Brain activation during emotion regulation in women with premenstrual dysphoric disorder.

BACKGROUND: Difficulties in regulating emotions are linked to the core symptoms of premenstrual dysphoric disorder (PMDD). We therefore investigated the neural substrates of emotion-regulation problems in women with PMDD. METHODS: On the basis of self-evaluations over 2 months on the Daily Record of Severity of Problems, eligible participants were assigned to two groups: PMDD and control (18 per group). Functional magnetic resonance imaging (fMRI) and a well-validated task were used to assess brain function during emotion regulation. Participants were tested twice, once during the follicular (asymptomatic) and once in the late luteal (symptomatic) phase of the menstrual cycle. RESULTS: Women with PMDD gave higher ratings of negative affect in the luteal phase than in the follicular phase, and compared with healthy control participants during the luteal phase. A region-of-interest fMRI analysis indicated that during the late luteal phase, women with PMDD had hypoactivation in right dorsolateral prefrontal cortex (dlPFC) during all conditions of the emotion-regulation task, not only in the contrast that isolated emotion regulation. An exploratory whole-brain, voxel-wise analysis showed that women with PMDD had less activation in the precentral gyrus during the luteal phase than the follicular phase, and less activation in the postcentral gyrus compared with control participants. CONCLUSIONS: During the luteal phase of the menstrual cycle, women with PMDD experience difficulty regulating emotions. Hypoactivation in the right dlPFC may contribute to this problem, but may be related more generally to other affective symptoms of PMDD. Hypofunction in the right pre- and postcentral gyri warrants additional study.

Effects of leptin deficiency and replacement on cerebellar response to food-related cues.

Leptin affects eating behavior partly by altering the response of the brain to food-related stimuli. The effects of leptin on brain structure have been observed in the cerebellum, where leptin receptors are most densely expressed, but the function of leptin in the cerebellum remains unclear. We performed a nonrandomized, prospective interventional study of three adults with genetically mediated leptin deficiency. FMRI was recorded three times each year during years 5 and 6 of leptin replacement treatment. Session 1 of each year occurred after 10 months of continuous daily replacement, session 2 after 33-37 days without leptin, and session 3 at 14-23 days after daily replacement was restored. Statistical parametric mapping software (SPM5) was employed to contrast the fMRI blood oxygenation level-dependent response to images of high-calorie foods versus images of brick walls. Covariate analyses quantified the effects of the duration of leptin replacement and concomitant changes in body mass on the cerebral responses. Longer duration of replacement was associated with more activation by food images in a ventral portion of the posterior lobe of the cerebellum, while simultaneous decreases in body mass were associated with decreased activation in a more dorsal portion of the same lobe. These findings indicate that leptin replacement reversibly alters neural function within the posterior cerebellum and modulates plasticity-dependent brain physiology in response to food cues. The results suggest an underexplored role for the posterior cerebellum in the regulation of leptin-mediated processes related to food intake.

Regional cerebral glucose metabolism and anxiety symptoms in bipolar depression: effects of levothyroxine.

We examined the relationships between regional brain activity and anxiety in bipolar depressed patients receiving adjunctive treatment with levothyroxine. Regional brain activity was assessed with positron emission tomography and [18F]fluorodeoxyglucose in 10 euthyroid, depressed bipolar women before and after 7 weeks of adjunctive therapy with levothyroxine. The primary biological measures were relative (to global) regional radioactivity as a surrogate index of glucose metabolism in pre-selected brain regions. Relationships were assessed between regional brain activity and anxiety symptoms while controlling for depression severity. At baseline, Trait Anxiety Inventory measures covaried positively with relative brain activity bilaterally in the dorsal anterior cingulate, superior temporal gyri, parahippocampal gyri, amygdala, hippocampus, ventral striatum, and right insula; state anxiety showed a similar pattern. After treatment anxiety was improved significantly. Change in trait anxiety covaried positively with changes in relative activity in right amygdala and hippocampus. Change in state anxiety covaried positively with changes in relative activity in the hippocampus bilaterally and left thalamus, and negatively with changes in left middle frontal gyrus and right dorsal anterior cingulate. Results indicate that comorbid anxiety symptoms have specific regional cerebral metabolic correlates in bipolar depression and cannot only be explained exclusively by the depressive state of the patients.

Reduced brainstem inhibition during anticipated pelvic visceral pain correlates with enhanced brain response to the visceral stimulus in women with irritable bowel syndrome.

Cognitive factors such as fear of pain and symptom-related anxiety play an important role in chronic pain states. The current study sought to characterize abnormalities in preparatory brain response before aversive pelvic visceral distention in irritable bowel syndrome (IBS) patients and their possible relationship to the consequences of distention. The brain functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to anticipated and delivered mild and moderate rectal distention was recorded from 14 female IBS patients and 12 healthy controls. During cued anticipation of distention, activity decreased in the insula, supragenual anterior cingulate cortex (sACC), amygdala, and dorsal brainstem (DBS) of controls. IBS patients showed less anticipatory inactivation. Group differences were significant in the right posterior insula and bilateral DBS. Self-rated measures of negative affect during scanning were higher in patients than controls (p < 0.001), and the anticipatory BOLD decreases in DBS were inversely correlated with these ratings. During subsequent distention, both groups showed activity increases in insula, dorsal ACC, and DBS and decreases in the infragenual ACC. The increases were more extensive in patients, producing significant group differences in dorsal ACC and DBS. The amplitude of the anticipatory decrease in the pontine portion of DBS was associated with greater activation during distention in right orbitofrontal cortex and bilateral sACC. Both regions have been associated previously with corticolimbic inhibition and cognitive coping. Deficits in preparatory inhibition of DBS, including the locus ceruleus complex and parabrachial nuclei, may interfere with descending corticolimbic inhibition and contribute to enhanced brain responsiveness and perceptual sensitivity to visceral stimuli in IBS.

D2 dopamine receptor (DRD2) gene, P300, and personality in children of alcoholics.

The D2 dopamine receptor (DRD2) gene has been associated with alcoholism and other drug use disorders. Reduced P300 amplitude has been noted in individuals with psychiatric disorders. Personality variables are also associated with reduced P300 amplitude. The current study was conducted to determine whether variants of the DRD2 would show differential relationships among P300 amplitude and personality traits. The study consisted of 101 adolescent children of alcoholics; 39 carried the A1(+) genotype (A1A1, A1A2) and 62 carried the A1(-) genotype (A2A2). The A1(+) genotype group had higher IQ and Self-Directedness scores than the A1(-) genotype group. As predicted, the negative relationship between Novelty Seeking and Harm Avoidance was present in A1(-) but not A1(+) participants. Additionally, in A1(+) but not in A1(-) participants, there was a negative relationship between Novelty Seeking and Self-Directedness and a positive relationship between P300 amplitude and Cooperativeness. The results suggest that in adolescent children of alcoholics, dopaminergic genetic determinants are critical modifiers of the relationship between neurocognitive and personality endophenotypes proposed as vulnerability markers for substance use disorders.

Effect of the TaqIA polymorphism on ethanol response in the brain.

Acute ethanol administration increases striatal dopamine release and decreases cerebral glucose metabolism. The A1 allele of the ANKK1 TaqIa polymorphism is associated with lower dopaminergic tone and greater risk for alcoholism, but the mechanisms are unclear. We hypothesized that ethanol would be more reinforcing in men with the A1 allele (A1+) than in men without it (A1-), as indicated by decreased anxiety and fatigue and altered activity in associated brain regions. In a pilot study, A1+ and A1- men (6/group) drank ethanol (0.75 ml/kg) or placebo beverages on each of 2 days. Positron emission tomography with [F-18]fluorodeoxyglucose (FDG) was used to assess regional cerebral glucose metabolism as a measure of relative brain activity while participants performed a vigilance task. Significant findings were as follows: Ethanol decreased anxiety and fatigue in A1+ men but increased them in A1- men. Ethanol increased activity in the striatum and insula of A1+ men, but reduced activity in the anterior cingulate of A1- men. Reduced anxiety and fatigue in A1+ men were significantly associated with greater activity within a right orbitofrontal region previously implicated in cognitive control, and less activity in structures associated with anxiety (amygdala), fatigue (thalamus), and craving/reinforcement (striatum). In contrast, anxiety and fatigue changes were unrelated to brain activity in A1- men. Although these results require replication in a larger sample, alcohol-induced negative reinforcement may explain the greater risk for alcoholism associated with the A1 allele.

Resting-state functional connectivity in women with PMDD.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is an understudied, debilitating disorder of women. Given evidence for prefrontal cortical and limbic dysfunction in PMDD, we compared intrinsic connectivity of the executive control network (ECN), default mode network (DMN), and amygdala in women with PMDD vs. controls. METHODS: Thirty-six women (18 PMDD, 18 control) participated in fMRI during the follicular and luteal phases of the menstrual cycle. At each time, resting-state functional connectivity was evaluated both before and after participants performed an emotion regulation task. The ECN was identified using independent components analysis, and connectivity of left and right amygdala seeds was also evaluated. RESULTS: Nonparametric permutation testing identified a cluster in the left middle temporal gyrus (MTG) with significantly stronger connectivity to the left ECN in women with PMDD vs. controls in all four fMRI sessions. Women with PMDD exhibited no difference in functional connectivity between menstrual cycle phases. Amygdala connectivity did not differ between the groups but differed significantly with menstrual phase, with left amygdala connectivity to cingulate cortex being significantly stronger during the follicular vs. luteal phase. Right amygdala connectivity to the middle frontal gyrus was also stronger during the follicular vs. luteal phase, with no group differences. These findings suggest that women with PMDD have different intrinsic network dynamics in the left executive control network compared to healthy controls.

P300 development during adolescence: effects of DRD2 genotype.

OBJECTIVE: Young boys at high risk for alcoholism by having a family history of alcoholism (FH+) have lower amplitude of the visual P300 event-related scalp potential. They have also been reported to have a slowing in the rate of P300 amplitude change during adolescence. The present study examined whether the change in P300 amplitude during adolescence in sons of alcoholics and nonalcoholics is affected by D2 dopamine receptor (DRD2) polymorphism. METHODS: P300 was elicited with a visual discrimination task from 71 adolescent sons of alcoholics and social drinkers (Time 1, T1). The task was readministered 2 years later (Time 2, T2). Comparisons were made between boys who had the DRD2 A1 allele (A1+) and boys who did not (A1-), and between boys with one or both parents being alcoholic (FH+) and boys having no alcoholic parents (FH-). RESULTS: Discrimination task accuracy was lowest in the highest risk group (A1+, FH+) at T1, and highest in the lowest risk group (A1-, FH-) at T2, producing a significant interaction of allelic group x family history group x session. Reaction time was faster at T2 than T1, and this effect was larger in FH-boys (125 ms) than FH+boys (40 ms). Overall, the behavioral results suggest mild performance deficits on the discrimination task are associated with higher risk for alcoholism. In both testing sessions, P300 attained larger amplitudes in sons of nonalcoholics than sons of alcoholics. At T2 compared to T1, both the latency and amplitude of the P300 were decreased. However, while the developmental P300 latency effect was equivalent in both the A1+ and A1- allelic groups, the P300 amplitude reduction during adolescence, measured both in response to targets and in target minus non-target subtraction waveforms, was only found in boys with the A1- allele. CONCLUSION: Differences in the developmental course of P300 amplitude over the course of adolescence are dependent on DRD2 polymorphism. SIGNIFICANCE: These results suggest the importance of genetic determinants of the dopaminergic system in understanding the P300 as a risk marker for substance abuse using an integrative developmental perspective.

Cerebral metabolic dysfunction and impaired vigilance in recently abstinent methamphetamine abusers.

BACKGROUND: Methamphetamine (MA) abusers have cognitive deficits, abnormal metabolic activity and structural deficits in limbic and paralimbic cortices, and reduced hippocampal volume. The links between cognitive impairment and these cerebral abnormalities are not established. METHODS: We assessed cerebral glucose metabolism with [F-18]fluorodeoxyglucose positron emission tomography in 17 abstinent (4 to 7 days) methamphetamine users and 16 control subjects performing an auditory vigilance task and obtained structural magnetic resonance brain scans. Regional brain radioactivity served as a marker for relative glucose metabolism. Error rates on the task were related to regional radioactivity and hippocampal morphology. RESULTS: Methamphetamine users had higher error rates than control subjects on the vigilance task. The groups showed different relationships between error rates and relative activity in the anterior and middle cingulate gyrus and the insula. Whereas the MA user group showed negative correlations involving these regions, the control group showed positive correlations involving the cingulate cortex. Across groups, hippocampal metabolic and structural measures were negatively correlated with error rates. CONCLUSIONS: Dysfunction in the cingulate and insular cortices of recently abstinent MA abusers contribute to impaired vigilance and other cognitive functions requiring sustained attention. Hippocampal integrity predicts task performance in methamphetamine users as well as control subjects.

Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers.

BACKGROUND: Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood. OBJECTIVE: To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers. DESIGN: Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task. SETTING: Participants were recruited from the general community to a research center. PARTICIPANTS: Seventeen abstaining (4-7 days) MA abusers (6 women) were compared with 18 control subjects (8 women). MAIN OUTCOME MEASURES: Self-reports of depressive symptoms and anxiety were measured, as were global and relative glucose metabolism in the orbitofrontal, cingulate, lateral prefrontal, and insular cortices and the amygdala, striatum, and cerebellum. RESULTS: Abusers of MA provided higher self-ratings of depression and anxiety than control subjects and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula and higher in the lateral orbitofrontal area, middle and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA abusers, self-reports of depressive symptoms covaried positively with relative glucose metabolism in limbic regions (eg, perigenual anterior cingulate gyrus and amygdala) and ratings of state and trait anxiety covaried negatively with relative activity in the anterior cingulate cortex and left insula. Trait anxiety also covaried negatively with relative activity in the orbitofrontal cortex and positively with amygdala activity. CONCLUSIONS: Abusers of MA have abnormalities in brain regions implicated in mood disorders. Relationships between relative glucose metabolism in limbic and paralimbic regions and self-reports of depression and anxiety in MA abusers suggest that these regions are involved in affective dysregulation and may be an important target of intervention for MA dependence.

DRD2 genotypes and substance use in adolescent children of alcoholics.

Research has identified children of alcoholics (COAs) as a population at increased risk for developing substance use problems. Genetic studies support the Al allele of the D2 dopamine receptor gene (DRD2) as a risk marker for alcoholism and substance use disorders. In this study, substance use was assessed in 48 adolescent boys of alcoholics with the DRDR A1(+) allele (A1A1/A1A2 genotypes) or the A1(-) allele (A2A2 genotype). The results revealed that boys with the A1(+) allele tried (p=0.0001) and got intoxicated on alcohol more often (p=0.009) than boys with the A1(-) allele. Boys with the A1(+) allele tried more (p=0.004) and used more substances overall (p=0.008) than boys with the A1(-) allele. Boys with the A1(+) allele developed a tobacco habit more often (p=0.03) and experienced marijuana high at an earlier age (p=0.001) than boys with the A1(-) allele. The best predictors of substance use severity in boys with the A1(+) allele were Psychoticism (p=0.01) and Negative Affect (p=0.04). The results provide support for the DRD2 A1 allele as a marker identifying a subgroup of COAs at high risk for developing substance use problems.

Impaired performance in a test of decision-making by opiate-dependent tobacco smokers.

This study tested whether opiate dependence, tobacco smoking, or their combination accompanied impaired performance on the gambling task (GT), which tests decision-making. GT previously detected impairments in patients with lesions of the ventromedial prefrontal cortex and in substance abusers. Four groups were matched on demographic characteristics and intelligence: methadone-maintained smokers (n = 9) and nonsmokers (n = 9), and control (i.e., not opiate-dependent) smokers (n = 9) and nonsmokers (n = 10). The Wisconsin Card Sorting Task (WCST) was administered to test whether differences in GT performance reflected generalized deficits in prefrontal cortical function. While there were no significant group differences on the WCST, groups differed significantly on GT performance (F(3,31) = 2.95, P = 0.048), controlling for depressive symptom ratings and childhood attention deficit hyperactivity disorder. Methadone-maintained smokers (but not nonsmokers) performed more poorly than either of the two control groups (P = 0.007 versus smokers; P = 0.024 versus nonsmokers). In a planned analysis of methadone-maintained subjects, smokers scored more poorly on GT than nonsmokers (F(1,18) = 5.64, P = 0.032) and had more treatment failures (67% heroin use during the last 30 days versus 20%). The findings suggest that among opiate-dependent individuals, tobacco smoking may be a marker for a more severe form of substance abuse disorder, reflecting impaired decision-making, as modeled by GT.

Differential associations of sex and D2 dopamine receptor (DRD2) genotype with negative affect and other substance abuse risk markers in children of alcoholics.

Children of alcoholics have increased risk for substance abuse problems. Self-medication of negative affect may be one developmental path to future substance abuse. Because the 146 young (adolescent) children of alcoholics in the current sample had not used enough abused substances to study substance use directly, the relation of substance abuse risk markers to negative affect was assessed. Because the D2 dopamine receptor (DRD2) A1 allele has been associated with alcoholism and other substance use disorders, negative affect, measured by the Beck Depression Inventory (BDI), was determined in four groups of children: boys and girls with the A1+ allele (A1A1 and A1A2 genotypes) and with the A1- allele (A2A2 genotype). The other risk markers were stress, low amplitude of the P300 evoked potential, poor visuospatial functioning, novelty seeking (NS), and harm avoidance (HA). Stress was correlated with BDI scores in all groups. In contrast, low P300 was associated with BDI scores only in boys with the A1+ allele (P = .04), NS was associated with BDI scores only in girls with the A1+ allele (P = .02), and HA was associated with BDI scores only in boys with the A1- allele (P = .01). In addition, boys with the A1+ allele had lower BDI (P = .05) and HA (P = .005) scores than the respective scores for boys with the A1- allele. Girls with the A1- allele had lower HA scores compared with scores for boys with the A1- allele (P = .02). Girls with the A1+ allele had lower visuospatial functioning than that of boys with the A1+ allele (P<.001). Results indicate that both sex and DRD2 genotype modify associations between negative affect and other substance abuse risk markers.

The Cerebellum and Premenstrual Dysphoric Disorder.

The cerebellum constitutes ten percent of brain volume and contains the majority of brain neurons. Although it was historically viewed primarily as processing motoric computations, current evidence supports a more comprehensive role, where cerebro-cerebellar feedback loops also modulate various forms of cognitive and affective processing. Here we present evidence for a role of the cerebellum in premenstrual dysphoric disorder (PMDD), which is characterized by severe negative mood symptoms during the luteal phase of the menstrual cycle. Although a link between menstruation and cyclical dysphoria has long been recognized, neuroscientific investigations of this common disorder have only recently been explored. This article reviews functional and structural brain imaging studies of PMDD and the similar but less well defined condition of premenstrual syndrome (PMS). The most consistent findings are that women with premenstrual dysphoria exhibit greater relative activity than other women in the dorsolateral prefrontal cortex and posterior lobules VI and VII of the neocerebellum. Since both brain areas have been implicated in emotional processing and mood disorders, working memory and executive functions, this greater activity probably represents coactivation within a cerebro-cerebellar feedback loop regulating emotional and cognitive processing. Some of the evidence suggests that increased activity within this circuit may preserve cerebellar structure during aging, and possible mechanisms and implications of this finding are discussed.

Elevated gray matter volume of the emotional cerebellum in women with premenstrual dysphoric disorder.

OBJECTIVE: Premenstrual dysphoric disorder (PMDD) is characterized by severe, negative mood symptoms during the luteal phase of each menstrual cycle. We recently reported that women with PMDD show a greater increase in relative glucose metabolism in the posterior cerebellum from the follicular to the luteal phase, as compared with healthy women, and that the phase-related increase is proportional to PMDD symptom severity. We extended this work with a study of brain structure in PMDD. METHODS: High-resolution magnetic resonance imaging (MRI) scans were obtained from 12 women with PMDD and 13 healthy control subjects (whole-brain volume-corrected p<.05). Voxel-based morphometry was used to assess group differences in cerebral grey-matter volume (GMV), using a statistical criterion of p<.05, correcting for multiple comparisons in the whole-brain volume. RESULTS: PMDD subjects had greater GMV than controls in the posterior cerebellum but not in any other brain area. Age was negatively correlated with GMV within this region in healthy women, but not in women with PMDD. The group difference in GMV was significant for women over age 30(p=.0002) but not younger participants (p>.1). CONCLUSIONS: PMDD appears to be associated with reduced age-related loss in posterior cerebellar GMV. Although the mechanism underlying this finding is unclear, cumulative effects of symptom-related cerebellar activity may be involved.

Neuroimaging evidence of cerebellar involvement in premenstrual dysphoric disorder.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a debilitating cyclic disorder that is characterized by affective symptoms, including irritability, depression, and anxiety, which arise in the luteal phase of the menstrual cycle and resolve soon after the onset of menses. Despite a prevalence of up to 8% in women of reproductive age, few studies have investigated the brain mechanisms that underlie this disorder. METHODS: We used positron emission tomography with [(18)F] fluorodeoxyglucose and self-report questionnaires to assess cerebral glucose metabolism and mood in 12 women with PMDD and 12 healthy comparison subjects in the follicular and late luteal phases of the menstrual cycle. The primary biological end point was incorporated regional cerebral radioactivity (scaled to the global mean) as an index of glucose metabolism. Relationships between regional brain activity and mood ratings were assessed. Blood samples were taken before each session for assay of plasma estradiol and progesterone concentrations. RESULTS: There were no group differences in hormone levels in either the follicular or late luteal phase, but the groups differed in the effect of menstrual phase on cerebellar activity. Women with PMDD but not comparison subjects showed an increase in cerebellar activity (particularly in the right cerebellar vermis) from the follicular phase to the late luteal phase (p = .003). In the PMDD group, this increase in cerebellar activity was correlated with worsening of mood (p = .018). CONCLUSIONS: These findings suggest that the midline cerebellar nuclei, which have been implicated in other mood disorders, also contribute to negative mood in PMDD.

Short-term plasticity of gray matter associated with leptin deficiency and replacement.

CONTEXT: Leptin affects neurogenesis, neuronal growth, and viability. We previously reported that leptin supplementation increased gray matter (GM) concentration in the anterior cingulate gyrus (ACG), cerebellum, and inferior parietal lobule, areas that are also involved in food intake. OBJECTIVE: The aim of this study was to report the changes in brain structure at different states of leptin supplementation. DESIGN: We conducted a nonrandomized trial. SETTING AND PATIENTS: We studied three adults with congenital leptin deficiency due to a mutation in the leptin gene. INTERVENTION: Patients received treatment with recombinant methionyl human leptin, with annual 11- to 36-d periods of treatment withholding followed by treatment restoration over 3 yr. MAIN OUTCOME MEASURES: GM concentration (by voxel-based morphometry analysis of magnetic resonance scans) was correlated with body mass index (BMI) and leptin supplementation. RESULTS: Annually withholding leptin supplementation for several weeks increased BMI and reversed the original effects of leptin in the cerebellum and ACG. The changes in the ACG were consistent with an indirect effect of leptin mediated through increased BMI. In the cerebellum, where leptin receptors are most dense, GM changes appeared to be direct effects of leptin. Leptin restoration did not lead to recovery of GM in the short term but did lead to an unexpected GM increase in the posterior half of the left thalamus, particularly the pulvinar nucleus. CONCLUSION: These findings provide the first in vivo evidence of remarkably plastic, reversible, and regionally specific effects of leptin on human brain morphology. They suggest that leptin may have therapeutic value in modulating plasticity-dependent brain functions.

Sex differences in regional brain response to aversive pelvic visceral stimuli.

To explore sex differences in the response of seven brain regions to an aversive pelvic visceral stimulus, functional magnetic resonance images were acquired from 13 healthy adults (6 women) during 15 s of cued rectal distension at two pressures: 25 mmHg (uncomfortable), and 45 mmHg (mild pain), as well as during an expectation condition (no distension). Random-effects analyses combining subject data voxelwise found 45-mmHg pressure significantly activated the insular and anterior cingulate cortices in both sexes. In men only, the left thalamus and ventral striatum were also activated. Although all activations appeared more extensive in men, no sex difference attained significance. To explore the presence of deactivations, which are generally cancelled by more numerous activations when subjects are combined for each voxel, the number of activated voxels, number of deactivated voxels, and ratio of deactivated voxels to total voxels affected were assessed via random-effects, mixed-model analyses combining subject data at the region level. Greater insula activation in men compared with women was seen during the expectation condition and during the 25-mmHg distension. Greater deactivations in women were seen in the amygdala (25-mmHg distension) and midcingulate (45-mmHg distension). Women had a significantly higher proportion of deactivated voxels than men in all four subcortical structures during 25-mmHg distension. Greater familiarity of females with physiological pelvic visceral discomfort may have enhanced brain systems that dampen arousal networks during lower levels of discomfort.

Complementary hemispheric specialization for word and accent detection.

When we hear a familiar word pronounced in a foreign accent, which parts of the brain identify the word and which identify the accent? Here we present converging evidence from PET blood flow, event-related scalp potentials, and behavioral responses during dichotic listening, showing homologous and complementary hemispheric specialization for word and accent detection. Accuracy of detecting target words was greater when stimuli were presented to the right ear, indicating left hemisphere specialization, with no ear advantage for detecting target accents. Detection of words also produced increased blood flow in a left frontal area associated with motor and phonetic processing, and a left temporal area associated with semantic memory. Homologous areas of the right hemisphere, together with right prefrontal and precuneus regions, showed increased blood flow during detection of accents. Separate analyses for each detection task indicated that voxels whose activity maximally correlated with accuracy were in the left hemisphere for word detection, but in the right hemisphere for accent detection. Voxels whose activity maximally correlated with inaccuracy were in the opposite hemisphere for both tasks, strengthening the interpretation that between-task differences in brain activation are related to lateralized specializations for task performance. ERP waveforms and reaction times suggested that greater left hemisphere activation during word detection preceded greater right hemisphere activation during accent detection. The results are interpreted as supporting left hemisphere specialization for extraction of the linguistic, phonetic, and semantic information contained in speech, and right hemisphere specialization for pragmatics, the social context of linguistic communication.