Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported i... more Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD. We examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene. While viewing fearful versus calm faces, HR-BD youth had significantly greater ac...
The prevalence of social anxiety disorder is high in offspring of parents with bipolar disorder (... more The prevalence of social anxiety disorder is high in offspring of parents with bipolar disorder (BD) and anxiety may be a significant risk factor in these youth for developing BD. We compared social anxiety symptoms between BD offspring with mood symptoms (high-risk group for developing BD I or II: HR) and healthy controls (HC). We also explored the correlations between the amygdalar volumes and social anxiety symptoms in the HR group with high social anxiety scores (HRHSA) due to the potential involvement of the amygdala in the pathophysiology of both BD and social anxiety. Youth participating in the study included 29h and 17HC of comparable age and gender. To assess social anxiety symptoms, we used the Multidimensional Anxiety Scale for Children (MASC) social anxiety subscale. The HR group's MASC social anxiety score was significantly higher than that of the HC group. Among the 29h, 17 subjects (58.6%) showed high social anxiety and they were classified as the HRHSA group. No ...
Methods: Eleven female subjects with fraX, aged 10 to 22 years, were compared with age-matched fe... more Methods: Eleven female subjects with fraX, aged 10 to 22 years, were compared with age-matched female con- trol subjects. Photographs of forward-facing and angled faces, each having direct and averted gaze (4 types of stimuli), were presented in an event-related design dur- ing functional magnetic resonance imaging. Subjects were instructed to determine the direction of gaze for each pho- tograph.
AbstractöMost functional imaging studies of memory retrieval investigate memory for standardized ... more AbstractöMost functional imaging studies of memory retrieval investigate memory for standardized laboratory stimuli. However, naturally acquired autobiographical memories di¡er from memories of standardized stimuli in important ways. Neuroimaging studies of natural memories may reveal distinctive patterns of brain activation and may have particular value in assessing clinical disorders of memory. This study used functional magnetic resonance imaging to investigate brain activation during successful retrieval of autobiographical memories elicited by name-cued recall of family members and friends. The caudal part of the left posterior cingulate cortex was the most strongly activated region and was signi¢cantly activated in all eight subjects studied. Most subjects also showed signi¢cant activation of the left anterior orbitomedial, anterior middle frontal, precuneus, cuneus, and posterior inferior parietal cortices, and the right posterior cingulate and motor cortices.
Objective Youth who experience interpersonal trauma and have posttraumatic stress symptoms (PTSS)... more Objective Youth who experience interpersonal trauma and have posttraumatic stress symptoms (PTSS) develop cognitive deficits that impact their development. Our goal is to investigate the function of the hippocampus in adolescents with PTSS during a memory processing task. Methods Twenty-seven adolescents between the ages of 10-17 years (16 with PTSS and 11 healthy controls) encoded and retrieved visually presented nouns (Verbal Declarative Memory Task) while undergoing fMRI scanning. Results The PTSS group demonstrated reduced activation of the right hippocampus during the retrieval component of the task. Further, severity of symptoms of avoidance and numbing correlated with reduced left hippocampal activation during retrieval. Conclusions Decreased activity of the hippocampus during a verbal memory task may be a neurofunctional marker of PTSS in youth with history of interpersonal trauma. The results of this study may facilitate the development of focused treatments and may be of utility when assessing treatment outcome for PTSS.
The amygdala has received great interest as a possible neurophysiological substrate of bipolar di... more The amygdala has received great interest as a possible neurophysiological substrate of bipolar disorder (BD). This review summarizes information about the structure and function of the amygdala with attention to its role in experienced emotion and mood. We review the evidence for amygdala pathology in psychiatric conditions and discuss the role of the amygdala in BD during development. There appear to be consistent findings in the neuroimaging literature that suggest an etiological model for BD that involves abnormalities in the structure and function of the amygdala, but also depends on the failure of prefrontal cortical regions to modulate amygdala activity. In addition, evidence is accumulating to suggest that this model has flexible outcomes, depending on factors intrinsic and extrinsic to BD, and may follow several possible paths across the course of maturational development.
Using functional magnetic resonance imaging (fMRI) to study brain activity related to the experie... more Using functional magnetic resonance imaging (fMRI) to study brain activity related to the experience of emotion presents unique challenges to neuroscientists. One important consideration arises when an experimentally induced subjective emotional response persists after the end of the emotional stimulation epoch. In this case, brain activity related to the emotional response may continue during the subsequent control or comparison epoch.
Turner syndrome (TS) results from partial or complete X-monosomy and is characterized by deficits... more Turner syndrome (TS) results from partial or complete X-monosomy and is characterized by deficits in visuospatial functioning as well as social cognition and memory. Neuroimaging studies have demonstrated volumetric differences in the parietal region of females with TS compared to controls. The present study examined amygdala and hippocampus morphology in an attempt to further understand the neural correlates of psychosocial and memory functioning in TS. Thirty females with TS age 7.6-33.3 years (mean = 14.7 ± 6.4) and 29 age-matched controls (mean age = 14.8 ± 5.9; range = 6.4-32.7) were scanned using high resolution MRI. Volumetric analyses of the MRI scans included whole brain segmentation and manual delineation of the amygdala and hippocampus. Compared to controls, participants with TS demonstrated significantly larger left amygdala gray matter volumes, irrespective of total cerebral tissue and age. Participants with TS also showed disproportionately reduced right hippocampal volumes, involving both gray and white matter. Amygdala and hippocampal volumes appear to be impacted by X-monosomy. Aberrant morphology in these regions may be related to the social cognition and memory deficits often experienced by individuals with TS. Further investigations of changes in medial temporal morphology associated with TS are warranted.
Journal of the American Academy of Child & Adolescent Psychiatry, 2012
Objective: Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar dis... more Objective: Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late phase of activation, suggesting different temporal characteristics of brain responses. Method: A total of 20 euthymic adolescents with familial BD (14 male) and 21 healthy control subjects (13 male) underwent fMRI scanning during presentation of happy, sad, and neutral facial expressions. Whole-brain voxelwise analyses were conducted in SPM5, using a three-way analysis of variance (ANOVA) with factors group (BD and healthy control [HC]), facial expression (happy, sad, and neutral versus scrambled), and phase (early and late, corresponding to the first and second half of each block of faces). Results: There were no significant group differences in task performance, age, gender, or IQ. Significant activation from the main effect of group included greater DLPFC activation in the HC group, and greater amygdala/ hippocampal activation in the BD group. The interaction of Group Ï« Phase identified clusters in the superior temporal sulcus/insula and visual cortex, where activation increased from the early to late phase of the block for the BD but not the HC group. Conclusions: These findings are consistent with previous studies that suggest deficient prefrontal cortex regulation of heightened amygdala response to emotional stimuli in pediatric BD. Increasing activation over time in superior temporal and visual cortices suggests difficulty processing or disengaging attention from emotional faces in BD. J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(8): 821-831.
Mood disorders are increasing in childhood, and often require multimodal and comprehensive treatm... more Mood disorders are increasing in childhood, and often require multimodal and comprehensive treatment plans to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for treatment and stabilization. Current evidence supports the use of a number of interventions in children and adolescents diagnosed with DSM-5 mood spectrum disorders, which are associated with impairments in prefrontal-striatal-limbic networks, which are key for emotional functioning and regulation. Yet, little is known about the neurobiological effects of interventions on the developing brain. This chapter provides a synopsis of the literature demonstrating the neural effects of psychotropic medications and psychotherapy in youth with depressive or bipolar spectrum disorders. Additional longitudinal and biological studies are warranted to characterize the effects of these interventions on all phases and stages of mood illness development in children and adolescents.
Hypothalamus communication with the rest of the brain and peripheral target tissues is critically... more Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the HPA-axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation.
Children of parents with bipolar disorder (BD), especially those with attention deficit hyperacti... more Children of parents with bipolar disorder (BD), especially those with attention deficit hyperactivity disorder (ADHD) and symptoms of depression or mania, are at significantly high risk for developing BD. As we have previously shown amygdalar reductions in pediatric BD, the current study examined amygdalar volumes in offspring of parents (BD offspring) who have not yet developed a full manic episode. Youth participating in the study included 22 BD offspring and 22 healthy controls of comparable age, gender, handedness, and IQ. Subjects had no history of a manic episode, but met criteria for ADHD and moderate mood symptoms. MRI was performed on a 3 T GE scanner, using a 3D volumetric spoiled gradient echo series. Amygdalae were manually traced using BrainImage Java software on positionally normalized brain stacks. Bipolar offspring had similar amygdalar volumes compared to the control group. Exploratory analyses yielded no differences in hippocampal or thalamic volumes. Bipolar offspring do not show decreased amygdalar volume, possibly because these abnormalities occur after more prolonged illness rather than as a preexisting risk factor. Longitudinal studies are needed to determine whether amygdalar volumes change during and after the development of BD.
The present study serves to detail the specific procedures for a mock scanner protocol, report on... more The present study serves to detail the specific procedures for a mock scanner protocol, report on its use in the context of a multisite study, and make suggestions for improving such protocols based on data acquired during study scanning. Specifically, a mock scanner compliance training protocol was used in a functional imaging study with a group of adolescents and adults with Attention Deficit Hyperactivity Disorder (ADHD) and a matched sample of healthy children and adults. Head motion was measured during mock and actual scanning. Participants across groups exhibited excess motion (>2 mm) on 43% of runs during the mock scanner. During actual scanning, excessive motion was limited to 10% of runs. There was a clear task-correlated head motion during a go/ no-go task that occurred even after the compliance training: participants had a tendency to respond with increased head motion immediately after committing an error. This study illustrates the need to (1) report data attrition due to head motion, (2) assess taskrelated motion, and (3) consider mock scanner training in functional imaging protocols.
Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported i... more Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD. We examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene. While viewing fearful versus calm faces, HR-BD youth had significantly greater ac...
The prevalence of social anxiety disorder is high in offspring of parents with bipolar disorder (... more The prevalence of social anxiety disorder is high in offspring of parents with bipolar disorder (BD) and anxiety may be a significant risk factor in these youth for developing BD. We compared social anxiety symptoms between BD offspring with mood symptoms (high-risk group for developing BD I or II: HR) and healthy controls (HC). We also explored the correlations between the amygdalar volumes and social anxiety symptoms in the HR group with high social anxiety scores (HRHSA) due to the potential involvement of the amygdala in the pathophysiology of both BD and social anxiety. Youth participating in the study included 29h and 17HC of comparable age and gender. To assess social anxiety symptoms, we used the Multidimensional Anxiety Scale for Children (MASC) social anxiety subscale. The HR group's MASC social anxiety score was significantly higher than that of the HC group. Among the 29h, 17 subjects (58.6%) showed high social anxiety and they were classified as the HRHSA group. No ...
Methods: Eleven female subjects with fraX, aged 10 to 22 years, were compared with age-matched fe... more Methods: Eleven female subjects with fraX, aged 10 to 22 years, were compared with age-matched female con- trol subjects. Photographs of forward-facing and angled faces, each having direct and averted gaze (4 types of stimuli), were presented in an event-related design dur- ing functional magnetic resonance imaging. Subjects were instructed to determine the direction of gaze for each pho- tograph.
AbstractöMost functional imaging studies of memory retrieval investigate memory for standardized ... more AbstractöMost functional imaging studies of memory retrieval investigate memory for standardized laboratory stimuli. However, naturally acquired autobiographical memories di¡er from memories of standardized stimuli in important ways. Neuroimaging studies of natural memories may reveal distinctive patterns of brain activation and may have particular value in assessing clinical disorders of memory. This study used functional magnetic resonance imaging to investigate brain activation during successful retrieval of autobiographical memories elicited by name-cued recall of family members and friends. The caudal part of the left posterior cingulate cortex was the most strongly activated region and was signi¢cantly activated in all eight subjects studied. Most subjects also showed signi¢cant activation of the left anterior orbitomedial, anterior middle frontal, precuneus, cuneus, and posterior inferior parietal cortices, and the right posterior cingulate and motor cortices.
Objective Youth who experience interpersonal trauma and have posttraumatic stress symptoms (PTSS)... more Objective Youth who experience interpersonal trauma and have posttraumatic stress symptoms (PTSS) develop cognitive deficits that impact their development. Our goal is to investigate the function of the hippocampus in adolescents with PTSS during a memory processing task. Methods Twenty-seven adolescents between the ages of 10-17 years (16 with PTSS and 11 healthy controls) encoded and retrieved visually presented nouns (Verbal Declarative Memory Task) while undergoing fMRI scanning. Results The PTSS group demonstrated reduced activation of the right hippocampus during the retrieval component of the task. Further, severity of symptoms of avoidance and numbing correlated with reduced left hippocampal activation during retrieval. Conclusions Decreased activity of the hippocampus during a verbal memory task may be a neurofunctional marker of PTSS in youth with history of interpersonal trauma. The results of this study may facilitate the development of focused treatments and may be of utility when assessing treatment outcome for PTSS.
The amygdala has received great interest as a possible neurophysiological substrate of bipolar di... more The amygdala has received great interest as a possible neurophysiological substrate of bipolar disorder (BD). This review summarizes information about the structure and function of the amygdala with attention to its role in experienced emotion and mood. We review the evidence for amygdala pathology in psychiatric conditions and discuss the role of the amygdala in BD during development. There appear to be consistent findings in the neuroimaging literature that suggest an etiological model for BD that involves abnormalities in the structure and function of the amygdala, but also depends on the failure of prefrontal cortical regions to modulate amygdala activity. In addition, evidence is accumulating to suggest that this model has flexible outcomes, depending on factors intrinsic and extrinsic to BD, and may follow several possible paths across the course of maturational development.
Using functional magnetic resonance imaging (fMRI) to study brain activity related to the experie... more Using functional magnetic resonance imaging (fMRI) to study brain activity related to the experience of emotion presents unique challenges to neuroscientists. One important consideration arises when an experimentally induced subjective emotional response persists after the end of the emotional stimulation epoch. In this case, brain activity related to the emotional response may continue during the subsequent control or comparison epoch.
Turner syndrome (TS) results from partial or complete X-monosomy and is characterized by deficits... more Turner syndrome (TS) results from partial or complete X-monosomy and is characterized by deficits in visuospatial functioning as well as social cognition and memory. Neuroimaging studies have demonstrated volumetric differences in the parietal region of females with TS compared to controls. The present study examined amygdala and hippocampus morphology in an attempt to further understand the neural correlates of psychosocial and memory functioning in TS. Thirty females with TS age 7.6-33.3 years (mean = 14.7 ± 6.4) and 29 age-matched controls (mean age = 14.8 ± 5.9; range = 6.4-32.7) were scanned using high resolution MRI. Volumetric analyses of the MRI scans included whole brain segmentation and manual delineation of the amygdala and hippocampus. Compared to controls, participants with TS demonstrated significantly larger left amygdala gray matter volumes, irrespective of total cerebral tissue and age. Participants with TS also showed disproportionately reduced right hippocampal volumes, involving both gray and white matter. Amygdala and hippocampal volumes appear to be impacted by X-monosomy. Aberrant morphology in these regions may be related to the social cognition and memory deficits often experienced by individuals with TS. Further investigations of changes in medial temporal morphology associated with TS are warranted.
Journal of the American Academy of Child & Adolescent Psychiatry, 2012
Objective: Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar dis... more Objective: Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late phase of activation, suggesting different temporal characteristics of brain responses. Method: A total of 20 euthymic adolescents with familial BD (14 male) and 21 healthy control subjects (13 male) underwent fMRI scanning during presentation of happy, sad, and neutral facial expressions. Whole-brain voxelwise analyses were conducted in SPM5, using a three-way analysis of variance (ANOVA) with factors group (BD and healthy control [HC]), facial expression (happy, sad, and neutral versus scrambled), and phase (early and late, corresponding to the first and second half of each block of faces). Results: There were no significant group differences in task performance, age, gender, or IQ. Significant activation from the main effect of group included greater DLPFC activation in the HC group, and greater amygdala/ hippocampal activation in the BD group. The interaction of Group Ï« Phase identified clusters in the superior temporal sulcus/insula and visual cortex, where activation increased from the early to late phase of the block for the BD but not the HC group. Conclusions: These findings are consistent with previous studies that suggest deficient prefrontal cortex regulation of heightened amygdala response to emotional stimuli in pediatric BD. Increasing activation over time in superior temporal and visual cortices suggests difficulty processing or disengaging attention from emotional faces in BD. J. Am. Acad. Child Adolesc. Psychiatry, 2012;51(8): 821-831.
Mood disorders are increasing in childhood, and often require multimodal and comprehensive treatm... more Mood disorders are increasing in childhood, and often require multimodal and comprehensive treatment plans to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for treatment and stabilization. Current evidence supports the use of a number of interventions in children and adolescents diagnosed with DSM-5 mood spectrum disorders, which are associated with impairments in prefrontal-striatal-limbic networks, which are key for emotional functioning and regulation. Yet, little is known about the neurobiological effects of interventions on the developing brain. This chapter provides a synopsis of the literature demonstrating the neural effects of psychotropic medications and psychotherapy in youth with depressive or bipolar spectrum disorders. Additional longitudinal and biological studies are warranted to characterize the effects of these interventions on all phases and stages of mood illness development in children and adolescents.
Hypothalamus communication with the rest of the brain and peripheral target tissues is critically... more Hypothalamus communication with the rest of the brain and peripheral target tissues is critically important for many physiological and psychological functions. These functions include maintaining neuroendocrine circadian rhythms and managing affective processes. The hypothalamus maintains both direct neural connections within the brain and it also controls a variety of neuroendocrine processes that can influence target tissues throughout the body. Dysregulation of the hypothalamic pituitary adrenal axis and hyperactivity of the subgenual cortex are both frequently observed in depression. However, many details of how the hypothalamus, the HPA-axis, and the subgenual cingulate interact with each other are unknown. We hypothesized that resting state functional connectivity between the hypothalamus and the subgenual cortex would be associated with altered circadian rhythm in patients with depression and depressive symptoms. We also hypothesized this would be most apparent in patients that have major depression with psychotic symptoms, who typically have the most robust HPA-axis dysregulation.
Children of parents with bipolar disorder (BD), especially those with attention deficit hyperacti... more Children of parents with bipolar disorder (BD), especially those with attention deficit hyperactivity disorder (ADHD) and symptoms of depression or mania, are at significantly high risk for developing BD. As we have previously shown amygdalar reductions in pediatric BD, the current study examined amygdalar volumes in offspring of parents (BD offspring) who have not yet developed a full manic episode. Youth participating in the study included 22 BD offspring and 22 healthy controls of comparable age, gender, handedness, and IQ. Subjects had no history of a manic episode, but met criteria for ADHD and moderate mood symptoms. MRI was performed on a 3 T GE scanner, using a 3D volumetric spoiled gradient echo series. Amygdalae were manually traced using BrainImage Java software on positionally normalized brain stacks. Bipolar offspring had similar amygdalar volumes compared to the control group. Exploratory analyses yielded no differences in hippocampal or thalamic volumes. Bipolar offspring do not show decreased amygdalar volume, possibly because these abnormalities occur after more prolonged illness rather than as a preexisting risk factor. Longitudinal studies are needed to determine whether amygdalar volumes change during and after the development of BD.
The present study serves to detail the specific procedures for a mock scanner protocol, report on... more The present study serves to detail the specific procedures for a mock scanner protocol, report on its use in the context of a multisite study, and make suggestions for improving such protocols based on data acquired during study scanning. Specifically, a mock scanner compliance training protocol was used in a functional imaging study with a group of adolescents and adults with Attention Deficit Hyperactivity Disorder (ADHD) and a matched sample of healthy children and adults. Head motion was measured during mock and actual scanning. Participants across groups exhibited excess motion (>2 mm) on 43% of runs during the mock scanner. During actual scanning, excessive motion was limited to 10% of runs. There was a clear task-correlated head motion during a go/ no-go task that occurred even after the compliance training: participants had a tendency to respond with increased head motion immediately after committing an error. This study illustrates the need to (1) report data attrition due to head motion, (2) assess taskrelated motion, and (3) consider mock scanner training in functional imaging protocols.
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