Child Trauma Australia Workshop

June 6, 2016

Slides from all day workshop presentation 6/6/16

Australian_Workshop_6_6_16_reduced

 

iPS Study of Family Members Discordant for ADHD

December 12, 2015

Recruiting Subjects

Currently recruiting pairs of subjects consisting of an adult (18 – 40 years of age) with ADHD plus an adult same-sex blood relative without ADHD or other psychiatric disorders for a very interesting study.  Participants with ADHD can be on or off medications.  The study involves comprehensive assessment and testing plus collection of a small skin sample. The skin sample will be cultured, converted into induced pluripotent stem cells (a very complex process), and the stem cells transformed into dopamine neurons.  We will then compare dopamine neurons of participants with ADHD to dopamine neurons from family members without ADHD. Subjects will be paid $75 for their participation. If you are interested and would like some more information, please call Cindy at (617) 855-2973 or email cmcgreenery@mclean.harvard.edu

 

For more about induced Pluripotent Stem Cells – see:

Robinton, D.A. and G.Q. Daley, The promise of induced pluripotent stem cells in research and therapy. Nature, 2012. 481(7381): p. 295-305

Bellin, M., et al., Induced pluripotent stem cells: the new patient? Nat Rev Mol Cell Biol, 2012. 13(11): p. 713-26.

Childhood Maltreatment Changes Cortical Network Architecture and May Raise Risk for Substance Use

December 7, 2015

An article, by Scott Eddie, highlighting our work on this topic  has been published in NIDA Notes.  I’ve attached the link. NIDA Notes Article

Non-Pharmacological Treatment for ADHD

November 20, 2015

Ongoing Studies

•Research Project 1. Comparison of Treatment with Hemi-Sync™ Sounds Versus Multimodal Sensory Enrichment for 8-12-Year-Old Children with ADHD.

 •Research Project 2. Open Evaluation of Brain Balance Exercises and Interactive Metronome for Treatment of 8-14-Year-Old Children with ADHD.

Background

The problem with current treatments for attention-deficit hyperactivity disorder (ADHD) is that medications typically play an important role in controlling symptoms, but symptoms resurface when the medication wears off1. Unfortunately, there are few if any enduring benefits from medications used to treat ADHD. This is seen most clearly in the follow-up analyses of the NIH-sponsored Multimodal Treatment Study of Children with ADHD (MTA)2. Initially they found that careful medication management, or medication management combined with behavioral treatment of children with ADHD, produced better outcomes at 14-months than did behavioral treatments alone or community care. However, when participants were reassessed 2 years after the studies end2, or 6-8 years post enrollment3, it was clear that there was no significant beneficial effects on ADHD symptoms or academic performance, of having received 14-months of medication management or medication management combined with behavioral treatments2, 3. Consequently, we are interested in non-pharmacological treatments that may have enduring beneficial effects on children with ADHD.

Treatments with enduring beneficial effects may require many weeks or months to work. Hence, an ideal long-term treatment might function in conjunction with pharmacological treatments so that ADHD children can receive some rapid short-term beneficial effects of medication, but they then may be able to stop using medications, or benefit from lower doses of medications, as the long-term treatment takes hold.

We are currently studying three potential non-pharmacological treatments for ADHD in the Developmental Biopsychiatry Research Program at McLean Hospital, a major Harvard Teaching Hospital.

Research Project 1. In this study we are comparing two non-pharmacological treatments in boys and girls with ADHD who are 8 – 12 years of age. This is a 6-month long free treatment program that we provide in addition to whatever treatments the child is currently receiving. Hence, they can be taking medication, receiving counseling, family therapy, school accomodations, etc. An important requirement though is that if they are taking medications that the medications be short acting (like Ritalin, Adderall or Atomoxetine) that can be stopped for 2 days so we can assess how symptomatic the child is off medication at the beginning, middle and end of the study. Non-invasive MRI scans will also be performed at the beginning and end of the study to determine if the non-pharmacological treatment led to any alterations in blood flow and connectivity in brain regions implicated in ADHD. Children will receive a comprehensive evaluation as part of the study. They can also enter the trial if they are not receiving any other treatments. All components of this study are free. Monies are provided to help cover local traveling expenses to McLean Hospital and to compensate children for their time going through the different evaluations. Participants are randomly assigned to either Treatment 1 or 2. If two children from the same family enroll they are randomly assigned to the same treatment. This is an ongoing study but still has several openings for new participants as of 11/20/15.

Treatment 1. Hemi-Sync™ sounds and classical music. Hemi sync™ is an “audio-guidance” technology, developed many years ago by Robert Monroe, that uses sound to influence brain wave activity to produce a focused, whole-brain state known as hemispheric synchronization, where the left and right hemispheres work together in a state of coherence. The specific Hemi Sync™ programs are designed to enhance concentration and attention by predominantly increasing alpha and beta EEG activity. Beneficial effects on sustained attention, resistance to distraction, alertness and irritability have been reported in a study of individuals with developmental disabilities4. Beta frequency binaural beats were also found to have a more beneficial effect on attention and mood than theta frequency beats5. Van der Schaar6 reported in a small study that Hemi-Synch ADD tapes hastened and augmented therapeutic benefits of a nutritional supplement for children with ADHD. These findings are also consistent with an expanding literature on the potential benefits of EEG-based neurofeedback approaches that augment beta activity in children with ADHD7, 8. While these Hemi-Sync™ findings are encouraging it must be pointed out that very few Hemi-Sync™ studies have been published in main-stream journals or even journals not directly linked to The Monroe Institute. Hence, a rigorous independent trial is needed.

Treatment 2. Multimodal Sensory Enrichment. This treatment derived from translational neuroscience studies showing that simultaneous exposure to multimodal sensory stimuli enhanced dendritic branching of brain cells, the density of synaptic connections within the brain, and the birth of new brain cells (neurogenesis)9, 10. Professor Michael Leon at the University of California, Irvine, developed a procedure to provide multimodal sensory enrichment to children and found in a randomized control trial that it was effective in ameliorating some of the symptoms of autism11; with 69% of parents of children in the enriched group versus 31% of parents of children in the control group reporting improvement in their child over the 6-month study11. In the course of treating children with autism the investigators also noted improvements in attention and impulsivity, and found in an open trial that multimodal sensory enrichment attenuated these symptoms in children with ADHD. Parents will be supplied with a kit that contains materials needed for the sensorimotor exercises and a URL to an internet-based program that teaches the parent and child how to do the exercises. The UC Irvine study with autism suggests that gains made from the enrichment exercises endure. This is an innovative potential treatment in need of rigorous evaluation.

Research Project 2 – Brain Balance Exercises and Interactive Metronome. In this study we are conducting an open evaluation of ‘brain balance’ and timing exercises for 8-14-year-old boys and girls with ADHD. Brain Balance treatments were developed by Robert Mellilo12, 13, a neurologically sophisticated chiropractor, and consists of exercises to foster right hemisphere development and right-left hemispheric integration. The focus on right-hemisphere development and right-left hemispheric integration fits with what we, and others, have observed to be key neurobiological deficits in children with ADHD14-20. Children with ADHD also have deficits in timing21-24, which are addressed using a device called the Interactive Metronome25-27. Brain balance and Interactive Metronome remediation was found to produce, within 12-weeks, a greater than two-year gain in grade level in all academic domains except mathematical reasoning in children with ADHD28. Hence, we are interested in assessing whether this type of treatment is associated with improvement in objective indices of symptom severity and in changes in brain activity and functional connectivity in brain regions associated with ADHD.

Brain Balance exercises are typically offered at Brain Balance Achievement Centers throughout the US. We have had Dr. Melillo, and his staff, develop for this study a specific ADHD-focused internet-based training program for use by parent and child at home. This complements the internet-based interactive metronome training program. This is a 14-week study conducted at home. Children receive comprehensive evaluations and MRI scans before and after treatment. The entire program is free. Monies are provided to help cover costs of local transportation to McLean Hospital and for children’s time in going through testing and MRI. This study is underway and we are recruiting new participants as of 11/20/2015.

If you are interested in either of these studies please contact Cindy McGreenery cmcgreenery@mclean.harvard.edu (617 855-2971). These studies are IRB-approved through Partner’s Health Care.

NOTE: Dr. Teicher and staff have no financial interest in any of these treatment modalities, and do not offer them as treatments outside of these IRB-approved research studies. We are interested in rigorously and objectively evaluating novel treatments that may be of benefit to children, adolescents and adults with ADHD, learning disabilities, depression and post-traumatic stress disorder. The research is conducted with the understanding that we will publish the results of these studies whether they are positive or negative. We have previously published negative results of novel technologies or treatments29-31. We do not presently recommend these treatments. Our decision to evaluate these treatments is an expression of interest but does not constitute an endorsement. We believe that there is a pressing need for new treatments that can produce enduring benefits and we are eager to rigorously evaluate potential treatments with plausible mechanisms or good preliminary data.

If you have developed a novel treatment and are interested in having it objectively evaluated by the Developmental Biopsychiatry Research Program at McLean Hospital please contact Dr. Teicher at martin_teicher@hms.harvard.edu to discuss policies, logistics and costs.

References

  1. Pliszka S. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2007 Jul;46(7):894-921.
  2. Jensen PS, Arnold LE, Swanson JM, et al. 3-year follow-up of the NIMH MTA study. J Am Acad Child Adolesc Psychiatry 2007 Aug;46(8):989-1002.
  3. Molina BS, Hinshaw SP, Swanson JM, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009 May;48(5):484-500.
  4. Guilfoyle G, Carbone D. The facilitation of attention utilizing therapeutic sounds. Hemi-Sync Journal 1997;XV(2).
  5. Lane JD, Kasian SJ, Owens JE, Marsh GR. Binaural auditory beats affect vigilance performance and mood. Physiol Behav 1998 Jan;63(2):249-252.
  6. Van Der Schaar PJ. Attention and learning deficit disorders: Impressions ofcombined treatment with amino acids and Hemi-Sync. TMI Journal, 2009( Winter).
  7. Gevensleben H, Holl B, Albrecht B, et al. Distinct EEG effects related to neurofeedback training in children with ADHD: a randomized controlled trial. Int J Psychophysiol 2009 Nov;74(2):149-157.
  8. Kropotov JD, Grin-Yatsenko VA, Ponomarev VA, Chutko LS, Yakovenko EA, Nikishena IS. ERPs correlates of EEG relative beta training in ADHD children. Int J Psychophysiol 2005 Jan;55(1):23-34.
  9. van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci 2000 Dec;1(3):191-198.
  10. Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 2006 Sep;7(9):697-709.
  11. Woo CC, Leon M. Environmental enrichment as an effective treatment for autism: a randomized controlled trial. Behav Neurosci 2013 Aug;127(4):487-497.
  12. Melillo R. Disconnected Kids: The Groundbreaking Brain Balance Program for Children with Autism, ADHD, Dyslexia, and Other Neurological Disorders. New York: Penguin Group; 2009.
  13. Melillo R. Reconnected Kids: Help Your Child Achieve Physical, Mental, and Emotional Balance. New York: Penguin Group; 2011.
  14. Arnsten AF. Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs 2009;23 Suppl 1:33-41.
  15. Casey BJ, Castellanos FX, Giedd JN, et al. Implication of right frontostriatal circuitry in response inhibition and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1997;36(3):374-383.
  16. Clark L, Blackwell AD, Aron AR, et al. Association between response inhibition and working memory in adult ADHD: a link to right frontal cortex pathology? Biol Psychiatry 2007 Jun 15;61(12):1395-1401.
  17. Qiu MG, Ye Z, Li QY, Liu GJ, Xie B, Wang J. Changes of brain structure and function in ADHD children. Brain Topogr 2011 Oct;24(3-4):243-252.
  18. Valera EM, Faraone SV, Murray KE, Seidman LJ. Meta-analysis of structural imaging findings in attention-deficit/hyperactivity disorder. Biol Psychiatry 2007 Jun 15;61(12):1361-1369.
  19. Wolf RC, Plichta MM, Sambataro F, et al. Regional brain activation changes and abnormal functional connectivity of the ventrolateral prefrontal cortex during working memory processing in adults with attention-deficit/hyperactivity disorder. Hum Brain Mapp 2009 Jul;30(7):2252-2266.
  20. Zang YF, He Y, Zhu CZ, et al. Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI. Brain Dev 2007 Mar;29(2):83-91.
  21. Smith A, Taylor E, Rogers JW, Newman S, Rubia K. Evidence for a pure time perception deficit in children with ADHD. J Child Psychol Psychiatry 2002 May;43(4):529-542.
  22. Sonuga-Barke E, Bitsakou P, Thompson M. Beyond the dual pathway model: evidence for the dissociation of timing, inhibitory, and delay-related impairments in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2010 Apr;49(4):345-355.
  23. Toplak ME, Tannock R. Time perception: modality and duration effects in attention-deficit/hyperactivity disorder (ADHD). J Abnorm Child Psychol 2005 Oct;33(5):639-654.
  24. Yang B, Chan RC, Zou X, Jing J, Mai J, Li J. Time perception deficit in children with ADHD. Brain Res 2007 Sep 19;1170:90-96.
  25. Cosper SM, Lee GP, Peters SB, Bishop E. Interactive Metronome training in children with attention deficit and developmental coordination disorders. Int J Rehabil Res 2009 Dec;32(4):331-336.
  26. Bartscherer ML, Dole RL. Interactive metronome training for a 9-year-old boy with attention and motor coordination difficulties. Physiother Theory Pract 2005 Oct-Dec;21(4):257-269.
  27. Shaffer RJ, Jacokes LE, Cassily JF, Greenspan SI, Tuchman RF, Stemmer PJ, Jr. Effect of interactive metronome training on children with ADHD. Am J Occup Ther 2001 Mar-Apr;55(2):155-162.
  28. Leisman G, Melillo R, Thum S, et al. The effect of hemisphere specific remediation strategies on the academic performance outcome of children with ADD/ADHD. Int J Adolesc Med Health 2010 Apr-Jun;22(2):275-283.
  29. Joffe RT, Moul DE, Lam RW, et al. Light visor treatment for seasonal affective disorder: a multicenter study. Psychiatry Res 1993 Jan;46(1):29-39.
  30. Teicher MH, Glod CA, Oren DA, et al. The phototherapy light visor: more to it than meets the eye. Am J Psychiatry 1995 Aug;152(8):1197-1202.
  31. Oren DA, Teicher MH, Schwartz PJ, et al. A controlled trial of cyanocobalamin (vitamin B12) in the treatment of winter seasonal affective disorder. J Affect Disord 1994 Nov;32(3):197-200.

 

 

 

Child Abuse, Brain Development and Psychopathology

March 16, 2012

McLean_Hospital_Child_abuse_talk      Talk presented at McLean Hospital 2012

NESTTD Keynote April 30th 2011

June 27, 2011

NESTTD keynote

Keynote: Pierre Janet Memorial Lecture ISSTD 10/18/10

November 21, 2010

Keynote: Pierre Janet memorial lecture ISSTD

Delayed Onset of Depression

June 15, 2009

Teicher MH, Samson JA, Polcari A. Andersen SL. Length of time between onset of childhood sexual abuse and emergence of depression in a young adult sample. Journal of Clinical Psychiatry 2009; 70(5): 684-691

Synopsis

Depression is the most extensively documented outcome of exposure to CSA in adults (1), but in children the most discernible manifestations are sexualized behaviors rather than depression or PTSD (1). Despite the numerous studies demonstrating an association between exposure to CSA and emergence of depression, we are not aware of any studies that have specifically reported on the length of time between exposure to CSA and development of major depression. There are several possibilities. One is that depression follows rapidly on the heels of exposure to CSA. Another possibility is that depression emerges after exposure or risk of exposure to CSA has abated. A third possibility is that CSA does not directly lead to depression, but that it sensitizes the individual, enhancing their risk of developing depression as they pass through adolescents into adulthood as part of a neuromaturational process (2). A fourth possibility is that CSA could both sensitize and accelerate the process leading to an earlier age of onset, as has been reported to occur in patients with bipolar (3) or substance abuse disorders (4). Finally, episodes of major depression may emerge in sensitized individuals only if they are exposed to new losses or traumas, resulting in a variable onset times.

Determining the temporal relationship between CSA and onset of depression is difficult, as CSA usually occurs in individuals who have been, or will be, exposed to multiple other forms of trauma5, 6. However, delineating the time course is a fundamental prerequisite for designing intervention strategies to prevent or minimize the long-term sequelae of abuse and for interrupting the cycle of violence. To begin to address this issue we retrospectively examined the temporal relationship between CSA and depression in this group of 29 women who were exposed to CSA but to no other forms of trauma or severe early stress. These subjects were 20 ± 1.3 years old. All were in college, and 90% came from a middle class or higher socioeconomic status family (SES 2.3 ± 1.0). Reported perpetrators were part of the extended family and/or members of the community, with only three perpetrators being step-parents. None of the subjects in this sample reported experiencing CSA by their biological parents.

Psychiatric history was assessed by certified mental health clinicians using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID), the Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D) (7) and the Diagnostic Interview for Borderline Patients (DIB) (8). Age of onset was assessed as a part of this interview, which can be reliably determined through this form of assessment (9, 10). Kaplan-Meier analysis (SPSS version 11.0) provided mean survival time (±95% confidence interval [CI]) for onset of CSA, and from onset of CSA to emergence of depression.

Subjects who developed major depression (n=18) had the onset occur between 10–20 years of age (mean survival 15.0 years; 95% CI: 13.6–16.4 years). The average time from onset of CSA to onset of major depression, in those who developed depression, was 9.2 ± 3.6 years. Mean survival time from onset of CSA to onset of depression for the entire sample was 11.47 years (95% CI: 9.80–13.13 years). Mean survival from offset of CSA (first episode if there were multiple perpetrators) was 9.55 years (95% CI: 7.45–11.65 years). Figure 1 illustrates the number of cases with a history of depression who experienced CSA in a given year, and the cumulative prevalence of depression. Note that many of the subjects who went on to develop major depression experienced CSA at ages 5 and 6, and that 56% of depressive episodes began between 12–15 years of age.

Abuse_depr_double_plot3

Figure 1. Age of abuse and cumulative incidence of depression for 18 CSA subjects developing depression. Red line and left axis indicate number of subjects exposed to CSA at each age. Blue shaded area and right axis indicate the percentage of subjects who had an episode of major depression prior to or during each year of age (11).

The key finding of this formative study is that episodes of major depression did not immediately occur following exposure to CSA, but took several years to emerge. Further, the onset of depression did not directly coincide with the abatement of CSA. Rather, there was typically a long delay between exposure to CSA and onset of depression, with a surge in new cases occurring between 12–15 years of age. This is somewhat earlier than the peak surge of newly emergent cases reported to occur in a prospective longitudinal study of a contemporary birth cohort (12). Overall, these findings are compatible with the hypothesis that CSA sensitizes the individual to later emergence of depression during adolescence, and that it shifts the peak period of risk from mid-adolescence to early adolescence. This finding is consistent with a previous report of earlier age of onset of depression in women with histories of childhood abuse (13). Clinically, this is important information as it shows that there may be substantial time available in which to potentially intervene to minimize or preempt the most common major psychiatric consequences of CSA.

References
1. Putnam FW. Ten-year research update review: child sexual abuse. J Am Acad Child Adolesc Psychiatry 2003;42:269-278
2. Andersen SL, Teicher MH. Stress, sensitive periods and maturational events in adolescent depression. Trends Neurosci 2008;31:183-191
3. Post RM, Leverich GS, Xing G, Weiss RB. Developmental vulnerabilities to the onset and course of bipolar disorder. Dev Psychopathol 2001;13:581-598.
4. Dube SR, Felitti VJ, Dong M, et al. Childhood abuse, neglect, and household dysfunction and the risk of illicit drug use: the adverse childhood experiences study. Pediatrics 2003;111:564-572
5. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med 1998;14:245-258
6. Teicher MH, Samson JA, Polcari A, McGreenery CE. Sticks, stones, and hurtful words: relative effects of various forms of childhood maltreatment. Am J Psychiatry 2006;163:993-1000
7. Bremner JD, Steinberg M, Southwick SM, et al. Use of the Structured Clinical Interview for DSM-IV Dissociative Disorders for systematic assessment of dissociative symptoms in posttraumatic stress disorder. Am J Psychiatry 1993;150:1011-1014
8. Gunderson JG, Kolb JE, Austin V. The diagnostic interview for borderline patients. Am J Psychiatry 1981;138:896-903
9. Farrer LA, Florio LP, Bruce ML, et al. Reliability of self-reported age at onset of major depression. J Psychiatr Res 1989;23:35-47
10. Prusoff BA, Merikangas KR, Weissman MM. Lifetime prevalence and age of onset of psychiatric disorders: recall 4 years later. J Psychiatr Res 1988;22:107-117
11. Teicher MH, Samson JA, Polcari A, Andersen SL. Length of time between onset of childhood sexual abuse and emergence of depression in a young adult sample: a retrospective clinical report. J Clin Psychiatry 2009
12. Hankin BL, Abramson LY, Moffitt TE, et al. Development of depression from preadolescence to young adulthood: emerging gender differences in a 10-year longitudinal study. J Abnorm Psychol 1998;107:128-140
13. Gladstone GL, Parker GB, Mitchell PB, et al. Implications of childhood trauma for depressed women: an analysis of pathways from childhood sexual abuse to deliberate self-harm and revictimization. Am J Psychiatry 2004;161:1417-1425

Parental Verbal Abuse Affects Brain White Matter

January 17, 2009

Choi J, Jeong B, Rohan ML, Polcari AM, Teicher MH.  Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biol Psychiatry. 2009 Feb 1;65(3):227-34.

We have just published findings from my laboratory that are beginning to illuminate the neurobiological effects of exposure to parental verbal abuse. We had previously shown that exposure to high levels of parental verbal abuse had the same impact (based on symptom ratings) as witnessing domestic violence and extrafamilial sexual abuse. It had somewhat more impact than exposure to parental physical abuse, but less impact than familial sexual abuse. Hence, it appears to be a potent form of childhood adversity.

Teicher MH, Samson JA, Polcari A, McGreenery CE. Sticks stones and hurtful words: Relative effects of various forms of childhood maltreatment. Am J Psychiatry 2006; 163: 993-1000

White Matter Tract Abnormalities in Young Adults Exposed to Parental Verbal Abuse

Synopsis

In this study we used a new MRI technique called diffusion tensor imaging (DTI) to ascertain whether exposure to a high level of parental verbal abuse (PVA) was associated with abnormalities in brain white matter (WM) tract integrity. The brain consists of regions of gray matter that contains the cell bodies and dendritic branches of neurons, and white matter, which are the myelinated axonal fiber tracts providing communication between neurons in different gray matter regions. We screen 1271 healthy young adults for exposure to childhood adversity, and collected DTI (Siemens 3.0 T Trio Scanner) on 16 unmedicated subjects with a history of high-level exposure to PVA but no other form of maltreatment (4M/12F, mean age 21.9±2.4 yrs), and 16 healthy controls (5M/11F, 21.0±1.6 yrs). Group differences in fractional anisotropy (FA), covaried by parental education and income, were evaluated using tract-based spatial statistics (TBSS), and correlated with symptom ratings and verbal IQ. FA is an index of the integrity of the fiber pathway. Reduced FA may indicate a reduction in myelin, number of axons, or diameter of axons.

Three WM tracts had significantly reduced FA: (1) arcuate fasciculus in left superior temporal gyrus, (2) cingulum bundle in the fusiform gyrus by the posterior tail of the left hippocampus, and (3) the left body of fornix. FA values were strongly associated with the maximal PVA scores (r=-0.806, P<10-7; r=-0.658, P<.0001; r=-0.584, P<.0001, respectively).

DTI verbal abuse image.

Figure 1.  Three white matter tract regions (shown in red) that differed significantly in fractional anisotropy (FA) between subjects with history of exposure to high levels of parental verbal aggression and healthy controls. Region 1 contained fibers from arcuate fasciculus. Region 2 contained fibers from the cingulum bundle near the tail of the hippocampus. Region 3 is part of the left fornix (hippocampal efferents). Green shows the mean FA skeleton and background image is in MNI 152. Tractography from representative subjects show tracts passing through the region identified by TBSS.

FA in region 1 correlated with verbal IQ (r=0.405, P<.03).  The arcuate fasciculus is the fiber pathway that connects Wenicke’s area in the temporal lobe to Broca’s area in the frontal lobe.  It plays an important role in verbal comprehension and communication.  FA in region 2 was inversely associated with ratings of depression (r=–0.442), dissociation (r=–0.447), and limbic irritability(r=–0.483). The cingulum bundle is the most prominent tract of the limbic lobe, and connects the limbic lobe with the neocortex, particularly the cingulate gyrus.  FA in region 3 was inversely correlated with anxiety (r=–0.36) and somatization (r=–0.371).  The fornix is a pathway that interconnects hippocampus with the septal area and mammillary bodies, and is known to play a role in anxiety and memory. Interestingly, the hippocampus receives serotonin fibers from the midbrain raphe via two pathways: the cingulum bundle (which predominantly innervates dorsal hippocampus), and the fornix (which innervates all portions).  Hence, two of the fiber tracts with segments of reduced FA in PVA subjects, provide pathways for serotonin fibers to innervate the hippocampus.

This study provides the first evidence that high levels of parental verbal aggression may be a form of abuse or adversity that alters trajectories of brain development.  It supports our previous hypothesis that different forms of childhood maltreatment will exert some comparable an array of consistent neurobiological effects (particularly on limbic regions or connection) as they are all stressors.  However, different forms of abuse will also have some unique effects based on sensory systems activated that convey the aversive stimulus to specific parts of the brain that process and interpret the information.

Support

This work was supported, in part, by National Institute of Mental Health RO1 grants MH53636 and MH-66222, and National Institute of Drug Abuse RO1 grants DA-016934 and DA-017846 to MHT.

Abuse and Sensitive Periods

December 14, 2008

Research from my laboratory, and from other labs here and abroad, have shown that exposure to childhood abuse is associated with alterations in brain structure and function.  This research has largely focused on brain regions known to be susceptible to the effects of stress, such as the hippocampus.  We have recently expanded our knowledge regarding the potential adverse effects of abuse by publishing the first preliminary data indicating that the neurobiological consequences of abuse depend on the age of exposure (Andersen et al 2008).

Andersen SL, Tomada A, Vincow ES, Valente E, Polcari A, Teicher MH (2008): Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. J Neuropsychiatry Clin Neurosci 20:292-301.

Synopsis:

Childhood Abuse and Regional Brain Development: Evidence for Sensitive Periods

Martin H. Teicher, Susan L. Andersen, Akemi Tomada, Evelyn Vincow, Elizabeth Valente, & Ann Polcari

Department of Psychiatry, Harvard Medical School; Developmental Biopsychiatry Research Program, McLean Hospital, Belmont MA 02478

Background

The brain is molded by experiences that occur throughout the lifespan. However, there are particular stages of development when experience exerts either a maximal (sensitive period) or essential (critical period) effect. Little direct evidence exists for sensitive or critical periods in human brain development. Based on differential rates of maturation specific brain regions should have their own unique periods of sensitivity to the effects of early experiences such as stress.

To ascertain if this is true in humans, the size of apriori selected target regions were measured from high-resolution volumetric MRI scans (1.5 T GE Echospeed) from unmedicated collegiate females with a history of repeated childhood sexual abuse and healthy sociodemographically comparable controls.

Subjects

Physically healthy, unmedicated, right-handed individuals aged 18–22 years with history of 3 or more episodes of forced contact childhood sexual abuse (CSA) prior to age 18.  Subjects had no history of neurological disorders; psychotic disorders; pregnancy; past or present alcohol/substance abuse; in utero exposure to alcohol or drugs; complication during prenancy or delivery; physical abuse  above shoulders; or exposure to any other forms of trauma. Abused and control subjects were predominantly middle class or above (96%) and the two groups were similar in measures of socioeconomic status (Hollingshead index (23): 2.3±0.9 versus 2.0±0.6; p = 0.17).  Subjects were paid for their participation, provided written, informed consent, and the study was approved and monitored by the McLean Hospital Institutional Review Board.

•CSA group:  26 abused women (mean age = 20.0 yr).
•Controls: 17 women (mean age = 19.4 yr) with no current or past DSM-IV Axis I disorder and no history of abuse or exposure to other traumatic events.

MRI Methods

Volumetric brain images were acquired using a 1.5 T magnetic resonance scanner (Echospeed; General Electric Medical Systems, Milwaukee, WI, USA) .   Hippocampus and amygdala were manually traced in their entirety according to the method detailed by Pruessner et al. (2000).   Anatomical measurements of corpus callosum area were obtained from the midsagittal image.  An automated algorithm created in NIH Image divided the manually-traced corpus callosum into seven regions as defined by Witelson (1989).  Region 3, rostral body, was selected for sensitive period analysis as this region showed the greatest overall vulnerability to CSA in the present sample.  Frontal cortex grey matter volume and intracranial  volume were ascertained using a semi-automated  program for cortical surface-based analysis (FreeSurfer; Dale et al., 1999; Fischl et al 1999, 2001).

Data Analysis

First, an exploratory analysis was performed using ANCOVA to compare brain regions in subjects who experienced CSA during a development stage (preschool 3-5 yrs, latency 6-8 yr,  prepubertal 9-10 yr, pubertal 11-13 yr and adolescent14-16 yr) versus healthy controls (“abuse-control comparison”). If a brain region was vulnerable at a particular stage, it should differ in size in subjects who experienced abuse at that stage relative to controls. Further, if one developmental stage was markedly more vulnerable than another developmental stage, then subjects who experienced CSA during the vulnerable stage should also show differences in regional brain size compared to subjects who experienced CSA during other stages (“within abuse comparison”).

To compensate statistically for the number of multiple comparisons made in each analysis, a sequential Sidak Bonferroni-type multiple comparison  procedure was used to adjust reported p-values {Sidak1967, Holland 1988}.

Second, path analysis was performed using structural equation modeling with Amos Graphics as a confirmatory statistical procedure.  Path analysis was used to simultaneously examine the association between the density of abuse during each of the aforementioned stages and measures of the hippocampal volume, frontal cortex GMV, and midsaggital area of the rostral body of the corpus callosum.
Results

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Figure 1.  Effect of exposure to childhood sexual abuse during different developmental stages on measures of hippocampal volume during early adulthood.  Data based on ANCOVA, with results expressed as effect size (eta-squared), indicating percent of variance that can be attributed to abuse during a given stage.

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Figure 2.  Path analysis based on structural equation modeling with Amos Graphics, showing the relationship between density of abuse during different developmental stages and measures of hippocampus, corpus callosum and frontal cortex size.  Data were covaried by SES and measures of overall brain size (intracranial volume, midsagittal area, total gray matter volume).

Summary

Within the same group of subjects there were marked differences between regions in the stages of greatest vulnerability.  The hippocampus was particularly sensitive to abuse reported to occur at 3-5 and 11-13 years of age.  In contrast, the rostral body of the corpus callosum was affected by abuse reported to have occurred at ages 9-10, and prefrontal cortex by abuse at ages 14-16.

Discussion

Childhood abuse has been associated with vulnerability to a host of psychiatric disorders and behavioral problems. Based on the present findings, there may be different abuse-related syndromes associated with particular stages of abuse and specific regional brain changes.

Identifying sensitive periods may also provide insight into key ages at which stimulation or environmental enrichment may optimally benefit development of specific brain regions.

Support

Supported, in part, by RO1 awards from the National Institute of Mental Health (MH-53636, MH-66222) and National Institute of Drug Abuse (DA-016934, DA-017846) to MHT.