Carryl P. Navalta

THE NEUROBIOLOGICAL CONSEQUENCES OF EARLY STRESS AND CHILDHOOD MALTREATMENT

Early severe stress and maltreatment produces a cascade of neurobiological events that have the potential to cause enduring changes in brain development. These changes occur on multiple levels, from neurohumoral (especially the hypothalamic-pituitary-adrenal [HPA] axis) to structural and functional. The major structural consequences of early stress include reduced size of the mid-portions of the corpus callosum and attenuated development of the left neocortex, hippocampus, and amygdala. Major functional consequences include increased electrical irritability in limbic structures and reduced functional activity of the cerebellar vermis. There are also gender differences in vulnerability and functional consequences. The neurobiological sequelae of early stress and maltreatment may play a significant role in the emergence of psychiatric disorders during development.

Developmental neurobiology of childhood stress and trauma.

Severe early stress and maltreatment produces a cascade of events that have the potential to alter brain development. The first stage of the cascade involves the stress-induced programming of the glucocorticoid, noradrenergic, and vasopressin-oxytocin stress response systems to augment stress responses. These neurohumors then produce effects on neurogenesis, synaptic overproduction and pruning, and myelination during specific sensitive periods. Major consequences include reduced size of the mid-portions of the corpus callosum; attenuated development of the left neocortex, hippocampus, and amygdala along with abnormal frontotemporal electrical activity; and reduced functional activity of the cerebellar vermis. These alterations, in turn, provide the neurobiological framework through which early abuse increases the risk of developing post-traumatic stress disorder (PTSD), depression, symptoms of attention-deficit/hyperactivity, borderline personality disorder, dissociative identity disorder, and substance abuse.

Effects of Childhood Sexual Abuse on Neuropsychological and Cognitive Function in College Women

Twenty-six college women with a history of repeated childhood sexual abuse were recruited from the community and compared with 19 healthy female collegiate subjects on neurocognitive measures. Abused subjects showed increased response latency variability and diminished inhibitory capacity during a GO/NO-GO/STOP vigilance task. A strong association was found between duration of abuse and memory impairments. Math Scholastic Aptitude Test (SAT) scores were significantly lower in abused subjects when matched against comparison subjects and when compared to their own Verbal SAT scores. Childhood sexual abuse appears to be associated with a constellation of neuropsychological deficiencies even in a group of relatively healthy women.

Altering the course of neurodevelopment: a framework for understanding the enduring effects of psychotropic drugs.

Childhood is a time filled with wondrous changes, as brain plasticity permits experiences to shape the immature brain to meet the demands of the environment. Change occurs at various levels—from neuroanatomy, including within a given region and its connectivity to other regions, to the function of neurotransmitter systems and their reactivity to pharmacological agents in the short‐ and long‐term. The nature and degree to which drug exposure influences the final adult topography is influenced greatly by the maturational phase of these critical factors. Moreover, evidence is slowly emerging that suggests that the long‐term effects of drug exposure are delayed and expressed once the vulnerable system reaches maturation (i.e., typically during adulthood). This phenomenon is known as neuronal imprinting and occurs when the effects of drug exposure outlast the drug itself. Thus, understanding the persistent effects critically depends on the window of observation. Embracing this concept should influence how we conduct preclinical assessments of developmental drug exposure, and ultimately how we conduct clinical assessments of drug efficacy, effectiveness, and safety for the treatment of childhood psychiatric disorders. In this article, we present a model to provide a heuristic framework for making predictions about imprinted effects of childhood drug exposure. We then review epidemiological data on attention deficit hyperactivity disorder (ADHD) and childhood depression, prescription practices, and what is known regarding the long‐term consequences of drug exposure in these populations. We conclude with a discussion of the current status of preclinical studies on juvenile stimulant exposure.

Childhood Sexual Abuse Is Associated with Reduced Gray Matter Volume in Visual Cortex of Young Women

BACKGROUND Childhood sexual abuse (CSA) has been associated with alterations in brain morphology using region of interest analyses that have focused on stress-sensitive target regions. This study was designed to ascertain the effects on gray matter volume (GMV) of exposure to CSA in healthy young adult college students selected based on exposure history regardless of psychiatric outcome. Voxel-based morphometry (VBM) provided unbiased delineation of the most significantly affected brain regions. METHODS High-resolution T1-weighted magnetic resonance imaging (MRI) datasets were obtained for 23 unmedicated female subjects with CSA and 14 healthy female control subjects of equivalent age and socioeconomic status with no history of trauma. Cortical surface-based analysis (FreeSurfer) was performed to verify VBM results. RESULTS Gray matter volume was reduced by 12.6% and 18.1% in right and left primary visual (V1) and visual association cortices of abused subjects. This reduction was directly related to duration of CSA before age 12. Gray matter volume of left and right V1 correlated with measure of visual memory (r = .353, p = .032 and r = .448, p = .005). Cortical surface-based analysis indicated that GMV of abused subjects was reduced in the left fusiform (p = .004), left middle occipital (p = .04), and right lingual (p = .002) gyri. CONCLUSIONS Early visual experience exerts a strong influence on the developing mammalian visual cortex. Present findings indicate that exposure to CSA may also affect the development of this region and are apparent even in a population of subjects who are sufficiently healthy to matriculate.

Exposure to Parental Verbal Abuse is Associated with Increased Gray Matter Volume in Superior Temporal Gyrus

OBJECTIVE Exposure to parental verbal aggression (PVA) during childhood increases risk for the development of psychopathology, particularly mood and anxiety disorders. Other forms of childhood abuse have been found to be associated with alterations in brain structure. The aim of this study was to ascertain whether exposure to PVA was associated with discernible effects on brain morphology. METHODS Optimized voxel-based morphometry was performed on 21 unmedicated, right-handed subjects (18-25 years) with histories of PVA and 19 psychiatrically healthy controls of comparable age and gender. Group differences in gray matter volume (GMV)--covaried by age, gender, parental education, financial stress, and total GMV--were assessed using high-resolution, T1-weighted, volumetric MRI data sets (Siemens 3T trio scanner). RESULTS GMV was increased by 14.1% in the left superior temporal gyrus (STG, BA 22) (P=0.004, corrected cluster level). GMV in this cluster was associated most strongly with levels of maternal (ß=0.544, P<0.0001) and paternal (ß=0.300, P<0.02) verbal aggression and inversely associated with parental education (ß=-0.577, P<0.0001). CONCLUSION Previous studies have demonstrated an increase in STG GMV in children with abuse histories, and found a reduction in fractional anisotropy in the arcuate fasciculus connecting Wernickes and frontal areas in young adults exposed to PVA. These findings and the present results suggest that the development of auditory association cortex involved in language processing may be affected by exposure to early stress and/or emotionally abusive language.

Trauma Systems Therapy in Residential Settings: Improving Emotion Regulation and the Social Environment of Traumatized Children and Youth in Congregate Care

Although abundant evidence exists indicating the prevalence of trauma exposure among youth in residential care, few models exist for creating trauma-informed milieu treatment. This article outlines the problem and describes the implementation of Trauma Systems Therapy (TST) in three residential centers. TST is unique in emphasizing youth emotions and behaviors as well as the role a distressed or threatening social environment may play in keeping a traumatized youth in a dysregulated state. This dual emphasis makes TST specifically appropriate to implementation in congregate care, focusing assessment and intervention strategies on both clinical treatment and the functioning of the therapeutic milieu itself. Data are reported on incidents of the use of physical restraint; numbers of disrupted foster care placements following discharge from residential treatment; and scores on psychometric measures of children’s functioning and emotion regulation capacity. Knowledge gained through TST implementation in these three residential centers has important implications for developing a model of trauma-informed congregate care.

Determination of hemispheric emotional valence in individual subjects: A new approach with research and therapeutic implications

BackgroundMuch has been theorized about the emotional properties of the hemispheres. Our review of the dominant hypotheses put forth by Schore, Joseph, Davidson, and Harmon-Jones on hemispheric emotional valences (HEV) shows that none are supported by robust data. Instead, we propose that individuals hemispheres are organized to have differing HEVs that can be lateralized in either direction.MethodsProbe auditory evoked potentials (AEP) recorded during a neutral and an upsetting memory were used to assess HEV in 28 (20 F) right-handed subjects who were either victims of childhood maltreatment (N = 12) or healthy controls. In a sub-population, we determined HEV by emotional response to lateral visual field stimulation (LVFS), in which vision is limited to one, then the other hemifield. We compare a number of morphometric and functional brain measures between individuals who have right-negative versus left-negative HEV.ResultsUsing AEPs to determine HEV, we found 62% of controls and 67% of maltreated subjects had right negative HEV. There was a strong interaction between HEV-laterality and gender, which together accounted for 60% of individual variability in total grey matter volume (GMV). HEV-laterality was associated with differences in hippocampal volume, amygdala/hippocampal ratios, and measures of verbal, visual and global memory. HEV-laterality was associated also with different constellations of symptoms comparing maltreated subjects to controls. Emotional response to LVFS provided a convenient and complementary measure of HEV-laterality that correlated significantly with the HEVs determined by AEPs.ConclusionOur findings suggest that HEV-laterality, like handedness or gender, is an important individual difference with significant implications for brain and behavioral research, and for guiding lateralized treatments such as rTMS.

Annual Research Review: New frontiers in developmental neuropharmacology: can long-term therapeutic effects of drugs be optimized through carefully timed early intervention?

Our aim is to present a working model that may serve as a valuable heuristic to predict enduring effects of drugs when administered during development. Our primary tenet is that a greater understanding of neurodevelopment can lead to improved treatment that intervenes early in the progression of a given disorder and prevents symptoms from manifesting. The immature brain undergoes significant changes during the transitions between childhood, adolescence, and adulthood. Such changes in innervation, neurotransmitter levels, and their respective signaling mechanisms have profound and observable changes on typical behavior, but also increase vulnerability to psychiatric disorders when the maturational process goes awry. Given the remarkable plasticity of the immature brain to adapt to its external milieu, preventive interventions may be possible. We intend for this review to initiate a discussion of how currently used psychotropic agents can influence brain development. Drug exposure during sensitive periods may have beneficial long-term effects, but harmful delayed consequences may be possible as well. Regardless of the outcome, this information needs to be used to improve or develop alternative approaches for the treatment of childhood disorders. With this framework in mind, we present what is known about the effects of stimulants, antidepressants, and antipsychotics on brain maturation (including animal studies that use more clinically-relevant dosing paradigms or relevant animal models). We endeavor to provocatively set the stage for altering treatment approaches for improving mental health in non-adult populations.

Hyperactivity persists in male and female adults with ADHD and remains a highly discriminative feature of the disorder: a case-control study

BackgroundSymptoms of hyperactivity are believed to fade with age leaving ADHD adults mostly inattentive and impulsive. Our aim was to test this assertion using objective measures of hyperactivity, impulsivity and inattention.MethodParticipants were 40 subjects with ADHD (23M/17F; 35±10 yrs) and 60 healthy adults (28M/32F; 29±9 yrs) blindly assessed using Wender-Reimherr interview ratings, Structured Clinical Interview for DSM-IV Disorders and DSM-IV criteria. Infrared motion capture systems tracked head and leg movements during performance of a No-4’s cognitive control task. Subjects also completed the Conners’ CPT-II.ResultsADHD and controls differed significantly in activity and attention. Effect sizes for activity measures (d’ = 0.7–1.6) were, on average, two-fold larger than differences in attention or impulsivity, correlated more strongly with executive function ratings and were more discriminatory (ROC area = 0.83 for activity composite, 0.65 for No-4’s distraction composite, 0.63 for Conners’ CPT-II confidence index, 0.96 for the combined activity and attention diagnostic index). This finding was true for subjects with the predominantly inattentive subtype as well as subjects with combined or predominantly hyperactive/impulsive subtype. Males and females with ADHD were equally active. The superior accuracy of activity measures was confirmed using Random Forest and predictive modeling techniques.ConclusionsObjectively measured hyperactivity persists in adults with ADHD and is a more discriminative feature of the disorder than computerized measures of inattention or impulsivity. This finding supports the hypothesis that a deficient ability to sit still remains a defining feature of the disorder in adults when it is measured objectively.