Structural Differences in Adult Orbital and Ventromedial Prefrontal Cortex Predicted by Infant Temperament at 4 Months of Age

“The details of these methods have been reported elsewhere.(35-46) The average volume for each subject was used to create a finite-element surface mesh model of the cortical surface, both at the gray matter–white matter junction and pial surface.”

“The average volume for each subject was used to create a finite-element surface mesh model of the cortical surface, both at the gray matter–white matter junction and pial surface.(35,36) The gray matter–white matter boundary and pial surfaces of each subject were carefully examined and edited to ensure fidelity to eac…”

“The average volume for each subject was used to create a finite-element surface mesh model of the cortical surface, both at the gray matter–white matter junction and pial surface.(35,36) The gray matter–white matter boundary and pial surfaces of each subject were carefully examined and edited to ensure fidelity to eac…”

“The details of these methods have been reported elsewhere.(35-46) The average volume for each subject was used to create a finite-element surface mesh model of the cortical surface, both at the gray matter–white matter junction and pial surface.”

“The details of these methods have been reported elsewhere.(35-46) The average volume for each subject was used to create a finite-element surface mesh model of the cortical surface, both at the gray matter–white matter junction and pial surface.”

“The details of these methods have been reported elsewhere.(35-46) The average volume for each subject was used to create a finite-element surface mesh model of the cortical surface, both at the gray matter–white matter junction and pial surface.”

“This has been cited as an advantage of FreeSurfer compared with other approaches to MRI analysis.(49) Results were visualized on a group brain generated by the actual subjects in the study rather than an average atlas brain, thereby reflecting more accurately any distinctive anatomical variation.”

“Functional neuroimaging studies support a central role for this subregion of the left OFC in hedonic processing(54,55) and the reappraisal of negative emotion in a more positive direction.(56) The posterior-lateral limb of the cluster may relate to a distinct pattern of heavy projections from the OFC to small inhibito…”

“The details of these methods have been reported elsewhere.(35-46) The average volume for each subject was used to create a finite-element surface mesh model of the cortical surface, both at the gray matter–white matter junction and pial surface.”

“Social anxiety disorder during adolescence in turn is an important predictor of subsequent depressive disorders(12) and social phobia in young adults.(13) Apreviousfunctionalmagneticresonanceimaging(MRI) study from our laboratory supported the hypothesis that the differences in physiology and behavior between inhibite…”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“pillary dilation during cognitive tasks, and vocal cord tension when speaking under moderate stress.(4,6) These physiological differences between the 2 temperamental groups were consistent with expected difAuthor Affiliations are listed at”

“The details of these methods have been reported elsewhere.(35-46) The average volume for each subject was used to create a finite-element surface mesh model of the cortical surface, both at the gray matter–white matter junction and pial surface.”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“For example, this subregion preferentially targets the lateral and dorsolateral columns of the periaqueductal gray, which are linked to defensive and somatovisceral responses.(66-70) The lateral column of the periaqueductal gray generates active avoidance and defensive behaviors including a response we called arching…”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“The 2 major contemporary maps of the human OFC are by Petrides and Mackey50 and Petrides and Pandya51 and by Price52 and Ongür et al.53 In the Petrides and colleagues map, the location of the left orbitofrontal cluster corresponded primarily to area 13, bounded by a transitional zone between 13 and 47/12 laterally, ar…”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“The posterior-lateral limb of the cluster may relate to a distinct pattern of heavy projections from the OFC to small inhibitory neurons, the intercalated cell masses of the amygdala.(57-59) These cells, interposed between the input to the basal complex and the output from the central nucleus, gate neuronal traffic an…”

“Using similar techniques, regional thickness differences in the cerebral cortex of about 10% have been found in subjects with autism (including OFC)(79) and 3% to 8% in patients with schizophrenia.(80) The variations in thickness of the cortex we report could be potenTable 4.”

“Independent prospective studies from several laboratories have demonstrated that an inhibited temperament is a risk factor for the development of anxiety disorder in childhood(8,9) and adolescence,(10) particularly social anxiety disorder.(10,11) Social anxiety disorder during adolescence in turn is an important predi…”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“Independent prospective studies from several laboratories have demonstrated that an inhibited temperament is a risk factor for the development of anxiety disorder in childhood(8,9) and adolescence,(10) particularly social anxiety disorder.(10,11) Social anxiety disorder during adolescence in turn is an important predi…”

“For example, this subregion preferentially targets the lateral and dorsolateral columns of the periaqueductal gray, which are linked to defensive and somatovisceral responses.(66-70) The lateral column of the periaqueductal gray generates active avoidance and defensive behaviors including a response we called arching…”

“Apreviousfunctionalmagneticresonanceimaging(MRI) study from our laboratory supported the hypothesis that the differences in physiology and behavior between inhibited and uninhibited temperaments might indeed reflect differential amygdalar reactivity to novelty.(14) There is rich bidirectional connectivity between the…”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“There is rich bidirectional connectivity between the ventral prefrontal cortex and the amygdala.(15,16) The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.”

“These cells, interposed between the input to the basal complex and the output from the central nucleus, gate neuronal traffic and modulate output from the central nucleus of the amygdala that produces bodily sensations that individuals interpret as signs of anxiety.(60) A previous functional MRI study suggested amygda…”

“uninhibited children who spontaneously approach unfamiliar situations.(1-4) This re-”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“The decision to define discrete groups based on the combination of motor activity and crying, rather than a continuum of reactivity, was supported by a taxonomic analysis of the 4-month data that implied that the combination of the 2 variables fit a categorical model better than a continuous one.(32,34)”

“uninhibited children who spontaneously approach unfamiliar situations.(1-4) This re-”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“The posterior-lateral limb of the cluster may relate to a distinct pattern of heavy projections from the OFC to small inhibitory neurons, the intercalated cell masses of the amygdala.(57-59) These cells, interposed between the input to the basal complex and the output from the central nucleus, gate neuronal traffic an…”

“There is rich bidirectional connectivity between the ventral prefrontal cortex and the amygdala.(15,16) The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.”

“A study of face perception showed greater activation of the right medial OFC, bilateral amygdalae, and right inferior parietal cortex when subjects viewed images of unfamiliar individuals, compared with viewing images of themselves.(75) In that study, the maximum functional MRI activation in the right medial OFC occur…”

“For example, this subregion preferentially targets the lateral and dorsolateral columns of the periaqueductal gray, which are linked to defensive and somatovisceral responses.(66-70) The lateral column of the periaqueductal gray generates active avoidance and defensive behaviors including a response we called arching…”

“The ventral prefrontal cortex, including the orbitofrontal cortex (OFC), plays a pivotal role in emotional regulation, reward processing, and an ability to inhibit behaviors.(17-31) We therefore wondered if differences in the thickness of the ventral prefrontal cortex in adults would differentiate high-reactive from l…”

“The decision to define discrete groups based on the combination of motor activity and crying, rather than a continuum of reactivity, was supported by a taxonomic analysis of the 4-month data that implied that the combination of the 2 variables fit a categorical model better than a continuous one.(32,34)”

“The posterior-lateral limb of the cluster may relate to a distinct pattern of heavy projections from the OFC to small inhibitory neurons, the intercalated cell masses of the amygdala.(57-59) These cells, interposed between the input to the basal complex and the output from the central nucleus, gate neuronal traffic an…”

“The details of the standard 45-minute battery are described elsewhere in detail.(3,5) Initially, the mother looked down at her infant smiling, but not talking, for 1 minute.”

“The striatum is activated by aversive, novel, unexpected, or intense stimuli.(78) Finally, the frequent distress vocalizations of high-reactive infants are mediated by direct projections from the medial prefrontal network to the periaqueductal gray and anterior cingulate.”

“Cortical parcellations were drawn on the anatomical atlas(48); parcellations were mapped back onto each individual subject’s surface by applying the subject-atlas registration described earlier.(36,41) For the vertex-by-vertex cluster analysis, the thickness maps for all subjects in both groups were converted to the c…”

“For example, this subregion preferentially targets the lateral and dorsolateral columns of the periaqueductal gray, which are linked to defensive and somatovisceral responses.(66-70) The lateral column of the periaqueductal gray generates active avoidance and defensive behaviors including a response we called arching…”

“Other research indicates that (a) behavioral inhibition in infancy predicts structural abnormalities in the ventromedial PFC in young adulthood (Schwartz et al., 2010); (b) early life stress mediates—via increased cortisol levels—decreased functional connectivity between the amygdala and the vmPFC…”

“Cerebellar volume differences between the two groups were not significant.”

“Taking our results and these 2 studies together (Schwartz et al. 2010; Kühn et al. 2011), this suggests that there could be a delay in maturation of the right vmPFC in subjects with elevated anxious/depressed problems, leading to thicker cortex in late teenage/early adulthood, but ultimately…”

“Second, early individual differences in brain development may lead to predispositions toward certain personality traits in adulthood [Schwartz et al., 2010] and complex abilities, such as creativity or musical skills [Gaser and Schlaug, 2003; Takeuchi et al., 2010].”

“…and risk taking at 5 years (Lahat et al. 2012), hyperreactivity in the first months of life predicts periodic syndromes at 10–11 years (Guidetti et al. 1984), and reactivity at 4 months correlates with ventromedial prefrontal structural brain differences at 18 years (Schwartz et al. 2010).”

“Although the current observations are cross-sectional, longer term implications are likely, and may begin to describe a route for recent reports suggesting the effects of early infant reactivity on adult brain structure (Schwartz et al., 2010).”

“Lysine acetylation, which neutralizes the positive charge of the amino acid, has been shown to be involved in regulation of protein interactions, DNA binding, RNA bindings, and many other various protein functions (Choudhary et al., 2009; Shakespear et al., 2011; Schwartz et al., 2010).”

“Reduced lObfc volume has also been observed in adult subjects previously classified as highreactive infants (Schwartz et al., 2010) and for cumulative adverse life events in chronically stressed subjects (Ansell et al., 2012)—groups that often display emotional dysregulation.”

“Although these studies suggest that BI-related amygdala hyperactivity can be detected into adulthood (15,50,52,53), it is difficult to disambiguate whether this dysfunction is a cause or consequence of long-term, stable inhibited temperament.”

“Given that structural abnormalities of the lateral OFC in patients with SAD and adults with behaviorally inhibited temperament probably originate early in life (Schwartz et al., 2010; Talati et al., 2013), altered responsiveness in this region might begin early before repetitive exposures to social threats.”

“Schwartz et al.(28) used a longitudinal design and compared cortical thickness in young adults with or without histories of high reactivity at 4 months of age, an early marker of BI.”

“Schwartz et al (2010) subsequently used structural MRI to show that adults who had had a lowreactive temperament in infancy showed greater left orbitofrontal cortex thickness, whereas those who had had high reactivity showed greater right ventromedial prefrontal cortex thickness.”

“The potential for OFC thickness is further supported by the observation that temperamental characteristics related to behavioral inhibition measured as early as 4 months of age are associated with thinner OFC in young adulthood (Schwartz et al., 2010).”

“…results, other studies have reported shyness-related variation in functional connectivity (Roy et al., 2014; Taber-Thomas et al., 2016), taskrelated activity (Clauss et al., 2016; Guyer et al., 2006, 2014), and structure (Schwartz et al., 2010; Sylvester et al., 2016) in networks beyond the DMN.”

“…(Clauss et al., 2014; Hill, Tessner, Wang, Carter, & McDermott, 2010), increased thickness in the ventromedial prefrontal cortex (Schwartz et al., 2010), and decreased thickness in the dorsal anterior cingulate and lateral orbitofrontal cortices (Schwartz et al., 2010; Sylvester et al., 2016).”

“The stable relation between Past-Positive TP and GMV of the OFC are consistent with the theory that Past-Positive orientation has been implicated in behavior of reinforcement to past tension experience and “low-reactive” of aversive emotional memory, which is considered to be involved in cortical thickness of prefront…”

“However, few neuroimaging studies have utilized cohorts followed from early childhood, and most of these have emphasized internalizing behaviors [11–16].”

“Moreover, 4-month-old babies with strong reactions to novel and unfamiliar stimuli showed an increase in the thickness of their cortex, speci fi - cally in the region of the right ventromedial prefrontal cortex (Schwartz et al ., 2010).”

“(Schwartz et al. 2010). to be done in a way that affirms the child and works to draw the child into empathic relationships.”

“Schwartz et al (58) have explored the relation between infant temperament at 4 months of age and its effect on 10 40 20 30 6 mths 1st yr Before birth Premature Term birth After birth Olfaction”

“This gap is particularly important as structural variations may be evident early in development and color subsequent variation in function (Schwartz et al., 2010; Sylvester et al., 2016).”

“• The limbic network, which includes the amygdala, striatum (nucleus accumbens, caudate, putamen), orbitofrontal cortex (OFC), medial temporal lobe, and rostral anterior cingulate cortex (rACC) and is implicated in threat detection, attention processes, goal maintenance, affect evaluation, and affect regulation.”

“…right frontal activation as measured by EEG in adolescence (McManis, Kagan, Snidman, & Woodward, 2002) and greater right mOFC volume in adulthood (Schwartz et al., 2010), as well as that high risk for alcohol dependence predicts greater right mOFC among adolescents (Hill, Tessner, Wang, Carter,…”

“…of children characterized as behaviorally inhibited have shown functional abnormalities in different brain regions, such as the prefrontal cortex (Schwartz et al., 2010; Sylvester et al., 2016), the cingulate cortex (Sylvester et al., 2016), the hippocampus (Blackford et al., 2013), and the…”

“The latter site mediates arching of the back, which was so frequent among high reactive infants at 4 months of age (Schwartz et al., 2010).”

“At 18 years old, individuals displayed thicker ventromedial PFC and thinner orbitofrontal cortex on magnetic resonance imaging (8).”

“The AWs inscribed in in dyn4-TAM-cube are full triadic signatures of affective traits and seemingly hardwired [52] within the three “temperamental” CSTCs [53].”

“Similar results were found by Schwartz et al (2010) who observed that temperamental differences at 4 months predicted differences in left orbital and right ventromedial PFC thickness at 18 years old [114].”

“Because Schwartz et al. used a sample of 76 participants, differences in statistical power could have contributed to the lack of replication.”

“…at 4-months-old has been shown to significantly predict behavioral inhibition (i.e., avoidance of novel stimuli) at 14-months-old (Moehler et al., 2008) and has been related to structural difference in the brain by age 18 compared to those who were uninhibited infants (Schwartz et al., 2010).”