Abstract
Behavioral inhibition (BI) is a genetically influenced behavioral profile seen in 15–20% of 2-year-old children. Children with BI are timid with people, objects and situations that are novel or unfamiliar, and are more reactive physiologically to these challenges as evidenced by higher heart rate, pupillary dilation, vocal cord tension and higher levels of cortisol. BI predisposes to the later development of anxiety, depression and substance abuse. Reduced hippocampal volumes have been observed in anxiety disorders, depression and posttraumatic stress disorder. Animal models have demonstrated that chronic stress can damage the hippocampal formation and implicated cortisol in these effects. We, therefore, hypothesized that the hippocampi of late adolescents who had been behaviorally inhibited as children would be smaller compared with those who had not been inhibited. Hippocampal volume was measured with high-resolution structural magnetic resonance imaging in 43 females and 40 males at 17 years of age who were determined to be BI+ or BI− based on behaviors observed in the laboratory as young children. BI in childhood predicted reduced hippocampal volumes in the adolescents who were offspring of parents with panic disorder, or panic disorder with comorbid major depression. We discuss genetic and environmental factors emanating from both child and parent that may explain these findings. To the best of our knowledge, this is the first study to demonstrate a relationship between the most extensively studied form of temperamentally based human trait anxiety, BI, and hippocampal structure. The reduction in hippocampal volume, as reported by us, suggests a role for the hippocampus in human trait anxiety and anxiety disorder that warrants further investigation.
Similar content being viewed by others
Introduction
Behavioral inhibition (BI) is a distinctive, genetically influenced1, 2 behavioral profile that is seen in 15–20% of children in the second year of life.3 Children born with an inhibited temperament (BI+) are timid with people, objects and situations that are novel or unfamiliar.3 More than 25 years before the transdiagnostic and subdiagnostic approaches in RDoC were articulated, a small group of investigators recognized the value of this human phenotype as important orthogonal approach to those then enshrined in the DSM-III for the understanding of psychiatric disorder.4, 5, 6, 7 BI was shown to be a risk factor for the subsequent development of anxiety to the unexpected and some anxiety disorders,5, 7, 8, 9 as well as depression6, 10, 11 and substance abuse12 in children, adolescents and adults.
The functional neurocircuitry of BI in humans as a putative intermediate phenotype has become an area of active investigation over the past 10 years. Longitudinal studies have shown that BI observed in childhood, as well as infant high reactivity—a precursor of BI than can be observed at 4 months of age—predict enduring differences in brain function and structure in adults that can be detected after two decades of development.13, 14, 15, 16, 17, 18, 19 Although difficult and costly, longitudinal studies remain the gold standard for identifying the developmental trajectory of this phenotype, and require the direct observation of young infants or children and multiple subsequent reassessments. Altered amygdala function in BI subjects, characterized by either increased responses to novel neutral faces and/or sustained responses to neutral faces has been detected in longitudinal samples of subjects classified in infancy or childhood,13, 17 a finding replicated in studies of adult subjects who retrospectively reported both inhibited behavior in childhood and current high levels of social inhibition.20, 21 Investigators of BI have begun to examine aspects of connectivity between the amygdala and other brain regions.22, 23, 24 In addition, other longitudinal cohorts that were first characterized in infancy have demonstrated the involvement of striatal structures in this behavioral profile.14, 16, 18, 19
Despite evidence of hippocampal involvement in mood and anxiety disorders, no studies have examined hippocampal structure or function in subjects who were characterized as BI early in life. However, in a study of young adults who respectively identified themselves on questionnaires as both extremely inhibited in childhood and as adults, hippocampal (as well as amygdala) BOLD response failed to habituate to repetitive presentations of neutral faces.21
Reduced hippocampal volumes have been observed in depression25, 26 and anxiety disorders,27, 28 and most frequently and consistently in posttraumatic stress disorder (PTSD).29, 30, 31, 32, 33, 34 Given these volumetric findings, and the demonstration that BI in childhood is a prospective risk factor for mood and anxiety disorders later in life,5, 6, 7, 8, 9, 10, 11 it is surprising that there are no previous studies of hippocampal structure in BI. Animal models provide clear evidence that severe chronic stress can damage the hippocampal formation.35 Cortisol, a stress-related hormone that can be neurotoxic, has been implicated in these effects.36 Behaviorally inhibited children are more reactive physiologically as well as behaviorally to unfamiliar or threatening situations, as evidenced by higher heart rate, pupillary dilation, vocal cord tension and, most salient here, higher levels of cortisol at some ages.3, 37 We, therefore, hypothesized that the hippocampi of late adolescents who had been behaviorally inhibited early in life would be smaller compared with those classified as not inhibited.
Materials and methods
The Massachusetts General Hospital institutional review board approved the experimental protocol. Informed consent was obtained after the nature and possible consequences of the study were explained. Hippocampal volumes were examined in 83 late adolescents enrolled in a longitudinal study who had been assessed for BI in the laboratory as young children using standardized batteries as detailed previously.8, 38, 39
Each subject underwent two three-dimensional magnetization-prepared rapid gradient-echo (MPRAGE) structural scans on a 3T Siemens (Malvern, PA, USA) TrioTim scanner (128 sagital slices; 1.3 × 1.3 × 1 mm; TR=2530 ms; TE=3.39 ms; flip angle 7°, bandwidth 190 Hz/Px). The two three-dimensional MPRAGE structural scans from each subject were averaged, after motion correction, to create a single high signal-to-noise volume.40, 41 This volume was analyzed using Freesurfer v5.0.0 (www.nmr.mgh.harvard.edu/martinos) to calculate left and right hippocampal volumes in cubic millimeters, as previously described.42, 43 Freesurfer v5.0.0 computer code is available at https://surfer.nmr.mgh.harvard.edu/fswiki/ReadOnlyCVS. Each scan was manually inspected in simultaneous sagittal, coronal and axial planes by an investigator (PSK) who was masked to the subject’s BI status to ensure accurate segmentation. The effects of both BI and familial loading (parental illness type, PIT) on hippocampal volume were analyzed with mixed models (PROC MIXED with LSMEANS/tdiff; SAS v9.3, SAS Institute, Cary, NC, USA), with left and right hippocampal volumes as intra-subject repeated measures, controlling for age, sex, socioeconomic status and intracranial volume. All the statistical tests were two sided. We controlled for socioeconomic status because studies have suggested a relationship between hippocampal volume and social class.44, 45 Additional analyses were tested for interactions between sex, BI and PIT.
Results
High-resolution structural magnetic resonance imaging was used to determine the volume of the left and right hippocampi in 43 females (mean age 17.7±1.9 years) and 40 males (mean age 17.4±1.7 years) from this longitudinal cohort. Twenty-two of the subjects who were imaged had been categorized as behaviorally inhibited (BI+) and 61 as not behaviorally inhibited (BI−) in childhood. Fourteen females and eight males were BI+; 29 females and 32 males were BI−. These subjects were offspring recruited from one of three groups of parents (1) parents with either panic disorder, or panic disorder with comorbid major depression (PD); (2) parents with major depression and no history of panic disorder (pure MD); and (3) control parents without any history of major anxiety disorder or mood disorder (CN).8, 38, 39 The young adult subjects therefore had both a measure of familial loading PIT (offspring of PD, pure MD or CN) and a measure of BI (BI+ or BI−). Table 1 gives the mean age and s.d., and the number of subjects in each cell of this 2 × 3 matrix.
Table 2 presents the mean (±s.e.m.) hippocampal volume (average of left and right) for 83 BI+ and BI− subjects in each of the three PIT groups (PD, pure MD, CN). The mean hippocampal volume in BI+ subjects when pooled across the three PIT groups (4367±126 mm3) did not differ compared with that in BI− subjects (4330±58 mm3; F(1,71)=0.09, P=0.77). However, those BI+ subjects who were offspring of PD parents did have smaller hippocampal volumes (4080±88 mm3) compared with BI− offspring of PD parents (4346±73 mm3; t(74)=2.53, P=0.01). This reduction in hippocampal volume was seen only in the BI+ offspring of PD parents, reflecting a significant BI × PIT interaction (F(2,71)=3.52, P=0.03). In contrast, in the offspring of pure MD parents, no difference was seen in hippocampal volume in BI+ vs BI− subjects (4620±147 mm3 vs 4390±99 mm3; t(71)=−1.32, P=0.20).
Underlining the fact that familial loading (PIT) alone did not account for the observed differences, neither the hippocampal volume of the BI− offspring of PD parents (4346±73 mm3) nor the hippocampal volume of BI− offspring of pure MD parents (4390±99 mm3) differed from controls (4254±84 mm3). These volumetric differences were seen in both and right hippocampi; there were no significant interactions with side (BI × PIT × sides (F(2,71)=0.01, P=0.99)). Additional analyses revealed no significant interactions involving sex (BI × sex: F(1,70)=0.03, P=0.86; PIT × sex: F(2,70)=0.3, P=0.74; BI × PIT × sex: F(1,70)=0.21, P=0.65).
Discussion
We believe this is the first study to demonstrate a relationship between a temperamental profile observed and measured in the laboratory in early childhood, BI and hippocampal structure at adolescence. In this 16-year longitudinal study, a behaviorally inhibited temperament in childhood was associated with smaller bilateral hippocampal volumes in late adolescence in the offspring of parents with PD. The reduction in hippocampal volume was not observed unless both childhood BI and parental PD were present. If we had not possessed these data on parental psychopathology, we would have come to the erroneous conclusion that there was no relationship between BI in childhood and hippocampal volumes in adulthood. Imaging studies of BI have not typically examined such relationships.
What mechanisms and pathways might lead to the decreased hippocampal volume observed in BI+ offspring of parents with PD, and what is the functional relevance of the small hippocampal volumes to state and trait anxiety, including the vulnerability to develop anxiety disorders? We suggest that the reduced hippocampal volume detected in this subset of young adults who had been behaviorally inhibited as young children reflects the interplay of genetic and environmental factors that might emanate from both child and parent. Inhibited children in the second year typically interrupt ongoing play, cease vocalizing, seek comfort from a familiar person or withdraw when presented with people, objects and situations that are novel or unfamiliar. When presented with such situations in the laboratory, behaviorally inhibited children show enhanced physiological reactivity as evidenced by a higher heart rate, decreased heart rate variability, pupillary dilation, increased vocal cord tension and higher levels of cortisol.3, 37 The hippocampus is densely populated with receptors for cortisol; stress and glucocorticoids not only cause cell and atrophy but also inhibit adult neurogenesis.46 Animal studies suggest that impairing neurogenesis in the hippocampi of adults slows the recovery of glucocorticoid levels after stress responses and increases depression-like behaviors in behavioral tests commonly used to assess antidepressant response.47 Because stress and glucocorticoids regulate the production of new neurons, a positively reinforcing toxic loop could be created for aberrant and pathological responses to stress in the future. Such a mechanism of reduced hippocampal reserve might be important in the genesis and subsequent maintenance of clinical anxiety and mood disorder in humans.
It has been suggested that an impairment in contextual fear discrimination could cause a bias towards encoding potentially ambiguous cues as threatening (the thud of fireworks vs the thud of a mortar explosion), providing a possible explanation for the overgeneralization seen in PTSD and PD.48, 49 Neuroimaging studies have implicated the hippocampus in the contextual modulation of both fear-conditioning50 and fear-extinction recall51 in healthy adults. Deficient extinction retention and attendant decreases in hippocampal activation have been reported in patients with PTSD when compared with subjects without PTSD who have been exposed to major emotional trauma.52 Antidepressant medications, which are also anxiolytic, increase adult hippocampal neurogenesis.53, 54, 55 A genetically induced increase in hippocampal neurogenesis enhances the ability of animals to differentiate between two similar conditioning contexts.56 Small hippocampal volumes, on the other hand, are associated with a failure to learn to discriminate between conditioned contexts in a contextual fear-conditioning paradigm in humans.57 A study of autonomic responses and contingency awareness during fear conditioning demonstrated that individuals with smaller hippocampal volumes were less successful in identifying the safety signal represented by the conditioned stimulus that was never followed by a painful electric shock during acquisition.58 Another line of research has demonstrated reduced hippocampal volume in subjects with childhood maltreatment31, 32, 34, 45 and one longitudinal study discovered that a reduction in hippocampal volumes not only mediated the relationship between early-life stress and trait anxiety but also predicted the levels of anxiety symptoms in response to stress 1 year later.59
The studies reviewed above suggest a functional link between the small hippocampal volumes in BI+ offspring of parents with PD, and the increased vulnerability of behavioral inhibited subjects to anxiety and anxiety disorders. Larger samples would permit mediation analyses to explore the pathways between parental illness, BI, hippocampal volume and specific illnesses or symptoms in the offspring. However, consistent with the notion of antecedent-reduced hippocampal reserve, a twin study has suggested that a smaller hippocampal volume may be a pre-existing vulnerability factor for the development of PTSD.60 Unfortunately, the incidence of serious trauma and PTSD is too low in our sample to directly investigate this potential link.
Parental PD, the second factor required for the observed reduction in hippocampal volume, could relate to the influence of parenting style and family stress on the developmental trajectory of children with BI.61, 62, 63, 64, 65, 66, 67, 68 A particularly elegant longitudinal study by Kiel and Buss68 measured both BI and maternal overprotective behavior at 2 years, as predictors of social withdrawal at 5 years of age when the children entered kindergarten. The authors defined overprotective behavior as protective behavior that occurs in novel or uncertain situations that, despite inducing discomfort for some children, present no actual danger.68 Path analyses suggested that at 2 years of age, temperamentally fearful children elicited protective behaviors from their mothers (occurring most strongly when mothers accurately predicted that their child would become upset by an upcoming situation), and that this overprotective behavior at 2 years of age, in turn, predicted social withdrawal 3 years later.68 Taking the next step along this translational path, investigators have sought to influence the interactions of parents with their BI+ offspring to decrease the probability of developing anxiety disorders.69, 70, 71, 72, 73 One longitudinal intervention study targeted the parents of BI+ children between 3 and 5 years of age at risk for anxiety with a brief education program that specifically addressed the role of overprotective behavior in maintaining anxiety. One, 2 and 3 years after the parental intervention,70, 73 the offspring of parents in the intervention group had lower rates of anxiety disorders—and 11 years later, at age 15, they showed lower rates of both anxiety and depression, when compared with a passively-monitored control group.69 These studies of parenting and studies of interventions aimed at changing parental behaviors support the plausibility and developmental salience of the BI × PIT interaction reported here and, in turn, generate testable hypotheses regarding mechanistic paths to the reduced hippocampal volumes detected in BI+ offspring of parents with PD. For example, if parents with PD were more likely to interact with their inhibited children in a stress-inducing overprotective manner that led to elevated cortisol levels in their child, this could impair hippocampal neurogenesis resulting in the decreased volumes that we detected.
Turning to consider genetic factors, twin studies have demonstrated the substantial influence of genes on inhibited temperament. In a population-based sample of more than 4500 4-year-old twin pairs,74 the largest heritability estimates (64–76%) were observed for inhibition/shyness. Overall, estimates of the heritability of BI in these studies have ranged from 0.41–0.76, with estimates as high as >0.9 for extreme BI.1, 74, 75, 76, 77, 78 These estimates are substantially higher than those reported for social anxiety disorder and other anxiety disorders (range 20–40%), suggesting that the temperamental precursor phenotype is under stronger genetic influence than the disorders to which it predisposes. Therefore, although our discussion to this point has posited a central role for environmental stress in generating the decreased hippocampal volumes in the subset of behaviorally inhibited adolescents reported here, it is also possible that the reduction in hippocampal volumes reported could have genetic determinants, and constitute a pre-existing risk factor that is subsequently amplified by experience during development. In line with this possibility, there is evidence that genetic factors independent of environmental stress can influence hippocampal size. A longitudinal study in monkeys found that hippocampal volumes in early adulthood did not differ on the basis of experimentally induced stress in the postnatal period, but the observed variation in monkey hippocampal volumes was heritable.79
Given that the reduction in hippocampal volume in our study occurred only in the subset of those BI+ subjects with PD parents, BI and PD might be characterized by partially overlapping polygenetic influences, both of which are required for the observed change in hippocampal structure. Consistent with this notion, and in light of the role, as suggested by us, of cortisol in these findings, it is interesting that an association between BI and a microsatellite marker tightly linked to the corticotropin-releasing hormone gene in 84 families of children assessed for BI was particularly marked in the offspring of parents with PD.80 This marker and multiple single-nucleotide polymorphisms encompassing the corticotropin-releasing hormone gene were subsequently genotyped in an expanded sample of families of children at risk for PD.81 The BI phenotype remained significantly associated with the microsatellite marker and was associated with several single-nucleotide polymorphisms including a single-nucleotide polymorphism in the coding sequence of the corticotropin-releasing hormone gene; haplotype-specific tests revealed an association for a haplotype comprising all the markers.81
Methodological considerations, limitations and directions for future inquiry
The present study cannot definitively disentangle the potential contributions of the genetic, developmental and environmental mechanisms to the behaviorally inhibited phenotype, including the structural differences reported here. New longitudinal studies will be needed to identify and image high-reactive infants, the infant precursor profile to BI in childhood and define the state of brain circuitry at the very beginning of the developmental trajectory of this phenotype, while gathering home-based measures of parenting and other environmental variables such as social class and the size of social networks, in concert with genome-wide association studies and studies of gene regulation and expression. Following such a cohort of infants throughout their development into young adults would elucidate both causality and mechanism, and suggest new strategies for early intervention. As the above discussion of the present findings demonstrates, the study of BI has required translational bridges between psychology and psychiatry, with a longitudinal multimethods developmental approach that could be a fruitful model for the study of other psychiatric symptomatology such as psychosis.
This report demonstrates that data about parental psychopathology may reveal relationships between brain circuitry and BI in their children that are otherwise not detectable. The finding that hippocampal volume in the offspring of pure MD parents did not differ significantly on the basis of BI status must be interpreted with caution, given the small number of subjects in the BI+/pure MD cell relative to the other main cells of interest. Although this represents a limitation of this study, one hint that this cell might convey a meaningful biological signal in the opposite direction of that seen in the offspring of PD parents was the fact that the mean hippocampal volume of subjects in this cell (4660±138 mm3) was larger than the hippocampal volume of the BI− offspring of controls (4262±67 mm3; t(74)=−2.60, P=0.01). Studies in larger samples will be required to clarify this. The fact that there was just one behaviorally inhibited subject among the offspring of the control parents (that is, families without parental PD or major depression) is consistent with reports in larger samples that BI is rare in parents without a history of PD or major depression.4, 38
The preponderance of neuroimaging literature on anxiety and anxiety disorders in humans to date has focused on the amygdala, ventromedial prefrontal cortex and anterior cingulate. The reduction in hippocampal volume reported in this longitudinal study in a subset of behaviorally inhibited adolescents, when considered in concert with a previous functional magnetic resonance imaging study showing impaired hippocampal habituation in adults who retrospectively identified themselves as inhibited children21 and recent studies in non-human primate models of anxious temperament,82, 83, 84, 85 suggests that the hippocampus has an important role in human trait anxiety and anxiety disorder that warrants further investigation.
References
Robinson J, Kagan J, Reznick J, Corley R . The heritability of inhibited and uninhibited behavior: a twin study. Dev Psychol 1992; 28: 1030–1037.
DiLalla L, Kagan J, Reznick J . Genetic etiology of behavioral inhibition among 2-year-old children. Infant Behav Dev 1994; 17: 405–412.
Kagan J, Reznick JS, Snidman N . Biological bases of childhood shyness. Science 1988; 240: 167–171.
Rosenbaum JF, Biederman J, Gersten M, Hirshfeld DR, Meminger SR, Herman JB et al. Behavioral inhibition in children of parents with panic disorder and agoraphobia. A controlled study. Arch Gen Psychiatry 1988; 45: 463–470.
Biederman J, Rosenbaum JF, Hirshfeld DR, Faraone SV, Bolduc EA, Gersten M et al. Psychiatric correlates of behavioral inhibition in young children of parents with and without psychiatric disorders. Arch Gen Psychiatry 1990; 47: 21–26.
Caspi A, Moffitt TE, Newman DL, Silva PA . Behavioral observations at age 3 years predict adult psychiatric disorders. Longitudinal evidence from a birth cohort. Arch Gen Psychiatry 1996; 53: 1033–1039.
Schwartz CE, Snidman N, Kagan J . Adolescent social anxiety as an outcome of inhibited temperament in childhood. J Am Acad Child Adolesc Psychiatry 1999; 38: 1008–1015.
Biederman J, Hirshfeld-Becker DR, Rosenbaum JF, Herot C, Friedman D, Snidman N et al. Further evidence of association between behavioral inhibition and social anxiety in children. Am J Psychiatry 2001; 158: 1673–1679.
Chronis-Tuscano A, Degnan KA, Pine DS, Perez-Edgar K, Henderson HA, Diaz Y et al. Stable early maternal report of behavioral inhibition predicts lifetime social anxiety disorder in adolescence. J Am Acad Child Adolesc Psychiatry 2009; 48: 928–935.
Caspi A, Henry B, McGee RO, Moffitt TE, Silva PA . Temperamental origins of child and adolescent behavior problems: from age three to age fifteen. Child Dev 1995; 66: 55–68.
Gladstone GL, Parker GB, Mitchell PB, Wilhelm KA, Malhi GS . Relationship between self-reported childhood behavioral inhibition and lifetime anxiety disorders in a clinical sample. Depress Anxiety 2005; 22: 103–113.
Lahat A, Perez-Edgar K, Degnan KA, Guyer AE, Lejuez CW, Ernst M et al. Early childhood temperament predicts substance use in young adults. Transl Psychiatry 2012; 2: e157.
Schwartz CE, Wright CI, Shin LM, Kagan J, Rauch SL . Inhibited and uninhibited infants "grown up": adult amygdalar response to novelty. Science 2003; 300: 1952–1953.
Guyer AE, Nelson EE, Perez-Edgar K, Hardin MG, Roberson-Nay R, Monk CS et al. Striatal functional alteration in adolescents characterized by early childhood behavioral inhibition. J Neurosci 2006; 26: 6399–6405.
Perez-Edgar K, Roberson-Nay R, Hardin MG, Poeth K, Guyer AE, Nelson EE et al. Attention alters neural responses to evocative faces in behaviorally inhibited adolescents. Neuroimage 2007; 35: 1538–1546.
Bar-Haim Y, Fox NA, Benson B, Guyer AE, Williams A, Nelson EE et al. Neural correlates of reward processing in adolescents with a history of inhibited temperament. Psychol Sci 2009; 20: 1009–1018.
Schwartz CE, Kunwar PS, Greve DN, Kagan J, Snidman NC, Bloch RB . A phenotype of early infancy predicts reactivity of the amygdala in male adults. Mol Psychiatry 2011.
Helfinstein SM, Benson B, Perez-Edgar K, Bar-Haim Y, Detloff A, Pine DS et al. Striatal responses to negative monetary outcomes differ between temperamentally inhibited and non-inhibited adolescents. Neuropsychologia 2011; 49: 479–485.
Jarcho JM, Fox NA, Pine DS, Etkin A, Leibenluft E, Shechner T et al. The neural correlates of emotion-based cognitive control in adults with early childhood behavioral inhibition. Biol Psychol 2013; 92: 306–314.
Blackford JU, Avery SN, Cowan RL, Shelton RC, Zald DH . Sustained amygdala response to both novel and newly familiar faces characterizes inhibited temperament. Soc Cogn Affect Neurosci 2011; 6: 621–629.
Blackford JU, Allen AH, Cowan RL, Avery SN . Amygdala and hippocampus fail to habituate to faces in individuals with an inhibited temperament. Soc Cogn Affect Neurosci 2013; 8: 143–150.
Hardee JE, Benson BE, Bar-Haim Y, Mogg K, Bradley BP, Chen G et al. Patterns of neural connectivity during an attention bias task moderates associations between early childhood temperament and internalizing symptoms in young adulthood. Biol Psychiatry 2013.
Blackford JU, Clauss JA, Avery SN, Cowan RL, Benningfield MM, Vanderklok RM . Amygdala-cingulate intrinsic connectivity is associated with degree of social inhibition. Biol Psychol 2014; 99C: 15–25.
Roy AK, Benson BE, Degnan KA, Perez-Edgar K, Pine DS, Fox NA et al. Alterations in amygdala functional connectivity reflect early temperament. Biol Psychol 2014; 103: 248–254.
Savitz J, Drevets WC . Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neurosci Biobehav Rev 2009; 33: 699–771.
Treadway MT, Waskom ML, Dillon DG, Holmes AJ, Park MT, Chakravarty MM et al. Illness progression, recent stress, and morphometry of hippocampal subfields and medial prefrontal cortex in major depression. Biol Psychiatry 2015; 77: 285–294.
Irle E, Ruhleder M, Lange C, Seidler-Brandler U, Salzer S, Dechent P et al. Reduced amygdalar and hippocampal size in adults with generalized social phobia. J Psychiatry Neurosci 2010; 35: 126–131.
Dresler T, Guhn A, Tupak SV, Ehlis AC, Herrmann MJ, Fallgatter AJ et al. Revise the revised? New dimensions of the neuroanatomical hypothesis of panic disorder. J Neural Transm 2013; 120: 3–29.
Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry 1995; 152: 973–981.
Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B . Hippocampal volume in women victimized by childhood sexual abuse. Psychol Med 1997; 27: 951–959.
Kitayama N, Vaccarino V, Kutner M, Weiss P, Bremner JD . Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord 2005; 88: 79–86.
Smith ME . Bilateral hippocampal volume reduction in adults with post-traumatic stress disorder: a meta-analysis of structural MRI studies. Hippocampus 2005; 15: 798–807.
Gurvits TV, Shenton ME, Hokama H, Ohta H, Lasko NB, Gilbertson MW et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 1996; 40: 1091–1099.
Bremner JD, Randall P, Vermetten E, Staib L, Bronen RA, Mazure C et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report. Biol Psychiatry 1997; 41: 23–32.
Sapolsky RM, Uno H, Rebert CS, Finch CE . Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci 1990; 10: 2897–2902.
McEwen BS . Effects of adverse experiences for brain structure and function. Biol Psychiatry 2000; 48: 721–731.
Kagan J, Reznick JS, Snidman N . The physiology and psychology of behavioral inhibition in children. Child Dev 1987; 58: 1459–1473.
Rosenbaum JF, Biederman J, Hirshfeld-Becker DR, Kagan J, Snidman N, Friedman D et al. A controlled study of behavioral inhibition in children of parents with panic disorder and depression. Am J Psychiatry 2000; 157: 2002–2010.
Hirshfeld-Becker DR, Biederman J, Henin A, Faraone SV, Davis S, Harrington K et al. Behavioral inhibition in preschool children at risk is a specific predictor of middle childhood social anxiety: a five-year follow-up. J Dev Behav Pediatr 2007; 28: 225–233.
Segonne F, Dale AM, Busa E, Glessner M, Salat D, Hahn HK et al. A hybrid approach to the skull stripping problem in MRI. Neuroimage 2004; 22: 1060–1075.
Reuter M, Rosas HD, Fischl B . Highly accurate inverse consistent registration: a robust approach. Neuroimage 2010; 53: 1181–1196.
Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002; 33: 341–355.
Fischl B, Salat DH, van der Kouwe AJ, Makris N, Segonne F, Quinn BT et al. Sequence-independent segmentation of magnetic resonance images. Neuroimage 2004; 23: S69–S84.
Hanson JL, Chandra A, Wolfe BL, Pollak SD . Association between Income and the Hippocampus. PLoS One 2011; 6: e18712.
Hanson JL, Nacewicz BM, Sutterer MJ, Cayo AA, Schaefer SM, Rudolph KD et al. Behavioral problems after early life stress: contributions of the hippocampus and amygdala. Biol Psychiatry 2015; 77: 314–323.
Mirescu C, Gould E . Stress and adult neurogenesis. Hippocampus 2006; 16: 233–238.
Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA . Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 2011; 476: 458–461.
Peri T, Ben Shakhar G, Orr SP, Shalev AY . Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder. Biol Psychiatry 2000; 47: 512–519.
Lissek S, Rabin S, Heller RE, Lukenbaugh D, Geraci M, Pine DS et al. Overgeneralization of conditioned fear as a pathogenic marker of panic disorder. Am J Psychiatry 2010; 167: 47–55.
Alvarez RP, Biggs A, Chen G, Pine DS, Grillon C . Contextual fear conditioning in humans: cortical-hippocampal and amygdala contributions. J Neurosci 2008; 28: 6211–6219.
Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL . Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry 2007; 62: 446–454.
Milad MR, Pitman RK, Ellis CB, Gold AL, Shin LM, Lasko NB et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatry 2009; 66: 1075–1082.
Malberg JE, Eisch AJ, Nestler EJ, Duman RS . Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000; 20: 9104–9110.
Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003; 301: 805–809.
Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 2008; 59: 399–412.
Sahay A, Scobie KN, Hill AS, O'Carroll CM, Kheirbek MA, Burghardt NS et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 2011; 472: 466–470.
Pohlack ST, Nees F, Liebscher C, Cacciaglia R, Diener SJ, Ridder S et al. Hippocampal but not amygdalar volume affects contextual fear conditioning in humans. Hum Brain Mapp 2012; 33: 478–488.
Cacciaglia R, Pohlack ST, Flor H, Nees F . Dissociable roles for hippocampal and amygdalar volume in human fear conditioning. Brain Struct Funct 2014.
Gorka AX, Hanson JL, Radtke SR, Hariri AR . Reduced hippocampal and medial prefrontal gray matter mediate the association between reported childhood maltreatment and trait anxiety in adulthood and predict sensitivity to future life stress. Biol Mood Anxiety Disord 2014; 4: 12.
Gilbertson MW, Shenton ME, Ciszewski A, Kasai K, Lasko NB, Orr SP et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat Neurosci 2002; 5: 1242–1247.
Arcus D, McCartney K . When baby makes four: family influences in the stability of behavioral inhibition. In: Reznick JS (ed). Perspectives on Behavioral Inhibition. University of Chicago Press: Chicago, IL, USA, 1989; pp 197–218.
Arcus D . Inhibited and uninhibited children. In: Wachs TD, Kohnstamm GA (eds). Temperament in Context. Lawrence Erlbaum Associates: Mahwah, NJ, USA, 2001; pp 43–60.
Rubin KH, Burgess KB, Hastings PD . Stability and social-behavioral consequences of toddlers' inhibited temperament and parenting behaviors. Child Dev 2002; 73: 483–495.
Kagan J, Snidman N . The Long Shadow of Temperament. Belknap Press of the Harvard University Press: Cambridge, MA, USA, 2004.
Degnan KA, Henderson HA, Fox NA, Rubin KH . Predicting social wariness in middle childhood: the moderating roles of child care history, maternal personality and maternal behavior. Soc Dev 2008; 17: 471–487.
Williams LR, Degnan KA, Perez-Edgar KE, Henderson HA, Rubin KH, Pine DS et al. Impact of behavioral inhibition and parenting style on internalizing and externalizing problems from early childhood through adolescence. J Abnorm Child Psychol 2009; 37: 1063–1075.
Degnan KA, Almas AN, Fox NA . Temperament and the environment in the etiology of childhood anxiety. J Child Psychol Psychiatry 2010; 51: 497–517.
Kiel E, Buss K . Prospective relations among fearful temperament, protective parenting, and social withdrawal: the role of maternal accuracy in a moderated mediation framework. J Abnorm Child Psychol 2011; 39: 953–966.
Rapee RM . The preventative effects of a brief, early intervention for preschool-aged children at risk for internalising: follow-up into middle adolescence. J Child Psychol Psychiatry 2013; 54: 780–788.
Rapee RM, Kennedy S, Ingram M, Edwards S, Sweeney L . Prevention and early intervention of anxiety disorders in inhibited preschool children. J Consult Clin Psychol 2005; 73: 488–497.
Hirshfeld-Becker DR, Masek B, Henin A, Blakely LR, Rettew DC, Dufton L et al. Cognitive-behavioral intervention with young anxious children. Harv Rev Psychiatry 2008; 16: 113–125.
Kennedy SJ, Rapee RM, Edwards SL . A selective intervention program for inhibited preschool-aged children of parents with an anxiety disorder: effects on current anxiety disorders and temperament. J Am Acad Child Adolesc Psychiatry 2009; 48: 602–609.
Rapee RM, Kennedy SJ, Ingram M, Edwards SL, Sweeney L . Altering the trajectory of anxiety in at-risk young children. Am J Psychiatry 2010; 167: 1518–1525.
Eley TC, Bolton D, O'Connor TG, Perrin S, Smith P, Plomin R . A twin study of anxiety-related behaviours in pre-school children. J Child Psychol Psychiatry 2003; 44: 945–960.
DiLalla L, Kagan J, Reznick J . Genetic etiology of behavioral inhibition among 2-year-old children. Infant Behav Dev 1994; 17: 405–412.
Plomin R, Emde R, Braungart J, Campos J, Corley R, Fulker D et al. Genetic change and continuity from fourteen to twenty months: the MacArthur Longitudinal Twin Study. Child Dev 1993; 64: 1354–1376.
Matheny AP Jr . Children's behavioral inhibition over age and across situations: genetic similarity for a trait during change. J Pers 1989; 57: 215–235.
Goldsmith HH, Lemery KS . Linking temperamental fearfulness and anxiety symptoms: a behavior-genetic perspective. Biol Psychiatry 2000; 48: 1199–1209.
Lyons DM, Yang C, Sawyer-Glover AM, Moseley ME, Schatzberg AF . Early life stress and inherited variation in monkey hippocampal volumes. Arch Gen Psychiatry 2001; 58: 1145–1151.
Smoller J, Rosenbaum J, Biederman J, Kennedy J, Dai D, Racette S et al. Association of a genetic marker at the corticotropin releasing hormone locus with behavioral inhibition. Biol Psychiatry 2003; 54: 1376–1381.
Smoller JW, Yamaki LH, Fagerness JA, Biederman J, Racette S, Laird NM et al. The corticotropin-releasing hormone gene and behavioral inhibition in children at risk for panic disorder. Biol Psychiatry 2005; 57: 1485–1492.
Oler JA, Fox AS, Shelton SE, Rogers J, Dyer TD, Davidson RJ et al. Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature 2010; 466: 864–868.
Fox AS, Oler JA, Shelton SE, Nanda SA, Davidson RJ, Roseboom PH et al. Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates. Proc Natl Acad Sci USA 2012; 109: 18108–18113.
Alisch RS, Chopra P, Fox AS, Chen K, White AT, Roseboom PH et al. Differentially methylated plasticity genes in the amygdala of young primates are linked to anxious temperament, an at risk phenotype for anxiety and depressive disorders. J Neurosci 2014; 34: 15548–15556.
Roseboom PH, Nanda SA, Fox AS, Oler JA, Shackman AJ, Shelton SE et al. Neuropeptide Y receptor gene expression in the primate amygdala predicts anxious temperament and brain metabolism. Biol Psychiatry 2014; 76: 850–857.
Acknowledgements
We thank the families and children who have participated in the study over 16 years. This study was supported by the National Institutes of Mental Health R01MH074848 (CES, SLR, JFR, JB). This research was carried out in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers or the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
About this article
Cite this article
Schwartz, C.E., Kunwar, P.S., Hirshfeld-Becker, D.R. et al. Behavioral inhibition in childhood predicts smaller hippocampal volume in adolescent offspring of parents with panic disorder. Transl Psychiatry 5, e605 (2015). https://doi.org/10.1038/tp.2015.95
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/tp.2015.95
This article is cited by
-
Prediction of clinical anxious and depressive problems in mid childhood amongst temperamentally inhibited preschool children: a population study
European Child & Adolescent Psychiatry (2023)
-
Predicting Temperamentally Inhibited Young Children’s Clinical-Level Anxiety and Internalizing Problems from Parenting and Parent Wellbeing: a Population Study
Journal of Abnormal Child Psychology (2019)