case-control study. SETTING Academic medical center. PARTICIPANTS Among 44 individuals with MDD and 137 healthy controls, 152 (84%) had an NPY genotype classified as low, intermediate, or high expression according to previously established haplotype-based expression data. MAIN OUTCOME MEASURES Healthy subjects participated in functional magnetic resonance imaging while viewing negative (vs neutral) words (n = 58) and rated positive and negative affect during a pain-stress challenge (n = 78). Genotype distribution was compared between 113 control subjects and 39 subjects with MDD. RESULTS Among healthy individuals, negatively valenced words activated the medial prefrontal cortex. Activation within this region was inversely related to genotype-predicted NPY expression (P = .03). Whole-brain regression of responses to negative words showed that the rostral anterior cingulate cortex activated in the low-expression group and deactivated in the high-expression group (P < .05). During the stress challenge, individuals with low-expression NPY genotypes reported more negative affective experience before and after pain (P = .002). Low-expression NPY genotypes were overrepresented in subjects with MDD after controlling for age and sex (P = .004). Population stratification did not account for the results. CONCLUSIONS These findings support a model in which NPY genetic variation predisposes certain individuals to low NPY expression, thereby increasing neural responsivity to negative stimuli within key affective circuit elements, including the medial prefrontal and anterior cingulate cortices. These genetically influenced neural response patterns appear to mediate risk for some forms of MDD.

What is a representative brain? Neuroscience meets population science

The last decades of neuroscience research have produced immense progress in the methods available to understand brain structure and function. Social, cognitive, clinical, affective, economic, communication, and developmental neurosciences have begun to map the relationships between neuro-psychological processes and behavioral outcomes, yielding a new understanding of human behavior and promising interventions. However, a limitation of this fast moving research is that most findings are based on small samples of convenience. Furthermore, our understanding of individual differences may be distorted by unrepresentative samples, undermining findings regarding brain–behavior mechanisms. These limitations are issues that social demographers, epidemiologists, and other population scientists have tackled, with solutions that can be applied to neuroscience. By contrast, nearly all social science disciplines, including social demography, sociology, political science, economics, communication science, and psychology, make assumptions about processes that involve the brain, but have incorporated neural measures to differing, and often limited, degrees; many still treat the brain as a black box. In this article, we describe and promote a perspective—population neuroscience—that leverages interdisciplinary expertise to (i) emphasize the importance of sampling to more clearly define the relevant populations and sampling strategies needed when using neuroscience methods to address such questions; and (ii) deepen understanding of mechanisms within population science by providing insight regarding underlying neural mechanisms. Doing so will increase our confidence in the generalizability of the findings. We provide examples to illustrate the population neuroscience approach for specific types of research questions and discuss the potential for theoretical and applied advances from this approach across areas.

Nucleus Accumbens Response to Incentive Stimuli Anticipation in Children of Alcoholics: Relationships with Precursive Behavioral Risk and Lifetime Alcohol Use

Children of alcoholics (COAs) are at elevated risk to develop alcohol and other substance use disorders. The neurobiological underpinnings of this heightened vulnerability are presently not well understood. This study investigated whether, in humans, COAs have different functioning of the mesolimbic reward circuitry beyond previous substance use confounds and examined potential group differences in neural response in relation to alcohol use and behavioral risk. We studied 20 18- to 22-year-old COAs and 20 controls, developmentally well characterized for substance use and selected to match on sex, age, IQ, lifetime substance use and associated problems, and precursive (ages 12–14 years) externalizing behavioral risk. None met criteria for Diagnostic and Statistical Manual of Mental Disorders IV diagnosis. Neural responses to anticipation of reward and loss were assessed using functional magnetic resonance imaging during a monetary incentive delay task. Overall, COAs showed reduced ventral striatum activation during anticipation of monetary reward and loss compared with controls. However, additional analysis revealed that blunted nucleus accumbens (NAcc) response was only observed in COAs who have not demonstrated any problem drinking behavior. In addition, uniquely in COAs, NAcc activation was positively correlated with precursive externalizing risk, as well as current and lifetime alcohol consumption. These findings suggest a multilevel developmental process whereby lower precursive behavioral risk appears protective of later problem alcohol use in COAs, which is further associated with a blunted NAcc response to incentive anticipation, potentially reflecting a resilience mechanism. Moreover, the results suggest that a close association between motivational responses, alcohol consumption, and behavioral risk may underlie addiction vulnerability in COAs.

Trajectories of childhood aggression and inattention/hyperactivity: Differential effects on substance abuse in adolescence

OBJECTIVE Aggression and hyperactivity/inattention each are linked to risk of alcohol use disorder (AUD), but their unique contributions remain ambiguous. The present study disaggregated these two domains developmentally and examined the relation between childhood behavior trajectories and adolescent substance use. METHOD A total of 335 children of alcoholic and nonalcoholic fathers were studied prospectively. Parallel process latent trajectory class analysis was developed with behavioral ratings by parents and teachers of aggression and inattention/hyperactivity across ages 7 to 16. Membership in the four latent classes was used as a predictor for problem adolescence alcohol use and substance onset. RESULTS Youths in the four latent trajectory classes differed in number of alcohol problems at age 16: healthy class (39% of sample, mean 2.1 alcohol-related problems), inattentive/hyperactive but not aggressive (33%; mean 2.7 problems), aggressive but not inattentive/hyperactive (4%, mean 5.0 problems), and comorbid (24%; mean 4.0 problems). Survival analysis revealed that the aggressive, comorbid, and inattentive/hyperactive classes had significantly earlier onsets of drinking, drunkenness, and marijuana use than the healthy class. Illicit drug use was also significantly increased in the comorbid, aggressive, and inattentive/hyperactive classes compared to the healthy class. CONCLUSIONS Three levels of behavioral risk of substance abuse exist, the highest having trajectories of increased aggressive and inattentive/hyperactive problems throughout childhood, the next involving only an increased inattentive/hyperactive behavioral trajectory, and the lowest involving those with neither type of problem. Children with both inattention/hyperactivity and aggression have the greatest need for childhood intervention to prevent substance abuse in adolescence.

Accumbens functional connectivity during reward mediates sensation-seeking and alcohol use in high-risk youth

BACKGROUND Differences in fronto-striatal connectivity in problem substance users have suggested reduced influence of cognitive regions on reward-salience regions. Youth with a family history of alcoholism (FH+) have disrupted ventral striatal processing compared with controls with no familial risk (FH-). As sensation-seeking represents an additional vulnerability factor, we hypothesized that functional connectivity during reward anticipation would differ by family history, and would mediate the relationship between sensation-seeking and drinking in high-risk subjects. METHODS Seventy 18-22 year olds (49 FH+/21 FH-) performed a monetary incentive delay task during functional magnetic resonance imaging. Group connectivity differences for incentive (reward/loss) vs. neutral conditions were evaluated with psychophysiological interaction (PPI) analysis, seeded in nucleus accumbens (NAcc). Indirect effects of sensation-seeking on drinking volume through accumbens connectivity were tested. RESULTS NAcc connectivity with paracentral lobule/precuneus and sensorimotor areas was decreased for FH- vs. increased for FH+ during incentive anticipation. In FH+, task-related functional coupling between left NAcc and supplementary sensorimotor area (SSMA) and right precuneus correlated positively with sensation-seeking and drinking volume and mediated their relationship. In FH-, left NAcc-SSMA connectivity correlated negatively with sensation-seeking but was not related to drinking. CONCLUSIONS These results suggest preexisting differences in accumbens reward-related functional connectivity in high-risk subjects. NAcc coupling with SSMA, involved in attention and motor networks, and precuneus, a default mode structure, appear to mediate sensation-seekings effect on drinking in those most at-risk. Differences in accumbens connectivity with attention/motor/default networks, rather than control systems, may influence the reward systems role in vulnerability for substance abuse.

Variation in the Corticotropin-Releasing Hormone Receptor 1 (CRHR1) Gene Influences fMRI Signal Responses during Emotional Stimulus Processing

The corticotropin-releasing hormone (CRH) system coordinates neuroendocrine and behavioral responses to stress and has been implicated in the development of major depressive disorder (MDD). Recent reports suggest that GG-homozygous individuals of a single nucleotide polymorphism (rs110402) in the CRH receptor 1 (CRHR1) gene show behavioral and neuroendocrine evidence of stress vulnerability. The present study explores whether those observations extend to the neuronal processing of emotional stimuli in humans. CRHR1 was genotyped in 83 controls and a preliminary sample of 16 unmedicated patients with MDD who completed a functional magnetic resonance imaging scan while viewing blocks of positive, negative, and neutral words. In addition, potential mediating factors such as early life stress, sex, personality traits, and negative memory bias were examined. Robust differences in blood oxygenation level-dependent (BOLD) signal were found in healthy controls (A allele carriers > GG-homozygotes) in the right middle temporal/angular gyrus while subjects were viewing negative versus neutral words. Among GG-homozygotes, BOLD signal in the subgenual cingulate was greater in MDD participants (n = 9) compared with controls (n = 33). Conversely, among A-carriers, BOLD signal was smaller in MDD (n = 7) compared with controls (n = 50) in the hypothalamus, bilateral amygdala, and left nucleus accumbens. Early life stress, personality traits, and levels of negative memory bias were associated with brain activity depending on genotype. Results from healthy controls and a preliminary sample of MDD participants show that CRHR1 single nucleotide polymorphism rs110402 moderates neural responses to emotional stimuli, suggesting a potential mechanism of vulnerability for the development of MDD.