Matthew J. Sutterer

Behavioral Problems After Early Life Stress: Contributions of the Hippocampus and Amygdala

BACKGROUND Early life stress (ELS) can compromise development, with higher amounts of adversity linked to behavioral problems. To understand this linkage, a growing body of research has examined two brain regions involved with socioemotional functioning-amygdala and hippocampus. Yet empirical studies have reported increases, decreases, and no differences within human and nonhuman animal samples exposed to different forms of ELS. This divergence in findings may stem from methodological factors, nonlinear effects of ELS, or both. METHODS We completed rigorous hand-tracing of the amygdala and hippocampus in three samples of children who experienced different forms of ELS (i.e., physical abuse, early neglect, or low socioeconomic status). Interviews were also conducted with children and their parents or guardians to collect data about cumulative life stress. The same data were also collected in a fourth sample of comparison children who had not experienced any of these forms of ELS. RESULTS Smaller amygdala volumes were found for children exposed to these different forms of ELS. Smaller hippocampal volumes were also noted for children who were physically abused or from low socioeconomic status households. Smaller amygdala and hippocampal volumes were also associated with greater cumulative stress exposure and behavioral problems. Hippocampal volumes partially mediated the relationship between ELS and greater behavioral problems. CONCLUSIONS This study suggests ELS may shape the development of brain areas involved with emotion processing and regulation in similar ways. Differences in the amygdala and hippocampus may be a shared diathesis for later negative outcomes related to ELS.

Arrested development: early prefrontal lesions impair the maturation of moral judgement

Learning to make moral judgements based on considerations beyond self-interest is a fundamental aspect of moral development. A deficit in such learning is associated with poor socialization and criminal behaviour. The neural systems required for the acquisition and maturation of moral competency are not well understood. Here we show in a unique sample of neurological patients that focal lesions involving ventromedial prefrontal cortex, acquired during development, result in an abnormally egocentric pattern of moral judgement. In response to simple hypothetical moral scenarios, the patients were more likely than comparison participants to endorse self-interested actions that involved breaking moral rules or physically harming others in order to benefit themselves. This pattern (which we also found in subjects with psychopathy) differs from that of patients with adult-onset ventromedial prefrontal cortex lesions--the latter group showed normal rejection of egocentric rule violations. This novel contrast of patients with ventromedial prefrontal cortex lesions acquired during development versus during adulthood yields new evidence suggesting that the ventromedial prefrontal cortex is a critical neural substrate for the acquisition and maturation of moral competency that goes beyond self-interest to consider the welfare of others. Disruption to this affective neural system early in life interrupts moral development.

Robust Automated Amygdala Segmentation via Multi-Atlas Diffeomorphic Registration

Here, we describe a novel method for volumetric segmentation of the amygdala from MRI images collected from 35 human subjects. This approach is adapted from open-source techniques employed previously with the hippocampus (Suh et al., 2011; Wang et al., 2011a,b). Using multi-atlas segmentation and machine learning-based correction, we were able to produce automated amygdala segments with high Dice (Mean = 0.918 for the left amygdala; 0.916 for the right amygdala) and Jaccard coefficients (Mean = 0.850 for the left; 0.846 for the right) compared to rigorously hand-traced volumes. This automated routine also produced amygdala segments with high intra-class correlations (consistency = 0.830, absolute agreement = 0.819 for the left; consistency = 0.786, absolute agreement = 0.783 for the right) and bivariate (r = 0.831 for the left; r = 0.797 for the right) compared to hand-drawn amygdala. Our results are discussed in relation to other cutting-edge segmentation techniques, as well as commonly available approaches to amygdala segmentation (e.g., Freesurfer). We believe this new technique has broad application to research with large sample sizes for which amygdala quantification might be needed.

Sex-related functional asymmetry of the ventromedial prefrontal cortex in regard to decision-making under risk and ambiguity

Previous work has provided preliminary indication of sex-related functional asymmetry of the ventromedial prefrontal cortex (vmPFC) in social and emotional functions and complex decision-making. Findings have been inconsistent, and based on small numbers of patients. Given the rarity of these neurological cases, replicable results across studies are important to build evidence for sex-related functional asymmetry of the vmPFC. Here we used a sample of sixteen neurological patients with unilateral damage to the left or right vmPFC and examined differences between men and women on a task that probed decision-making under risk or decision-making under ambiguity. We found that men with right-hemisphere vmPFC damage and women with left-hemisphere vmPFC damage demonstrated significantly reduced aversion to risk and ambiguity. Men with damage to the left vmPFC and women with damage to the right vmPFC showed aversion to risk and ambiguity comparable to participants with left or right-sided brain damage outside the vmPFC, and to comparison participants without brain damage. Our results add to previous findings of sex-related functional asymmetry of the vmPFC in decision-making. Our study also replicates findings of no observable behavioral differences between men and women without neurological damage on tests of decision-making. This pattern of neurobiological divergence but behavioral convergence between men and women may reflect a complex interplay of neuroendocrine, developmental, and psychosocial factors.

Mapping effective connectivity in the human brain with concurrent intracranial electrical stimulation and BOLD-fMRI

BACKGROUND Understanding brain function requires knowledge of how one brain region causally influences another. This information is difficult to obtain directly in the human brain, and is instead typically inferred from resting-state fMRI. NEW METHOD Here, we demonstrate the safety and scientific promise of a novel and complementary approach: concurrent electrical stimulation and fMRI (es-fMRI) at 3T in awake neurosurgical patients with implanted depth electrodes. RESULTS We document the results of safety testing, actual experimental setup, and stimulation parameters, that safely and reliably evoke activation in distal structures through stimulation of amygdala, cingulate, or prefrontal cortex. We compare connectivity inferred from the evoked patterns of activation with that estimated from standard resting-state fMRI in the same patients: while connectivity patterns obtained with each approach are correlated, each method produces unique results. Response patterns were stable over the course of 11min of es-fMRI runs. COMPARISON WITH EXISTING METHOD: es-fMRI in awake humans yields unique information about effective connectivity, complementing resting-state fMRI. Although our stimulations were below the level of inducing any apparent behavioral or perceptual effects, a next step would be to use es-fMRI to modulate task performances. This would reveal the acute network-level changes induced by the stimulation that mediate the behavioral and cognitive effects seen with brain stimulation. CONCLUSIONS es-fMRI provides a novel and safe approach for mapping effective connectivity in the human brain in a clinical setting, and will inform treatments for psychiatric and neurodegenerative disorders that use deep brain stimulation.

Two systems drive attention to rewards

How options are framed can dramatically influence choice preference. While salience of information plays a central role in this effect, precisely how it is mediated by attentional processes remains unknown. Current models assume a simple relationship between attention and choice, according to which preference should be uniformly biased towards the attended item over the whole time-course of a decision between similarly valued items. To test this prediction we considered how framing alters the orienting of gaze during a simple choice between two options, using eye movements as a sensitive online measure of attention. In one condition participants selected the less preferred item to discard and in the other, the more preferred item to keep. We found that gaze gravitates towards the item ultimately selected, but did not observe the effect to be uniform over time. Instead, we found evidence for distinct early and late processes that guide attention according to preference in the first case and task demands in the second. We conclude that multiple time-dependent processes govern attention during choice, and that these may contribute to framing effects in different ways.

Preschool externalizing behavior predicts gender-specific variation in adolescent neural structure.

Dysfunction in the prefrontal cortex, amygdala, and hippocampus is believed to underlie the development of much psychopathology. However, to date only limited longitudinal data relate early behavior with neural structure later in life. Our objective was to examine the relationship of early life externalizing behavior with adolescent brain structure. We report here the first longitudinal study linking externalizing behavior during preschool to brain structure during adolescence. We examined the relationship of preschool externalizing behavior with amygdala, hippocampus, and prefrontal cortex volumes at age 15 years in a community sample of 76 adolescents followed longitudinally since their mothers’ pregnancy. A significant gender by externalizing behavior interaction revealed that males—but not females—with greater early childhood externalizing behavior had smaller amygdala volumes at adolescence (t = 2.33, p = .023). No significant results were found for the hippocampus or the prefrontal cortex. Greater early externalizing behavior also related to smaller volume of a cluster including the angular gyrus and tempoparietal junction across genders. Results were not attributable to the impact of preschool anxiety, preschool maternal stress, school-age internalizing or externalizing behaviors, or adolescent substance use. These findings demonstrate a novel, gender-specific relationship between early-childhood externalizing behavior and adolescent amygdala volume, as well as a cross-gender result for the angular gyrus and tempoparietal junction.

Surgically disconnected temporal pole exhibits resting functional connectivity with remote brain regions

Functional connectivity, as measured by resting-state fMRI, has proven a powerful method for studying brain systems in the context of behavior, development, and disease states. However, the relationship of functional connectivity to structural connectivity remains unclear. If functional connectivity relies on structural connectivity, then anatomical isolation of a brain region should eliminate functional connectivity with other brain regions. We tested this by measuring functional connectivity of the surgically disconnected temporal pole in resection patients (N=5; mean age 37; 2F, 3M). Functional connectivity was evaluated based on coactivation of whole-brain fMRI data with the average low-frequency BOLD signal from disconnected tissue in each patient. In sharp contrast to our prediction, we observed significant functional connectivity between the disconnected temporal pole and remote brain regions in each disconnection case. These findings raise important questions about the neural bases of functional connectivity measures derived from the fMRI BOLD signal.

Examining neural correlates of psychopathology using a lesion-based approach

ABSTRACT Studies of individuals with focal brain damage have long been used to expand understanding of the neural basis of psychopathology. However, most previous studies were conducted using small sample sizes and relatively coarse methods for measuring psychopathology or mapping brain‐behavior relationships. Here, we examined the factor structure and neural correlates of psychopathology in 232 individuals with focal brain damage, using their responses to the Minnesota Multiphasic Personality Inventory‐2‐Restructured Form (MMPI‐2‐RF). Factor analysis and voxel‐based lesion symptom mapping were used to examine the structure and neural correlates of psychopathology in this sample. Consistent with existing MMPI‐2‐RF literature, separate internalizing, externalizing, and psychotic symptom dimensions were found. In addition, a somatic dimension likely reflecting neurological symptoms was identified. Damage to the medial temporal lobe, including the hippocampus, was associated with scales related to both internalizing problems and psychoticism. Damage to the medial temporal lobe and orbitofrontal cortex was associated with both a general distrust of others and beliefs that one is being personally targeted by others. These findings provide evidence for the critical role of dysfunction in specific frontal and temporal regions in the development of psychopathology.

Improved statistical power with a sparse shape model in detecting an aging effect in the hippocampus and amygdala

The sparse regression framework has been widely used in medical image processing and analysis. However, it has been rarely used in anatomical studies. We present a sparse shape modeling framework using the Laplace- Beltrami (LB) eigenfunctions of the underlying shape and show its improvement of statistical power. Tradition- ally, the LB-eigenfunctions are used as a basis for intrinsically representing surface shapes as a form of Fourier descriptors. To reduce high frequency noise, only the first few terms are used in the expansion and higher frequency terms are simply thrown away. However, some lower frequency terms may not necessarily contribute significantly in reconstructing the surfaces. Motivated by this idea, we present a LB-based method to filter out only the significant eigenfunctions by imposing a sparse penalty. For dense anatomical data such as deformation fields on a surface mesh, the sparse regression behaves like a smoothing process, which will reduce the error of incorrectly detecting false negatives. Hence the statistical power improves. The sparse shape model is then applied in investigating the influence of age on amygdala and hippocampus shapes in the normal population. The advantage of the LB sparse framework is demonstrated by showing the increased statistical power.