Aaron D. Boes

Right ventromedial prefrontal cortex: a neuroanatomical correlate of impulse control in boys

Emerging data on the neural mechanisms of impulse control highlight brain regions involved in emotion and decision making, including the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC) and amygdala. Variation in the development of these regions may influence ones propensity for impulsivity and, by extension, ones vulnerability to disorders involving low impulse control (e.g. substance abuse). Here we test the hypothesis that lower impulse control is associated with structural differences in these regions, particularly on the right side, in 61 normal healthy boys aged 7-17. We assessed parent- and teacher-reported behavioral ratings of impulse control (motor impulsivity and non-planning behavior) in relation to vmPFC, ACC and amygdala volume, measured using structural magnetic resonance imaging and FreeSurfer. A regression analysis showed that the right vmPFC was a significant predictor of impulse control ratings. Follow-up tests showed (i) a significant correlation between low impulse control and decreased right vmPFC volume, especially the medial sector of the vmPFC and (ii) significantly lower right vmPFC volume in a subgroup of 20 impulsive boys relative to 20 non-impulsive boys. These results are consistent with the notion that right vmPFC provides a neuroanatomical correlate of the normal variance in impulse control observed in boys.

Rostral Anterior Cingulate Cortex Volume Correlates with Depressed Mood in Normal Healthy Children

BACKGROUND The rostral anterior cingulate cortex (rACC) has been implicated as a structural neural correlate of familial major depressive disorder, raising the possibility that the structure of this region may act as a biologic marker of depression vulnerability. The aim of the current study was to determine whether children and adolescents with depressive symptoms have lower rACC volume relative to those without symptoms and examine how a positive family history of depression affects this relationship. METHODS One hundred twelve normal healthy children (59 boys, 53 girls), age 7 to 17, without a current diagnosis or history of depression or other psychiatric illness, were recruited from the community. Mood symptoms were collected using the Pediatric Behavior Scale, a parent- and teacher-reported questionnaire. Volumetric measures of the rACC were generated using structural magnetic resonance imaging (MRI). The relationship of depressive symptoms and rACC volume was examined. RESULTS 1) The rACC volume was significantly lower in boys with subclinical depressive symptoms compared with boys with no depressive symptoms, particularly on the left side (14.6% reduction; F = 8.90, p = .005). 2) There was a negative correlation of rACC volume and depressive symptoms in boys, a finding that was more robust in subjects with a positive family history of depression. 3) In girls, there was not a significant association of depressive symptoms and rACC volume. CONCLUSIONS These findings lend further support to the notion that rACC structure may act as a biologic marker of vulnerability or trait marker of depression.

Right anterior cingulate: a neuroanatomical correlate of aggression and defiance in boys.

Variation in emotional processes may contribute to aggressive and defiant behavior. This study assessed these problem behaviors in a large sample of children and adolescents in relation to the volume of two cortical regions with prominent roles in emotion processing, the anterior cingulate cortex (ACC) and ventromedial prefrontal cortex (vmPFC). One hundred seventeen participants (61 boys, 56 girls), ages 7-17, were recruited from the community. Aggressive and defiant behavior was measured using the parent- and teacher-reported Pediatric Behavior Scale and volumetric measures were generated using structural MRI. Regression analyses indicated a significant sex X ACC volume interaction in predicting aggressive and defiant behavior, without significant results for the vmPFC. Follow-up analyses showed that aggressive and defiant behavior is associated with decreased right ACC volume in boys and a nonsignificant reduction in left ACC volume in girls. These results are consistent with the notion that the right ACC acts as a neuroanatomical correlate of aggression and defiance in boys. The authors discuss this finding in light of its implications for understanding the neural correlates of antisocial behavior.

Network localization of neurological symptoms from focal brain lesions

A traditional and widely used approach for linking neurological symptoms to specific brain regions involves identifying overlap in lesion location across patients with similar symptoms, termed lesion mapping. This approach is powerful and broadly applicable, but has limitations when symptoms do not localize to a single region or stem from dysfunction in regions connected to the lesion site rather than the site itself. A newer approach sensitive to such network effects involves functional neuroimaging of patients, but this requires specialized brain scans beyond routine clinical data, making it less versatile and difficult to apply when symptoms are rare or transient. In this article we show that the traditional approach to lesion mapping can be expanded to incorporate network effects into symptom localization without the need for specialized neuroimaging of patients. Our approach involves three steps: (i) transferring the three-dimensional volume of a brain lesion onto a reference brain; (ii) assessing the intrinsic functional connectivity of the lesion volume with the rest of the brain using normative connectome data; and (iii) overlapping lesion-associated networks to identify regions common to a clinical syndrome. We first tested our approach in peduncular hallucinosis, a syndrome of visual hallucinations following subcortical lesions long hypothesized to be due to network effects on extrastriate visual cortex. While the lesions themselves were heterogeneously distributed with little overlap in lesion location, 22 of 23 lesions were negatively correlated with extrastriate visual cortex. This network overlap was specific compared to other subcortical lesions (P < 10(-5)) and relative to other cortical regions (P < 0.01). Next, we tested for generalizability of our technique by applying it to three additional lesion syndromes: central post-stroke pain, auditory hallucinosis, and subcortical aphasia. In each syndrome, heterogeneous lesions that themselves had little overlap showed significant network overlap in cortical areas previously implicated in symptom expression (P < 10(-4)). These results suggest that (i) heterogeneous lesions producing similar symptoms share functional connectivity to specific brain regions involved in symptom expression; and (ii) publically available human connectome data can be used to incorporate these network effects into traditional lesion mapping approaches. Because the current technique requires no specialized imaging of patients it may prove a versatile and broadly applicable approach for localizing neurological symptoms in the setting of brain lesions.

Amygdala volume correlates positively with fearfulness in normal healthy girls

Research into the neural underpinnings of fear and fear-related pathology has highlighted the role of the amygdala. For instance, bilateral damage to the amygdaloid complex is associated with decreased appreciation of danger and recognition of fear in humans, whereas enlarged amygdala volume is associated with internalizing syndromes. It is unknown whether amygdala volume and fearfulness are related in the absence of pathology. We examined the correlation between normal fearfulness and amygdala morphology in 116 healthy children and adolescents (60 boys, 56 girls, age 7-17 years). Fearfulness was measured using the parent ratings on the Pediatric Behavior Scale and amygdala volumes were determined by manual tracing. We found a positive correlation between right amygdala volume in girls (r = 0.29). This relationship was more robust and present bilaterally when analyses were limited to girls with a positive nuclear family history of depression (for left r = 0.63; for right r = 0.58). In boys there was no significant relationship which may suggest that biological mechanisms differ between sexes. Given the role of enlarged amygdala volume in pathology, these findings may indicate that variation in amygdala morphology marks susceptibility to internalizing disorders.

A human brain network derived from coma-causing brainstem lesions

Objective: To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network. Methods: We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness. Results: A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks. Conclusions: Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.

Social Function in Boys with Cleft Lip and Palate: Relationship to Ventral Frontal Cortex Morphology

Isolated clefts of the lip and/or palate (ICLP) are developmental craniofacial abnormalities that have consistently been linked to increased social inhibition or shyness. Two explanations have been proposed: (1) psychosocial factors related to differences in facial appearance may lead to low self-concept and subsequent shyness, or (2) abnormal development of brain structures involved in social function, such as the ventral frontal cortex (VFC), may underlie the difference. To investigate these two possibilities this study was designed to evaluate measures of social function in relation to measures of self-concept and VFC morphology. Subjects included 30 boys (age 7-12) with ICLP and a comparison group of 43 boys without cleft in the same age category. Social function and self-concept were assessed using questionnaires with standardized scoring filled out by subjects and one of their parents. The cortical volume and surface area of the VFC, composed of the orbitofrontal cortex (OFC) and straight gyrus (SG), were evaluated using structural magnetic resonance imaging. The ICLP subjects had significantly impaired social function relative to the comparison group. No difference in self-concept was identified. VFC morphology revealed significant differences between groups, particularly decreased volume and surface area in the left SG of the ICLP group. Moreover, abnormal VFC measures were correlated with social dysfunction but measures of self-concept were not. These results are consistent with the possibility that aberrant VFC development may partially underlie social dysfunction in boys with ICLP.

Network localization of hemichorea-hemiballismus

Objective: To determine whether neuroanatomically heterogeneous strokes causing hemichorea-hemiballismus localize to a common functional network. Methods: We identified 29 cases of lesion-induced hemichorea-hemiballismus from the literature and mapped each lesion volume onto a reference brain. Using a recently validated technique termed lesion network mapping, we tested whether these lesions belonged to the same functional network. To accomplish this, the network of brain regions functionally connected to each lesion was identified using a connectome dataset from healthy participants. Network maps were overlapped to identify any region functionally connected to our set of lesions. Specificity was evaluated using a case-control design; control cohorts included a group of similar lesions randomized to different brain locations and a second group of lesions causing a separate movement disorder, asterixis. Reproducibility was evaluated using an independent cohort of 10 additional hemichorea-hemiballismus cases. Results: Lesions showed heterogeneity in anatomical location, consistent with prior reports. However, at least 90% of these lesions showed network overlap in the posterolateral putamen. This result was specific to lesions causing hemichorea-hemiballismus and reproducible in an independent cohort. The putaminal overlap site was itself connected to a broader motor network that predicted the distribution of lesions causing hemichorea-hemiballismus. Conclusions: Strokes causing hemichorea-hemiballismus, while anatomically heterogeneous, localize to a common functional network. Specifically, lesions occur in regions functionally connected to the posterolateral putamen, a region previously implicated in hyperkinetic movement disorders. Lesion network mapping may be useful in identifying the neuroanatomical substrates of heterogeneous lesion-based disorders.

Noninvasive Brain Stimulation in Pediatric Attention-Deficit Hyperactivity Disorder (ADHD) : A Review

Attention-deficit hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in the pediatric population. The clinical management of ADHD is currently limited by a lack of reliable diagnostic biomarkers and inadequate therapy for a minority of patients who do not respond to standard pharmacotherapy. There is optimism that noninvasive brain stimulation may help to address these limitations. Transcranial magnetic stimulation and transcranial direct current stimulation are 2 methods of noninvasive brain stimulation that modulate cortical excitability and brain network activity. Transcranial magnetic stimulation can be used diagnostically to probe cortical neurophysiology, whereas daily use of repetitive transcranial magnetic stimulation or transcranial direct current stimulation can induce long-lasting and potentially therapeutic changes in targeted networks. In this review, we highlight research showing the potential diagnostic and therapeutic applications of transcranial magnetic stimulation and transcranial direct current stimulation in pediatric ADHD. We also discuss the safety and ethics of using these tools in the pediatric population.

Hyperactivity, impulsivity, and inattention in boys with cleft lip and palate: relationship to ventromedial prefrontal cortex morphology

The purpose of this study is to evaluate quantitative structural measures of the ventromedial prefrontal cortex (vmPFC) in boys with isolated clefts of the lip and/or palate (ICLP) relative to a comparison group and to associate measures of brain structure with quantitative measures of hyperactivity, impulsivity, and inattentiveness. A total of 50 boys with ICLP were compared to 60 healthy boys without clefts. Magnetic resonance imaging brain scans were used to evaluate vmPFC structure. Parents and teachers provided quantitative measures of hyperactivity, impulsivity, and inattentiveness using the Pediatric Behavior Scale. Boys with ICLP had significantly higher ratings of hyperactivity/impulsivity/inattention (HII) and significantly increased volume of the right vmPFC relative to the comparison group. There was a direct relationship between HII score and vmPFC volume in both the ICLP group and control group, but the relationship was in the opposite direction: in ICLP, the higher the vmPFC volume, the higher the HII score; for the comparison group, the lower the vmPFC volume, the greater the HII score. The vmPFC is a region of the brain that governs behaviors of hyperactivity, impulsivity and inattention (HII). In boys with ICLP, there are higher levels of HII compared to the controls and this is directly related to a significantly enlarged volume of the right vmPFC. Enlargement of this region of the brain is therefore considered to be pathological in the ICLP group and supports the notion that abnormal brain structure (from abnormal brain development) is the underlying etiology for the abnormal behaviors seen in this population.