Aging, cingulate cortex, and cognition: insights from structural MRI, emotional recognition, and theory of mind.

The cingulate cortex is a limbic structure involved in multiple functions, including emotional processing, pain, cognition, memory, and spatial orientation. The main goal of this structural Magnetic Resonance Imaging (MRI) study was to investigate whether age affects the cingulate cortex uniformly across its anteroposterior dimensions and determine if the effects of age differ based on sex, hemisphere, and regional cingulate anatomy, in a large cohort of healthy individuals across the adult lifespan. The second objective aimed to explore whether the decline in emotional recognition accuracy and Theory of Mind (ToM) is linked to the potential age-related reductions in the pregenual anterior cingulate (ACC) and anterior midcingulate (MCC) cortices. We recruited 126 healthy participants (18-85 years) for this study. MRI datasets were acquired on a 4.7 T system. The cingulate cortex was manually segmented into the pregenual ACC, anterior MCC, posterior MCC, and posterior cingulate cortex (PCC). We observed negative relationships between the presence and length of the superior cingulate gyrus and bilateral volumes of pregenual ACC and anterior MCC. Age showed negative effects on the volume of all cingulate cortical subregions bilaterally except for the right anterior MCC. Most of the associations between age and the cingulate subregional volumes were linear. We did not find a significant effect of sex on cingulate cortical volumes. However, stronger effects of age were observed in men compared to women. This study also demonstrated that performance on an emotional recognition task was linked to pregenual ACC volume, whist the ToM capabilities were related to the size of pregenual ACC and anterior MCC. These results suggest that the cingulate cortex contributes to emotional recognition ability and ToM across the adult lifespan.

Emotional recognition across the adult lifespan: Effects of age, sex, cognitive empathy, alexithymia traits, and amygdala subnuclei volumes.

The ability to recognize others' emotions is vital to everyday life. The goal of this study was to assess which emotions show age-related decline in recognition accuracy of facial emotional expressions across the entire adult lifespan and how this process is related to cognitive empathy (Theory of Mind [ToM]), alexithymia traits, and amygdala subnuclei volumes in a large cohort of healthy individuals. We recruited 140 healthy participants 18-85 years old. Facial affect processing was assessed with the Penn Emotion Recognition task (ER40) that contains images of the five basic emotions: Neutral, Happy, Sad, Angry, and Fearful. Structural magnetic resonance imaging (MRI) datasets were acquired on a 4.7T MRI system. Structural equation modeling was used to test the relationship between studied variables. We found that while both sexes demonstrated age-related reduction in recognition of happy emotions and preserved recognition of sadness, male participants showed age-related reduction in recognition of fear, while in female participants, age-related decline was linked to recognition of neutral and angry facial expressions. In both sexes, accurate recognition of sadness negatively correlated with alexithymia traits. On the other hand, better ToM capabilities in male participants were associated with improvement in recognition of positive and neutral emotions. Finally, none of the observed age-related reductions in emotional recognition were related to amygdala and its subnuclei volumes. In contrast, both global volume of amygdala and its cortical and centromedial subnuclei had significant direct effects on recognition of sad images.

Effects of prenatal alcohol exposure on neurobehavioural development and volume of rostral cingulate cortex subregions.

BACKGROUND: Maternal alcohol consumption during pregnancy can have widespread and long-lasting effects on children's cognition, behaviour, brain function and structure. The pregenual anterior cingulate cortex (ACC) and the anterior midcingulate cortex (MCC) mediate emotional and cognitive behaviours that are affected by prenatal alcohol exposure. However, the neurobehavioural development of the pregenual ACC and anterior MCC has not been examined in people with prenatal alcohol exposure. METHODS: We recruited 30 children and adolescents with prenatal alcohol exposure and 50 age- and gender-matched unexposed controls. We acquired structural MRI data sets on a 3 T scanner. We manually delineated 2 areas of the rostral cingulate cortex - the pregenual ACC and the anterior MCC - and compared them between groups. We measured behavioural and emotional problems using the Behaviour Assessment System for Children, 2nd Edition, Parent Rating Scale, and then explored their associations with rostral cingulate cortex volumes. RESULTS: Intracranial-normalized volumes of the right pregenual ACC and the right total rostral cingulate cortex were significantly smaller in individuals with prenatal alcohol exposure than in unexposed controls. The volume of the right anterior MCC had a significant positive association with scores on the Internalizing Problems scale in individuals with prenatal alcohol exposure. LIMITATIONS: This study was cross-sectional, and detailed information about the timing and amount of exposure was not always available. CONCLUSION: Prenatal alcohol exposure is associated with lower volumes in the right pregenual ACC. This finding may underlie some of the emotional and behavioural problems experienced by individuals with prenatal alcohol exposure.

Selective Effects of Healthy Cognitive Aging and Catechol-O-Methyl Transferase Polymorphism on Limbic White Matter Tracts.

Introduction: The cingulum bundle and uncinate fasciculus are major limbic white matter tracts involved in emotion, memory, and cognition. The main goal of the present study was to investigate the relationship between age and structural properties of the uncinate fasciculus and the cingulum bundle using diffusion tensor imaging (DTI) tractography in a large cohort of healthy individuals. The second goal was to determine the effects of the catechol-O-methyl transferase (COMT) gene polymorphism on the DTI measurements of these white matter tracts. Methods: We recruited 140 healthy participants (18-85 years old). DTI data sets were acquired on a 1.5T magnetic resonance imaging system. The rostral, dorsal, and parahippocampal cingulum, as well as uncinate fasciculus, were delineated using deterministic tractography. Fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivities, tract volume, linear (Cl), planar (Cp), and spherical (Cs) tensor shapes were calculated. The COMT polymorphism (methionine homozygous vs. valine carriers) was determined using single nucleotide polymorphism. Results: We found that age was negatively associated with FA, but positively associated with MD and RD for the rostral cingulum, dorsal cingulum, and the uncinate fasciculus but not for the parahippocampal cingulum. Furthermore, individuals with the COMT methionine homozygous had higher FA and lower MD, RD, AD, and Cs values in the right rostral cingulum compared with the valine carriers across the entire adult life span. Discussion: This study indicates that limbic tracts might be nonuniformly affected by healthy aging, and the methionine homozygous genotype might be associated with micro/macro white matter properties of the right rostral cingulum.

Effects of childhood adversity on the volumes of the amygdala subnuclei and hippocampal subfields in individuals with major depressive disorder.

Background: Reductions in total hippocampus volume have frequently been reported in MRI studies in major depressive disorder (MDD), but reports of differences in total amygdala volume have been inconsistent. Childhood maltreatment is an important risk factor for MDD in adulthood and may affect the volume of the hippocampus and amygdala. In the present study, we examined associations between the volumes of the amygdala subnuclei and hippocampal subfields and history of childhood maltreatment in participants with MDD. Methods: We recruited 35 patients who met the DSM-IV criteria for MDD and 35 healthy controls. We acquired MRI data sets on a 4.7 T Varian Inova scanner. We manually delineated the amygdala subnuclei (lateral, basal and accessory basal nuclei, and the cortical and centromedial groups) and hippocampal subfields (cornu ammonis, subiculum and dentate gyrus) using reliable volumetric methods. We assessed childhood maltreatment using the Childhood Trauma Questionnaire in participants with MDD. Results: In participants with MDD, a history of childhood maltreatment had significant negative associations with volume in the right amygdala, anterior hippocampus and total cornu ammonis subfield bilaterally. For volumes of the amygdala subnuclei, such effects were limited to the basal, accessory basal and cortical subnuclei in the right hemisphere, but they did not survive correction for multiple comparisons. We did not find significant effects of MDD or antidepressant treatment on volumes of the amygdala subnuclei. Limitations: Our study was a cross-sectional study. Conclusion: Our results provide evidence of negative associations between history of childhood maltreatment and volumes of medial temporal lobe structures in participants with MDD. This may help to identify potential mechanisms by which maltreatment leads to clinical impacts.

Amygdala subnuclei and healthy cognitive aging.

Amygdala is a group of nuclei involved in the neural circuits of fear, reward learning, and stress. The main goal of this magnetic resonance imaging (MRI) study was to investigate the relationship between age and the amygdala subnuclei volumes in a large cohort of healthy individuals. Our second goal was to determine effects of the apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) polymorphisms on the amygdala structure. One hundred and twenty-six healthy participants (18-85 years old) were recruited for this study. MRI datasets were acquired on a 4.7 T system. Amygdala was manually segmented into five major subdivisions (lateral, basal, accessory basal nuclei, and cortical, and centromedial groups). The BDNF (methionine and homozygous valine) and APOE genotypes (ε2, homozygous ε3, and ε4) were obtained using single nucleotide polymorphisms. We found significant nonlinear negative associations between age and the total amygdala and its lateral, basal, and accessory basal nuclei volumes, while the cortical amygdala showed a trend. These age-related associations were found only in males but not in females. Centromedial amygdala did not show any relationship with age. We did not observe any statistically significant effects of APOE and BDNF polymorphisms on the amygdala subnuclei volumes. In contrast to APOE ε2 allele carriers, both older APOE ε4 and ε3 allele carriers had smaller lateral, basal, accessory basal nuclei volumes compared to their younger counterparts. This study indicates that amygdala subnuclei might be nonuniformly affected by aging and that age-related association might be gender specific.

In vivo quantification of amygdala subnuclei using 4.7 T fast spin echo imaging.

The amygdala (AG) is an almond-shaped heterogeneous structure located in the medial temporal lobe. The majority of previous structural Magnetic Resonance Imaging (MRI) volumetric methods for AG measurement have so far only been able to examine this region as a whole. In order to understand the role of the AG in different neuropsychiatric disorders, it is necessary to understand the functional role of its subnuclei. The main goal of the present study was to develop a reliable volumetric method to delineate major AG subnuclei groups using ultra-high resolution high field MRI. 38 healthy volunteers (15 males and 23 females, 21-60 years of age) without any history of medical or neuropsychiatric disorders were recruited for this study. Structural MRI datasets were acquired at 4.7 T Varian Inova MRI system using a fast spin echo (FSE) sequence. The AG was manually segmented into its five major anatomical subdivisions: lateral (La), basal (B), accessory basal (AB) nuclei, and cortical (Co) and centromedial (CeM) groups. Inter-(intra-) rater reliability of our novel volumetric method was assessed using intra-class correlation coefficient (ICC) and Dice's Kappa. Our results suggest that reliable measurements of the AG subnuclei can be obtained by image analysts with experience in AG anatomy. We provided a step-by-step segmentation protocol and reported absolute and relative volumes for the AG subnuclei. Our results showed that the basolateral (BLA) complex occupies seventy-eight percent of the total AG volume, while CeM and Co groups occupy twenty-two percent of the total AG volume. Finally, we observed no hemispheric effects and no gender differences in the total AG volume and the volumes of its subnuclei. Future applications of this method will help to understand the selective vulnerability of the AG subnuclei in neurological and psychiatric disorders.

Amygdala subnuclei response and connectivity during emotional processing.

The involvement of the human amygdala in emotion-related processing has been studied using functional magnetic resonance imaging (fMRI) for many years. However, despite the amygdala being comprised of several subnuclei, most studies investigated the role of the entire amygdala in processing of emotions. Here we combined a novel anatomical tracing protocol with event-related high-resolution fMRI acquisition to study the responsiveness of the amygdala subnuclei to negative emotional stimuli and to examine intra-amygdala functional connectivity. The greatest sensitivity to the negative emotional stimuli was observed in the centromedial amygdala, where the hemodynamic response amplitude elicited by the negative emotional stimuli was greater and peaked later than for neutral stimuli. Connectivity patterns converge with extant findings in animals, such that the centromedial amygdala was more connected with the nuclei of the basal amygdala than with the lateral amygdala. Current findings provide evidence of functional specialization within the human amygdala.

Involvement of rat dopaminergic system of nucleus accumbens in nicotine-induced anxiogenic-like behaviors.

The objective of the present study was to investigate the involvement of dopamine D1 and D2 receptors of the nucleus accumbens (NAc) shell in the anxiogenic-like effect of intra-central amygdala (CeA) nicotine administration. Male Wistar rats with cannula implants in the left CeA and the left shell of NAc were submitted to the elevated plus-maze (EPM). Intra-CeA injections of nicotine (1 µg/rat) decreased % open arm time spent (%OAT) but not % open arm entries (%OAE) and locomotor activity, indicating the possibility of an anxiogenic-like response. Intra-NAc injection of D1 dopamine receptor antagonist, SCH23390 (0.5 µg/rat) but not other doses of the antagonist (0.06, 0.125 and 0.25 µg/rat) increased both %OAT and %OAE, showing an anxiolytic-like effect for the higher dose of the drug. Similar administration route of sulpiride (0.25, 0.5, 0.75 and 1 µg/rat), a selective antagonist at dopamine D2 receptor, had no significant effect on OAT%, OAE% and locomotor activity. Moreover, intra-CeA injection of nicotine (1 µg) with intra-NAc injection of sub-threshold doses of antagonists increased %OAT and %OAE without significant effect on locomotor activity. These findings may suggest the involvement of dopamine transmission, through D1 and D2 receptors of NAc shell, in the anxiogenic-like effect of nicotine in the EPM task.

Nicotine-induced anxiogenic-like behaviours of rats in the elevated plus-maze: possible role of NMDA receptors of the central amygdala.

The objective of the present study was to investigate the possible role of the N-methyl-D-aspartate (NMDA) receptor system of the central amygdala (CeA) in the anxiogenic-like effect of nicotine. Male Wistar rats with cannulas aimed to the CeA were submitted to the elevated plus-maze (EPM). Intraperitoneal (i.p.) injections of nicotine (0.6 and 0.8 mg/kg) decreased percentage open arm time spent (%OAT) and percentage open arm entries (%OAE), but not locomotor activity, indicating an anxiogenic-like response. Bilateral intra-CeA microinjection of NMDA (0.005-0.1 µ g/rat) decreased %OAT, but not %OAE and locomotor activity. Moreover, intra-CeA microinjection of NMDA (0.05 µ g) with an ineffective dose of nicotine (0.4 mg/kg, i.p.) reduced %OAT and %OAE without effect on locomotor activity. On the other hand, intra-CeA microinjection of the NMDA receptor antagonist D-AP5 (0.05-0.5 µ g/rat) increased both %OAT and %OAE, showing an anxiolytic-like effect of the drug. Co-administration of the same doses of D-AP5 with nicotine (0.6 mg/kg, i.p.) increased %OAT and %OAE, but not locomotor activity. Intra-CeA microinjection of D-AP5 reversed the response induced by NMDA (0.1 µ g/rat) in the EPM. The results may support the possible involvement of glutamate transmission, through NMDA receptors of central amygdala in the anxiogenic-like effect of nicotine in the EPM task.