It is poorly understood how stressors modulate neurobiological mechanisms that may contribute to the heterogeneity of Major Depressive Disorder (MDD). Unmedicated patients diagnosed with MDD (n = 15) and individually matched healthy controls (n = 15) completed stress questionnaires and were studied with functional magnetic resonance imaging while viewing emotional words. Significant effects of recent negative life stressors, but not early life stress/trauma, were observed on regional blood oxygen level dependent activity during presentation of negative words in patients with MDD. No significant effects of stress on brain activation to negative words were found in controls. In MDD patients, positive correlations were found bilaterally in orbitofrontal areas 11l/47/12m, which are involved in representing negatively-valenced stimuli. Negative correlations were also found in the right ventrolateral prefrontal area 45, subgenual cingulate area 25, and nucleus accumbens, all of which are implicated in the pathophysiology of MDD. Negative memory bias was additionally positively associated with recent negative life stress and negatively associated with subgenual cingulate activation, suggesting a mechanism by which stress may contribute to these abnormalities. The severity of recent negative life stressors is an important modifier of neurobiological and cognitive function in MDD and may help explain heterogeneity in the disorder.
orbital; subgenual; ventrolateral; accumbens; memory; depression
The endogenous opioid system and μ-opioid receptors are known to interface environmental events, both positive (e.g., relevant emotional stimuli) and negative (e.g., stressors) with pertinent behavioral responses, regulating motivated behavior. Here we examined the degree to which trait impulsiveness, the tendency to act on cravings and urges rather than delaying gratification, is predicted by either baseline μ-opioid receptor availability or the response of this system to a standardized, experientially-matched stressor.
Nineteen (19) young healthy male volunteers completed a personality questionnaire (NEO PI-R) and positron emission tomography scans with the μ-opioid receptor selective radiotracer [11C]carfentanil. Measures of receptor concentrations were obtained at rest and during the receipt of an experimentally maintained pain stressor of matched intensity between subjects. Baseline receptor levels and stress-induced activation of μ-opioid neurotransmission were compared between subjects scoring above and below the population median of the NEO impulsiveness subscale and the orthogonal dimension, deliberation, expected to interact with it.
High impulsiveness and low deliberation scores were associated with significantly higher regional μ-opioid receptor concentrations and greater stress-induced endogenous opioid system activation. Effects were obtained in regions involved in motivated behavior and the effects of drugs of abuse: prefrontal and orbitofrontal cortex, anterior cingulate, thalamus, nucleus accumbens and basolateral amygdala. Mu-opioid receptor availability, and the magnitude of stress-induced endogenous opioid activation in these regions accounted for 21 to 49% of the variance in these personality traits.
Our data demonstrate that individual differences in the function of the endogenous μ-opioid system predicts personality traits that confer vulnerability or resiliency for risky behaviors, such as the predisposition to develop substance use disorders. These personality traits are also implicated in psychopathological states (e.g., personality disorders), where variations in the function of this neurotransmitter system may play a role as well.
Positron emission tomography; pain; stress; opioid dopamine; placebo; human
The serotonergic system, including the serotonin 1A (5-HT1A) receptor, has been implicated in the pathophysiology of a number of neuropsychiatric disorders. Current data shows substantial inter-individual variation in the regional concentration of this receptor site, the source of which is unclear. Monoamine oxidase A (MAO-A) is a key regulator of serotonin metabolism, and polymorphic variation in the X-linked MAO-A gene influences its expression. We hypothesized that polymorphism in the MAO-A gene would be associated with sex-specific variation in 5-HT1A receptor expression. We used positron emission tomography and [11C]WAY-100635 to quantify 5-HT1A receptors in a group of 31 healthy and un-medicated depressed individuals. The same individuals were genotyped for an upstream variable number tandem repeat polymorphism in the promoter of the MAO-A gene. Analysis of variance of 5-HT1A receptor availability demonstrated a significant effect of MAO-A genotype in the raphe nuclei, medial and inferior temporal cortex, insula, medial prefrontal cortex, and anterior cingulate (p<0.05). The effect persisted when age, race, body mass index, and diagnosis were included in the model. Genotypes with greater putative MAO-A activity were associated with greater 5-HT1A receptor availability in women, but not in men. Genotype predicted a substantial 42-74% of the variance in receptor availability in women, depending on the brain region (p<0.05). Depression diagnosis was not associated with MAO-A genotype or 5-HT1A receptor availability in these regions. These results demonstrate a sex-specific interaction between two key molecules of the human serotonergic system, and suggest a neurobiological basis for sexual dimorphism in serotonin-modulated phenotypes.
sex difference; polymorphism; positron emission tomography; serotonin; serotonergic 1A receptor; monoamine oxidase; imaging; genetics; human; depression
Oxytocin, classically involved in social and reproductive activities, is increasingly recognized as an antinociceptive and anxiolytic agent, effects which may be mediated via oxytocin’s interactions with the dopamine system. Thus, genetic variation within the oxytocin gene (OXT) is likely to explain variability in dopamine-related stress responses. As such, we examined how OXT variation is associated with stress-induced dopaminergic neurotransmission in a healthy human sample.
Fifty-five young healthy volunteers were scanned using [11C] raclopride positron emission tomography while they underwent a standardized physical and emotional stressor that consisted of moderate levels of experimental sustained deep muscle pain, and a baseline, control state. Four haplotype tagging single nucleotide polymorphisms located in regions near OXT were genotyped. Measures of pain, affect, anxiety, well-being and interpersonal attachment were also assessed.
Female rs4813625 C allele carriers demonstrated greater stress-induced dopamine release, measured as reductions in receptor availability from baseline to the pain-stress condition relative to female GG homozygotes. No significant differences were detected among males. We also observed that female rs4813625 C allele carriers exhibited higher attachment anxiety, higher trait anxiety and lower emotional well-being scores. In addition, greater stress-induced dopamine release was associated with lower emotional well-being scores in female rs4813625 C allele carriers.
Our results suggest that variability within the oxytocin gene appear to explain interindividual differences in dopaminergic responses to stress, which are shown to be associated with anxiety traits, including those linked to attachment style, as well as emotional well-being in women.
oxytocin; genetics; dopamine; positron emission tomography; humans; sex differences
The personality trait resiliency is the ability to flexibly adapt impulse control relative to contextual demand. Low resiliency has been linked to later alcohol/drug problems. The underlying psychological and neural mechanisms are unknown but neurocomputational models suggested relations between resiliency and working memory. Cortical-striatal connectivity has been proposed to underlie adaptive switches between cautious and risky behaviors.
Working memory was probed in sixty-seven 18–22 year olds from a larger community study of alcoholism, using the n-back task during functional magnetic resonance imaging. Functional connectivity between task-related regions was investigated with psychophysiological interaction analysis. Resiliency was measured in early teen years and related to early adulthood measures of drinking/drug use, task activation and connectivity. Relationships with risk factors, including family history, age of drinking onset and number of alcohol problems were also investigated.
Higher resiliency was related to lower levels of substance use, fewer alcohol problems and better working memory performance. Whole brain regression revealed resiliency negatively correlated with activation of subthalamic nucleus (STN) and pallidum during the n-back. High and Low resiliency quartile groups (n=17 each) differed in coupling strength between STN and median cingulate cortex, a region of reduced activation during working memory. The High resiliency group had later onset of drinking, fewer alcohol problems, had used fewer illicit drugs and were less likely to smoke cigarettes than their Low resiliency counterparts,
These findings suggest that resiliency in early adolescence may protect against alcohol problems and drug use, though the direction of this effect is currently unknown. This protective factor may relate to executive functioning as supported by the finding of a neural link shared between resiliency and working memory in basal ganglia structures. The STN, a key basal ganglia structure, may adaptively link flexible impulse control with cognitive processing, potentially modulating substance use outcomes.
Resiliency; Substance Use; Working Memory; STN; fMRI; PPI
The perception that smoking relieves negative affect contributes to smoking persistence. Endogenous opioid neurotransmission, and the µ-opioid receptor (MOR) in particular, plays a role in affective regulation and is modulated by nicotine.
We examined the relationship of µ-opioid receptor binding availability in the amygdala to the motivation to smoke for negative affect relief and to the acute effects of smoking on affective responses.
Twenty-two smokers were scanned on two separate occasions after overnight abstinence using [11C]carfentanil positron emission tomography imaging: after smoking a nicotine-containing cigarette and after smoking a denicotinized cigarette. Self-reports of smoking motives were collected at baseline, and measures of positive and negative affect were collected pre- and post- cigarette smoking.
Higher MOR availability in the amygdala was associated with motivation to smoke to relieve negative affect. However, MOR availability was unrelated to changes in affect after smoking either cigarette.
Increased MOR availability in amygdala may underlie the motivation to smoke for negative affective relief. These results are consistent with previous data highlighting the role of µ-opioid receptor neurotransmission in smoking behavior.
Smoking motivation; µ-opioid receptor; amygdala; affect regulation
Affect identification accuracy paradigms have increasingly been utilized to understand psychiatric illness including Bipolar Disorder (BD) and Major Depressive Disorder (MDD). This investigation focused on perceptual accuracy in affect identification in both visual and auditory domains among patients with BD, relative to Healthy Controls (HC) and patients with MDD. Demographic and clinical variables, in addition to medications were also investigated.
The visual Facial Emotion Perception Test (FEPT) and auditory Emotional Perception Test (EPT) were administered to adults with BD (n = 119) and MDD (n = 78) as well as HC (n = 66).
Performance on the FEPT was significantly stronger than on the EPT irrespective of group. Performance on the EPT did not significantly differentiate the groups. On the FEPT, BD samples had the greatest difficulty relative to HC in identification of sad and fearful faces. BD participants also had greater difficulty identifying sad faces relative to MDD participants though not after controlling for severity of illness factors. For the BD (but not MDD) sample several clinical variables were also correlated with FEPT performance.
The findings suggest that disruptions in identification of negative emotions such as sadness and fear may be a characteristic trait of BD. However, this effect may be moderated by greater illness severity found in our BD sample.
Bipolar Disorder; Major Depressive Disorder; Affect perception
Neural systems that identify and respond to salient stimuli are critical for survival in a complex and changing environment. In addition, interindividual differences, including genetic variation, hormonal, and metabolic status likely influence the behavioral strategies and neuronal responses to environmental challenges. Here we examined the relationship between leptin allelic variation and plasma leptin levels with DAD2/3R availability in vivo as measured with [11C]raclopride Positron Emission Tomography (PET) at baseline and during a standardized pain stress challenge. Allelic variation in the leptin gene was associated with varying levels of DA release in response to the pain stressor, but not with baseline D2/3 receptor availability. Circulating leptin was also positively associated with stress-induced dopamine release. These results show that leptin serves as a regulator of neuronal function in humans and provides an etiological mechanism for differences in dopamine neurotransmission in response to salient stimuli as related to metabolic function. The capacity for leptin to influence stress-induced dopaminergic function is of importance for pathological states where dopamine is thought to play an integral role, such as mood, substance use disorders, eating disorders, and obesity.
Dopamine (DA) neurotransmission through D2 receptors (DRD2) has been implicated in the regulation of reward processing, cognition and the effects of drugs of abuse, and also has significant effects in responses to stressors and salient aversive stimuli. An examination of the influence of genetic variation across multiple psychophysical measures therefore appears critical to understand the neurobiology of DA-modulated complex personality traits and psychiatric illnesses. To examine interindividual variation in the function of DRD2 modulated mechanisms in healthy humans, we used a haplotype-based and single nucleotide polymorphism (SNP) investigation. Their effects were interrogated with functional magnetic resonance imaging (fMRI) during reward and emotional processing. We found that a haplotype block composed by two SNPs, rs4274224 and rs4581480, affected the hemodynamic responses of the dorsolateral prefrontal cortex (DLPFC) during reward expectation and the subgenual anterior cingulate cortices (sgACC) during implicit emotional processing. Exploratory analysis within the significant haplotype block revealed the same functional effects only for the SNP rs4274224. Further analysis on rs4274224 using functional connectivity and positron emission tomography (PET) measures of DA D2/3 receptor mediated neurotransmission confirmed a gene effect on the functional connectivity of the DLPFC during reward anticipation and subcortical stress induced dopamine release. At a phenotypic trait level, significant effects of genotype were obtained for the NEO PI-R “Openness to Experience” and further correlated with neuroimaging data. Overall, these results show significant neurobiological effects of genotype variation in DRD2 on multiple functional domains, such as emotional, stress and reward processing. As such, it contributes to normal variation and potentially to vulnerability to psychopathology associated with those functions, such as risk for mood and substance use disorders.
imaging; dopamine; DLPFC; reward; emotion
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 prior substance use confounds, and examined potential group differences in neural response in relation to alcohol use and behavioral risk. We studied twenty 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 (age 12–14) externalizing behavioral risk. None met criteria for DSM-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 to controls. However, further 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 a close association between motivational responses, alcohol consumption, and behavioral risk, may underlie addiction vulnerability in COAs.
Poor impulse inhibition is associated with behavioral problems including aggression and violence as well as clinical diagnoses such as attention deficit hyperactivity disorder (ADHD) and substance abuse, all of which are more prevalent in men than women. Studies have found that fronto-parietal and fronto-striatal-thalamic networks are critical for successful impulse inhibition. However, few studies have investigated neural differences in these networks between men and women. In this study, we use a well established behavioral task, the parametric Go/noGo task, to explore the relationships between brain regional activity during impulse control and impulsivity trait measures, as well as sex differences in these relationships. We found that males showed heightened activation of the rostral anterior cingulate, which correlated with ratings related to impulsivity. We also found that the activation/deactivation in males and females correlates with personality ratings in a sex-specific manner.
impulsivity; fMRI; impulsivity trait measure; Go/noGo task
Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT2C) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT2C receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT2C receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D2/D3 receptor radiotracer [11C]raclopride. Binding potential (BPND) was quantified before and after a standardized stress challenge consisting of 20 minutes of moderate deep muscular pain, and reduction in BPND served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BPND. These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders.
Cushing syndrome (CS) is the classic condition of cortisol dysregulation, and cortisol dysregulation is the prototypic finding in Major Depressive Disorder (MDD). We hypothesized that subjects with active CS would show dysfunction in frontal and limbic structures relevant to affective networks, and also manifest poorer facial affect identification accuracy, a finding reported in MDD.Twenty-one patients with confirmed CS (20 ACTH-dependent and 1 ACTH-independent) were compared to 21 healthy controlsubjects. Identification of affective facial expressions (Facial Emotion Perception Test) was conducted in a 3 Tesla GE fMRI scanner using BOLD fMRI signal. The impact of disease (illness duration, current hormone elevation and degree of disruption of circadian rhythm), performance, and comorbid conditions secondary to hypercortisolemia were evaluated.CS patients made more errors in categorizing facial expressions and had less activation in left anterior superior temporal gyrus, a region important in emotion processing. CS patients showed higher activation in frontal, medial, and subcortical regions relative to controls. Two regions of elevated activation in CS, left middle frontal and lateral posterior/pulvinar areas, were positively correlated with accuracy in emotion identification in the CS group, reflecting compensatory recruitment. In addition, within the CSgroup, greater activation in left dorsal anterior cingulatewas related to greater severity of hormone dysregulation. In conclusion, cortisol dysregulation in CS patients is associated with problems in accuracy of affective discrimination and altered activation of brain structures relevant to emotion perception, processing and regulation, similar to the performance decrements and brain regions shown to be dysfunctional in MDD.
HPA; cortisol; ACTH; emotion; affect; fMRI; Cushings
Despite considerable evidence for potential effects of estrogen on emotional processing, several studies of postmenopausal women who began hormone therapy (HT) remote from menopause report no effects of HT on emotional measures. As early HT initiation may preserve brain mechanisms, we examined effects of HT on emotional processing in postmenopausal women who started HT early after menopause. We performed a cross-sectional comparison of 52 postmenopausal women 66±5 years old, including 15 users of conjugated equine estrogen, 20 users of conjugated equine estrogen plus medroxyprogesterone acetate, and 17 who never used hormones (NT). All hormone users started therapy within two years of menopause, and received at least 10 years of continuous therapy. Outcomes were fMRI-detected brain activity and behavioral measures during an emotional processing picture rating task. During processing of positive pictures, NT women had greater activation than estrogen treated women in medial prefrontal cortex extending to the anterior cingulate, and more activation than estrogen plus progestin treated women in the insula. During processing of negative pictures, estrogen treated women had higher activation than NT women in the entorhinal cortex. Current compared to past HT users showed greater activation in the hippocampus and higher emotion recognition accuracy of neutral stimuli. Estrogen plus progestin treated women had slower response time than NT women when rating all pictures. In conclusion, hormone use was associated with differences in brain functional responses during emotional processing. These fMRI effects were more prominent than those observed for behavioral measures and involved brain regions implicated in cognitive-emotional integration.
Estrogen; Progesterone; Hormone Therapy; Postmenopause; Functional Magnetic Resonance Imaging; Emotion
We developed a unique protocol where transcranial direct current stimulation (tDCS) of the motor cortex is performed during positron emission tomography (PET) scan using a μ-opioid receptor (μOR) selective radiotracer, [11C]carfentanil. This is one of the most important central neuromechanisms associated with pain perception and regulation. We measured μOR non-displaceable binding potential (μOR BPND) in a trigeminal neuropathic pain patient (TNP) without creating artifacts, or posing risks to the patient (e.g., monitoring of resistance). The active session directly improved in 36.2% the threshold for experimental cold pain in the trigeminal allodynic area, mandibular branch, but not the TNP patient’s clinical pain. Interestingly, the single active tDCS application considerably decreased μORBPND levels in (sub)cortical pain-matrix structures compared to sham tDCS, especially in the posterior thalamus. Suggesting that the μ-opioidergic effects of a single tDCS session are subclinical at immediate level, and repetitive sessions are necessary to revert ingrained neuroplastic changes related to the chronic pain. To our knowledge, we provide data for the first time in vivo that there is possibly an instant increase of endogenous μ-opioid release during acute motor cortex neuromodulation with tDCS.
tDCS; PET; opioid receptors; neuroplasticity; trigeminal neuropathic pain; post-herpetic neuralgia
Predicting the trajectories of moving objects in our surroundings is important for many life scenarios, such as driving, walking, reaching, hunting and combat. We determined human subjects’ performance and task-related brain activity in a motion trajectory prediction task. The task required spatial and motion working memory as well as the ability to extrapolate motion information in time to predict future object locations. We showed that the neural circuits associated with motion prediction included frontal, parietal and insular cortex, as well as the thalamus and the visual cortex. Interestingly, deactivation of many of these regions seemed to be more closely related to task performance. The differential activity during motion prediction vs. direct observation was also correlated with task performance. The neural networks involved in our visual motion prediction task are significantly different from those that underlie visual motion memory and imagery. Our results set the stage for the examination of the effects of deficiencies in these networks, such as those caused by aging and mental disorders, on visual motion prediction and its consequences on mobility related daily activities.
The first implementation of real-time acquisition and analysis of Arterial Spin Labeling (ASL) based functional MRI time series is presented in this article. The implementation uses a pseudo-continuous labeling scheme followed by a spiral k-space acquisition trajectory. Real-time reconstruction of the images, preprocessing and regression analysis of the fMRI data were implemented on a laptop computer interfaced with the MRI scanner. The method allows the user to track the current raw data, subtraction images, and the cumulative t-statistic map overlaid on a cumulative subtraction image. The user is also able to track the time course of individual time courses, and interactively select an ROI as a nuisance covariate. The pulse sequence allows the user to adjust acquisition and labeling parameters while observing their effect on the image within two successive TRs. This method is illustrated on a stimulation paradigm consisting of simultaneous finger-tapping and visual stimulation and on a bimanual finger tapping task alternating hands.
arterial spin labeling (ASL); real-time; fMRI
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 gamma-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 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-PI-R Impulsiveness scores (rs279858 p = 0.016; rs279826 p = 0.012; haplotype p = 0.032) with a stronger effect in females (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.
Impulsiveness; GABRA2; SNP; alcohol dependence; Insula; fMRI
Using a randomized, double-blind placebo-controlled cross-over design, we showed that short-term hormone replacement therapy increases brain activation in parietal and prefrontal areas during verbal memory tasks in postmenopausal women.
To study the effects of hormone therapy on brain activation patterns during verbal memory in postmenopausal women.
A randomized, double-blind placebo-controlled cross-over study was performed.
A tertiary care university medical center.
Ten healthy postmenopausal women (age range 50-60 years) were recruited from the local community.
Women were randomized to the order they received combined hormone therapy, 5 ug ethinyl estradiol and 1 mg norethindrone acetate, and placebo. Volunteers received hormone therapy or placebo for 4 weeks, followed by a one month washout period, and then received the other treatment for 4 weeks. An fMRI was performed at the end of each 4 week treatment utilizing a verbal memory task.
Main Outcome Measure
Brain activation patterns were compared between hormone therapy and placebo.
Hormone therapy was associated with increased activation in left middle/superior frontal cortex (BA 6,9), medial frontal cortex and dorsal anterior cingulate (BA 24,32), posterior cingulate (BA 6), and left inferior parietal (BA 40) during memory encoding. All regions were significant at p ≤ 0.05 with correction for multiple comparisons.
Hormone therapy increased neural activation in frontal and parietal areas in postmenopausal women during a verbal memory task.
Brain; women’s health; neuroimaging; fMRI; verbal memory; estrogen; progestin; hormones; menopause
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 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) while viewing negative versus neutral words in the right middle temporal/angular gyrus. Among GG-homozygotes, BOLD signal in the subgenual cingulate was greater in MDD participants (n = 9) compared to controls (n = 33). Conversely, among A-carriers, BOLD signal was smaller in MDD (n = 7) compared to 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 SNP rs110402 moderates neural responses to emotional stimuli, suggesting a potential mechanism of vulnerability for the development of MDD.
Pain problems are exceedingly prevalent among psychiatric patients. Moreover, clinical impressions and neurobiological research suggest that physical and psychological aspects of pain are closely related entities. Nonetheless, remarkably few pain-related themes are presently included in psychiatric residency training.
Our objective is twofold: (1) to provide clinical and scientific rationale for psychiatric training enrichment with basic tenets of pain medicine and (2) to raise the awareness and sensitivity of clinicians, scientists and educators alike to the important yet unmet clinical and public health need.
Three lines of translational research evidence, extracted from the comprehensive literature review, are presented in support of the objective. First, the neuroanatomical and functional overlap between pain and emotion/reward/motivation brain circuits suggests integration and mutual modulation of these systems. Second, psychiatric disorders are commonly associated with alterations in pain processing, whereas chronic pain may impair emotional and neurocognitive functioning. Third, pain may serve as a functional probe for unraveling pathophysiological mechanisms inherent in psychiatric morbidity given its stressful nature for the organism.
Pain training in psychiatry will not only contribute to deeper and more sophisticated insights into pain syndromes but also into psychiatric morbidity at large regardless of patients’ pain status. Furthermore, it will ease artificial boundaries separating psychiatric and medical formulations of brain disorders, thus fostering cross-fertilizing interactions between specialists in various disciplines entrusted with the care of pain patients.
Pain; stress; reward; opioid; dopamine; nucleus accumbens; depression; anxiety; post-traumatic; borderline personality; comorbidity; education; interdisciplinary
Parental alcoholism substantially raises risk for offspring alcoholism, an effect thought to be mediated by a dysregulation in impulse control. Adult alcoholics have alterations in the frontostriatal system involved in regulating impulsive responses. However, it remains controversial whether these alterations reflect pre-existing traits predisposing to problem alcohol use, or are secondary to alcohol involvement.
Sixty-one 16 to 22 year olds were tested using a go/no-go task during functional MRI. Forty-one had at least one parent with a diagnosis of alcohol use disorder (AUD; FH+) and 20 had no parent with AUD (FH−). Two FH+ subgroups were created to disentangle alcohol involvement from preexisting risk: the FH+ control (n=20) group had low alcohol problems, differing from the FH− group only by family history. The FH+ problem group (n=21) had high alcohol problems.
The ventral caudate deactivated during successful inhibition in the FH− but not the FH+ groups, regardless of problem alcohol involvement. Regression analyses showed that ventral caudate deactivation was related to fewer externalizing problems as well as family history. Orbital and left medial prefrontal regions were deactivated in both the FH− and FH+ control groups but not the FH+ problem group. Activation in these regions was associated with alcohol and other drug use.
These findings suggest a preexisting abnormality in ventral striatal function in youth at risk for AUD, which may lead to inappropriate motivational responding; and suggest that with alcohol use, the prefrontal “control” mechanism loses efficiency, further dysregulating the frontostriatal motivational circuitry.
Adolescent; Medial Prefrontal; Ventral Striatum; Caudate; Response Inhibition; Alcoholism; Vulnerability
Cognitive benefit of postmenopausal hormone use is controversial; however, timing treatment close to menopause may increase the likelihood of preserving cognitive function. We examined effects of early-initiation hormone use on visual working memory, hypothesizing that long-term hormone use is associated with greater brain activation during visual working memory.
This is a cross-sectional comparison of long-term early hormone users – current (n=13) and past (n=24, 2.1±1.0 years off hormones) – to never-users (n=18), using a visual memory task and functional MRI. We evaluated 55 women over age 60 at the University of Michigan’s General Clinical Research Center. Hormone users had completed at least ten continuous years of conjugated equine estrogens with or without medroxyprogesterone acetate, began within two years of menopause. Women were excluded for illness, medication, intermittent estrogen use, phytoestrogen use, recent smoking, and MRI contraindications. The primary outcome was functional MRI-detected brain activity during the visual memory task.
Compared to never-users, both hormone-user groups had increased activation in the frontal and parietal cortices, insula, hippocampus, and cingulate; combined hormone-users also had increased activation in the putamen and raphe (corrected p<0.05 or uncorrected p<0.001 with a priori hypothesis). Across the entire sample, medial temporal cortex (p<0.000 right; p<0.018 left) and right hippocampus (p<0.000) positively correlated with task performance.
Hormone use was associated with increased brain activation during the visual memory task, in regions used for visual working memory. A positive correlation between activation and task performance suggests that early-initiated long-term postmenopausal hormone use may benefit visual working memory.
Estrogen; Hormone Therapy; Postmenopause; Functional Magnetic Resonance Imaging; Memory; Cognition
With the dawn of the 21st Century, imaging has assumed a new role in disease-oriented science. Regarding pain, the emphasis clearly turned from structural to functional imaging with functional molecular imaging assuming the leading edge. This trend parallels the efforts of biologists working to understand the molecular messages of cell and cell systems’ of relevance to human disease processes. While originally imaging has been a stand-alone, documentary tool, today’s metabolic and molecular imaging technologies provide quantitative insight into inter-and intra-individual pathogenetic processes of relevance to human disease, complementing and expanding upon bench-type research. Imaging has become an indispensable tool in pain research.
Functional imaging; metabolic imaging; molecular imaging; fMRI; PET; SPECT; complex disease