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.

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.

Investigating the effects of healthy cognitive aging on brain functional connectivity using 4.7 T resting-state functional magnetic resonance imaging.

Functional changes in the aging human brain have been previously reported using functional magnetic resonance imaging (fMRI). Earlier resting-state fMRI studies revealed an age-associated weakening of intra-system functional connectivity (FC) and age-associated strengthening of inter-system FC. However, the majority of such FC studies did not investigate the relationship between age and network amplitude, without which correlation-based measures of FC can be challenging to interpret. Consequently, the main aim of this study was to investigate how three primary measures of resting-state fMRI signal-network amplitude, network topography, and inter-network FC-are affected by healthy cognitive aging. We acquired resting-state fMRI data on a 4.7 T scanner for 105 healthy participants representing the entire adult lifespan (18-85 years of age). To study age differences in network structure, we combined ICA-based network decomposition with sparse graphical models. Older adults displayed lower blood-oxygen-level-dependent (BOLD) signal amplitude in all functional systems, with sensorimotor networks showing the largest age differences. Our age comparisons of network topography and inter-network FC demonstrated a substantial amount of age invariance in the brain's functional architecture. Despite architecture similarities, old adults displayed a loss of communication efficiency in our inter-network FC comparisons, driven primarily by the FC reduction in frontal and parietal association cortices. Together, our results provide a comprehensive overview of age effects on fMRI-based FC.

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.

The associations of the BDNF and APOE polymorphisms, hippocampal subfield volumes, and episodic memory performance across the lifespan.

In this study, we explored the associations between the brain derived neurotrophic factor (BDNF) and the apolipoprotein E (APOE) polymorphisms and hippocampal subfields in 127 healthy participants (18-85 years). MRI datasets were collected on a 4.7 T system. Participants were administered the Wechsler Memory Scale to evaluate episodic memory function. Significant associations of both polymorphisms were present only in older adults (≥50 years). BDNF polymorphism was associated with larger dentate gyrus volumes within the anterior hippocampus (head) in Met-carriers compared to Val/Val homozygotes. We found that in Met-carriers total hippocampal volume predicted performance on visuospatial memory tasks. APOE polymorphism was associated with larger total hippocampal volume, especially in cornu ammonis 1-3 and subiculum in APOE ɛ2 carriers compared to both ɛ4 and ɛ3 carriers, while APOE ɛ3 and ɛ4 carriers did not differ from each other. APOE polymorphism was associated with better performance on visuospatial memory tasks in APOE ε2 carriers in comparison to ε4 carriers.

Diffusion tensor imaging of the corpus callosum in healthy aging: Investigating higher order polynomial regression modelling.

Previous diffusion tensor imaging (DTI) studies confirmed the vulnerability of corpus callosum (CC) fibers to aging. However, most studies employed lower order regressions to study the relationship between age and white matter microstructure. The present study investigated whether higher order polynomial regression modelling can better describe the relationship between age and CC DTI metrics compared to lower order models in 140 healthy participants (ages 18-85). The CC was found to be non-uniformly affected by aging, with accelerated and earlier degradation occurring in anterior portion; callosal volume, fiber count, fiber length, mean fibers per voxel, and FA decreased with age while mean, axial, and radial diffusivities increased. Half of the parameters studied also displayed significant age-sex interaction or intracranial volume effects. Higher order models were chosen as the best fit, based on Bayesian Information Criterion minimization, in 16 out of 23 significant cases when describing the relationship between DTI measurements and age. Higher order model fits provided different estimations of aging trajectory peaks and decline onsets than lower order models; however, a likelihood ratio test found that higher order regressions generally did not fit the data significantly better than lower order polynomial or linear models. The results contrast the modelling approaches and highlight the importance of using higher order polynomial regression modelling when investigating associations between age and CC white matter microstructure.

Involvement of hippocampal subfields and anterior-posterior subregions in encoding and retrieval of item, spatial, and associative memories: Longitudinal versus transverse axis.

The functional role of the hippocampal formation in episodic memory has been studied using functional magnetic resonance imaging (fMRI) for many years. The hippocampus can be segmented into three major anteroposterior sections, called head, body and tail, and into the Cornu Ammonis (CA), dentate gyrus (DG), and subiculum (Sub) subfields based on its transverse axis. However, the exact role of these subregions and subfields in memory processes is less understood. In the present study we combined ultra-high-resolution structural Magnetic Resonance Imaging (MRI) at 4.7 T with an event-related high-resolution fMRI paradigm based on the 'Designs' subtest of the Wechsler Memory Scale to investigate how the hippocampal subfields and longitudinal subregions are involved in encoding and retrieval of item, spatial, and associative memories. Our results showed that during memory encoding, regardless of the type of memory being learned, all subregions and all subfields were active. During the retrieval phase, on the other hand, we observed an anterior to posterior gradient in hippocampal activity for all subfields and all types of memory. Our findings also confirmed presence of an anterior to posterior gradient in hippocampal activity during spatial learning. Comparing subfield activities to each other revealed that the DG was more active than the CA1-3 and Sub during both encoding and retrieval. Finally, our results showed that for every subfield, encoding vs. retrieval activity differences were larger in the hippocampal head than in the hippocampal body and tail. Furthermore, these encoding vs. retrieval activity differences were similar in all subfields, highlighting the importance of studying both the longitudinal and transverse axis specialization simultaneously. Current findings further elucidate the structure-function relationship between the human hippocampus and episodic memory.

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.

Differential vulnerability of hippocampal subfields and anteroposterior hippocampal subregions in healthy cognitive aging.

In the present study, we investigated whether hippocampal subfields (cornu ammonis 1-3, dentate gyrus, and subiculum) and anteroposterior hippocampal subregions (head, body, and tail) follow the same trajectory with age using structural magnetic resonance imaging. We recruited 129 healthy volunteers, aged 18-85 years. Structural magnetic resonance imaging scans were acquired on a 4.7T system. Hippocampal subfields and subregions were manually segmented using reliable volumetric protocols. We found that all effects of age on the hippocampal volumes were nonlinear and were mainly found in the hippocampal body, while the hippocampal head and the tail volumes were not associated with age. The total subiculum and the total dentate gyrus volumes were associated with age, while the total cornu ammonis 1-3 was not. Significant associations with age for the cornu ammonis 1-3 and the dentate gyrus volumes were present only in the hippocampal body, while the subiculum volumes were associated with age throughout the entire hippocampus. Subiculum volumes were more negatively related to age in men than in women.

Effects of cortisol on hippocampal subfields volumes and memory performance in healthy control subjects and patients with major depressive disorder.

Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis in major depressive disorder (MDD) is among the most consistently replicated biological findings in psychiatry. Magnetic resonance imaging (MRI) studies have consistently demonstrated that hippocampal (HC) volume is decreased in patients with MDD. The improved spatial resolution of high field strength MRI has recently enabled measurements of HC subfield volumes in vivo. The main goal of the present study was to examine the relationship between cortisol concentrations over a day and HC subfield volumes in patients with MDD compared to healthy controls and to investigate whether diurnal cortisol measures are related to memory performance. Fourteen MDD patients with moderate or severe episodes were recruited, together with 14 healthy controls. Imaging was performed using a 4.7T whole-body imaging system. HC subfields and subregions were segmented manually using previously defined protocol. Memory performance was assessed using the Wechsler Memory Scale IV. The salivary cortisol levels were measured over the course of one day. We found that cortisol awakening response to 8h (CAR-8h) was higher in MDD patients compared to controls and that this increase in CAR-8h in MDD patients correlated negatively with left total Cornu Ammonis (CA)1-3 and left HC head volume. In healthy controls mean cortisol levels were negatively associated with right total CA1-3, right HC head, and right total HC volume. In addition, in healthy controls higher CAR-8h was related to worse performance on the immediate content memory. These results provide the first in vivo evidence of the negative associations between cortisol level, CA1-3 HC subfield volume and memory performance in patients with MDD and healthy controls.

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.

Dentate gyrus volume and memory performance in major depressive disorder.

BACKGROUND: Magnetic resonance imaging (MRI) has shown lower hippocampal volume in major depressive disorder (MDD). Patients with MDD have consistently demonstrated worse performance than healthy controls a number of memory tests. Memory functions within the hippocampus in healthy younger subjects appear to be linked to cornu ammonis (CA1-3) and dentate gyrus (DG) subfields. Therefore, the main goal of the present study was to investigate whether memory deficits in MDD patients are related to reduction in hippocampal subfields volumes, particularly DG and CA 1-3. METHODS: 15 MDD patients meeting DSM-IV criteria for MDD with moderate or severe episodes were recruited, together with 15 healthy controls. We used T2-weighted 2D Fast Spin Echo (FSE) and T1-weighted 3D MPRAGE sequences at 4.7 T to compare hippocampal subfield volumes at 0.09 µl voxel volume. Participants were administered the Wechsler Memory Scale. RESULTS: MDD patients underperformed in several episodic visual memory tasks, as well as in visual working memory, compared to healthy controls. Global hippocampal volumes were similar between groups; however, MDD patients showed significantly reduced DG volumes within the hippocampal body. Duration of depression correlated with MDD patients׳ total volumes in the hippocampal body and CA1-3 and DG subfields within it. LIMITATIONS: Our study sample was relatively small and the majority of patients were on antidepressant treatment. CONCLUSIONS: Our findings suggest that DG volumes in particular may be worthy of further study to further elucidate their precise role in MDD, both by itself as well as in relation to memory.

Structural changes in hippocampal subfields in major depressive disorder: a high-field magnetic resonance imaging study.

BACKGROUND: Magnetic resonance imaging (MRI) has shown lower hippocampal volume in major depressive disorder (MDD). Preclinical and postmortem studies show that chronic stress and MDD may affect hippocampal subfields differently, but MRI spatial resolution has previously been insufficient to measure subfield volumes. METHODS: Twenty MDD participants (9 unmedicated and 11 medicated, both > 6 months) and 27 healthy control subjects were studied. We used T2-weighted two-dimensional fast spin echo and T1-weighted three-dimensional magnetization prepared rapid acquisition gradient-echo sequences at 4.7 T to compare hippocampal subfield volumes at .09 µL voxel volume. RESULTS: Unmedicated MDD participants had a lower dentate gyrus volume than control subjects or medicated MDD participants and a lower cornu ammonis (CA1-3) volume in the hippocampal body subregion than control subjects. CONCLUSIONS: Hippocampal volumes in unmedicated MDD showed evidence of localization to specific subfields and subregions, findings that appear, on the surface, consistent with preclinical evidence for localized mechanisms of hippocampal neuroplasticity. Strengths include in vivo measurement of entire hippocampal subfields and separation between unmedicated and medicated MDD. Limitations include power to control for multiple comparisons and that MRI landmarks approximate the subfields defined by cellular microstructure.

Fronto-limbic volumetric changes in major depressive disorder.

BACKGROUND: Fronto-limbic dysregulation in major depressive disorder (MDD) may be influenced by early life stress and antidepressant treatment. The present structural MRI study aimed to determine the relationship between amygdala, cingulate and subgenual prefrontal cortex volumes in MDD and their associations with child abuse and antidepressants. METHODS: Right-handed subjects (21-50 years), meeting DSM-IV criteria for MDD, either with (n=19) or without (n=20) childhood sexual or physical abuse. Healthy controls (n=34) were matched for age, sex, education and smoking. 3D-MPRAGE images with a spatial resolution of 1.5 mm×1.0 mm×1.0 mm were acquired with a Siemens Sonata 1.5 T system. Volumes of subgenual prefrontal cortex, amygdala and affective, cognitive, superior and posterior divisions of cingulate cortex were analyzed using DISPLAY software using reliable volumetric protocols. Groups were compared using ANCOVA, with intracranial volume as a covariate. RESULTS: MDD subjects had low cingulate (cognitive division) and high amygdala volumes. Low cingulate volume was related to abuse and treatment history. Amygdala volume was predicted by subgenual prefrontal and cingulate (cognitive division) volumes and the presence of paracingulate cortex. LIMITATIONS: This study was cross sectional and the sample size was limited for subgroup and correlational analyses. SUMMARY: Our data suggest that MDD may be associated with alterations in anterior cingulate cortex and amygdala. Morphological variation, early stress and stress-protective factors may contribute to differences in fronto-limbic structures in MDD.

Structural changes in the hippocampus in major depressive disorder: contributions of disease and treatment.

BACKGROUND: Previous magnetic resonance imaging (MRI) studies of patients with major depressive disorder (MDD) have consistently shown bilateral and unilateral reductions in hippocampal volume relative to healthy controls. Recent structural MRI studies have addressed the question of whether changes in the volume of hippocampal subregions may be associated with MDD. METHODS: We used a comprehensive and reliable 3-dimensional tracing protocol that enables delineation of hippocampal subregions (head, body, tail) to study changes in the hippocampus of patients with MDD. We recruited 39 MDD patients (16 medicated, 23 unmedicated) and 34 healthy age- and sex-matched controls. We acquired images using a magnetization-prepared rapid acquisition gradient echo sequence on a 1.5-T scanner with a spatial resolution of 1.5 mm x 0.5 mm x 0.5 mm. We performed volumetric analyses, blinded to diagnosis, using the interactive software package Display. All volumes were adjusted for intracranial volume. RESULTS: We found a significant reduction in the volume of the hippocampal tail bilaterally, right hippocampal head and right total hippocampus in MDD patients. Medicated MDD patients showed increased hippocampal body volume compared with both healthy controls and unmedicated patients. LIMITATIONS: This study was cross-sectional. Further prospective studies are needed to determine the direct effect of antidepressant treatment. CONCLUSION: Our results suggest that decreased hippocampal tail and hippocampal head volumes could be trait changes, whereas hippocampal body changes may be dependent on treatment. We showed that long-term antidepressant treatment may affect hippocampal volume in patients with MDD.

Aging hippocampus and amygdala.

Earlier studies suggest that the anterior hippocampus may show resilience to age-associated volume loss. This study compared high-resolution magnetic resonance images obtained from younger (n=28; age range: 22-50 years) and older (n=39; age range: 65-84 years) healthy right-handed individuals to determine whether age-related volume changes varied between the hippocampal head, body and tail. Volumetric reductions were progressively more severe from hippocampal head to tail. Amygdala volume differences were intermediate in size. Although limited by the cross-sectional design, these data suggest that hippocampal subregions show a gradient of volume reduction in healthy aging that contrasts with the preferential reduction of anterior hippocampal volumes in Alzheimer's and Parkinson's diseases.

Three-dimensional volumetric analysis and reconstruction of amygdala and hippocampal head, body and tail.

Volumetric changes in the amygdala and hippocampus are relevant to many disorders, but their close proximity makes it difficult to separate these structures by magnetic resonance imaging, leading many volumetric protocols to exclude problematic slices from analysis, or to analyze the amygdalo-hippocampal complex conjointly. The hippocampus tail is also often excluded, because of the difficulty in separating it from the thalamus. We have developed a reliable protocol for volumetric analysis and 3-D reconstruction of the amygdala and hippocampus (as a whole and in its anatomical parts). Twenty volunteers from clinical and healthy populations were recruited. T1-weighted images were acquired at 1.5 Tesla with native spatial resolution of 1.5 mm x 1.0 mm x 1.0 mm. Volumetric analyses were performed blind to diagnosis, using the interactive software package DISPLAY. Inter-rater (intrarater) intraclass correlations for the method were: 0.95 (0.88) for hippocampus tail, 0.83 (0.93) for hippocampus body, 0.95 (0.92) for hippocampus head, 0.96 (0.86) for total hippocampus and 0.86 (0.94) for amygdala. Volumes (mean+/-S.D.) corrected for intracranial volume for this mixed group were for the hippocampal tail: 0.325+/-0.087 cm(3); hippocampal body: 0.662+/-0.120 cm(3); hippocampal head: 1.23+/-0.174 cm(3); total hippocampus: 2.218+/-0.217 cm(3), and amygdala: 0.808+/-0.185 cm(3). In conclusion, the study demonstrates that the amygdala and hippocampal parts can be quantified reliably.