Martin Teicher, MD, PhD

Dr. Teicher’s Developmental Biopsychiatry Research Program was founded in 1988 with the aim of improving the lives of children, adolescents, and adults by exploring the causes of psychiatric disorders that arise during development, and by creating medical devices for their assessment. Dr. Teicher is particularly focused on the enduring effects of childhood maltreatment.

Research reveals a strong link between physical, sexual, and emotional maltreatment and bullying on the risk for depression, anxiety, post-traumatic stress, and substance misuse. Research pioneered by Dr. Teicher’s lab shows that childhood maltreatment alters brain structure and function, depending on the type of abuse and the stage of development.

The lab’s research goals include identifying sensitive periods when brain regions are maximally vulnerable to early life stress and associated with greatest risk for mental illness; assessing whether alterations in brain structure, function, connectivity and associated neurocognitive symptoms can predict future risk for substance addiction; identifying changes in brain network architecture associated with resilience and recovery; and developing tools to better diagnose and assess psychiatric disorders and to evaluate novel treatments.

To identify sensitive exposure periods, Dr. Teicher and Angelika Parigger developed the Maltreatment and Abuse Chronology of Exposure (MACE) scale, which provides highly reliable information on severity of exposure to ten types of maltreatment across each year of childhood. This is a sophisticated instrument developed using item response theory and it is becoming increasingly popular, with translations into German, Norwegian, Spanish, French, Portuguese, Serbian, Chinese, Japanese, and Korean.

Identifying sensitive periods in the MACE data is a challenging statistical problem, as there is substantial collinearity between severity of exposure across adjacent ages and conventional analytical tools, such as multiple regression, are not suitable. Dr. Teicher developed a solution using artificial intelligence predictive analytics to identify the most important type/time risk factor. A series of Monte-Carlo simulations were run to identify the most accurate AI algorithms, using MACE data with predefined outcomes to provide ‘ground truth.’ Random forest regression with conditional inference trees proved to be substantially more accurate than other algorithms in identifying the underlying predictors. This work was done in collaboration with Inga Schalinski at the University of Konstanz, who is now working with Professor Christine Heim at Charité – Universitätsmedizin Berlin.

Using these tools, Dr. Teicher’s team have identified the types of maltreatment at specific ages that emerge as the most important risk factors for alterations in hippocampal subfield volume, corpus callosum myelination and axonal integrity, as well as in response of the amygdala and other key corticolimbic regions (hippocampus, fusiform gyrus, inferior frontal gyrus pars triangularis, anterior cingulate, ventromedial and dorsomedial prefrontal cortex) to threat.

This later work, conducted by Jainjun Zhu who was a visiting graduate student from China and is now faculty at Guangzhou University, was particularly informative as it showed that these brain regions had two distinct sensitive periods, with exposure to maltreatment during the prepubertal sensitive period leading to a blunted response and exposure during the postpubertal period resulting in an exaggerated response to threat.

Dr. Kyoko Ohashi also contributed substantially to this work and is lead author on the corpus callosum studies, which revealed prominent gender differences in susceptibility and neurobiological consequences of maltreatment.

Dr. Teicher’s team has also used this approach to identify type and time risk factors for multiple clinical outcomes, such as major depression, anxiety disorders, suicidal ideation, personality disorders, ‘limbic irritability,’ and different types of substance use. This effort is being led by Dr. Alaptagin Khan. Dr. Schalinski has also used this approach collaboratively to identify type time risk factors for positive and negative schizophrenic symptoms, cognitive consequences of psychosis, post-traumatic stress, dissociation, and cortisol regulation. Dr. Khan is also spearheading efforts with Drs. Kerry Ressler and Torsten Klengel at McLean to determine the extent to which genetic polymorphisms affect susceptibility to psychiatric disorders by altering timing or duration of sensitive periods.

A concern that Institutional Review Boards (IRBs) have had about assessing exposure to childhood maltreatment is how stressful and disturbing individuals with histories of maltreatment may find it to complete the MACE scale. A few IRBs at other institutions have not permitted investigators to use this instrument.

In contrast, Dr. Teicher’s lab has collected MACE data on more than 3,000 individuals with no instances of untoward distress. The team will conduct a detailed study to measure how stressful or distressing it is for maltreated individuals to provide detailed information regarding their exposure to maltreatment. The hypothesis is that providing this information will be more helpful than stressful and that even individuals reporting substantial histories of maltreatment will find this less stressful than taking timed math tests. This study, and all ongoing investigations, will be coordinated by Elizabeth Bolger.

Intergenerational effects of childhood maltreatment are being explored in collaboration with Drs. Karlen Lyons-Ruth at Cambridge Health Alliance, Ellen Grant and Michelle Bosquet Enlow at Boston Children’s Hospital, and Dr. Kerry Ressler at McLean. This is one of the first mother-infant dyadic brain studies.

Mothers with four-month-old infants were recruited and infant attachment and mother-infant stress responses were assessed by Drs. Lyons-Ruth and Enlow. Dr. Teicher’s group is assessing the effects of childhood maltreatment on maternal brain structure and regional brain response to psychosocial stress, while Dr. Grant’s team is assessing alterations in brain structure and function in the infants. Dr. Ressler’s team has recently received funding to study associated epigenetic alterations. Recent results indicate that maternal maltreatment history is associated with delayed development of key brain regions in their infants.

Dr. Teicher’s team has recently completed a longitudinal study to determine whether brain regions and clinical symptoms identified as potential predictors of substance use in cross-sectional studies were prospectively predictive of escalating drug use in emerging adults with histories of childhood maltreatment. Morphology of the cerebellar vermis emerged as a key risk factor for alcohol use, and alterations in blood flow in the dorsolateral prefrontal cortex prospectively predicted escalating use of drugs other than marijuana.

The lab also found that symptoms of ‘limbic irritability’ was the most important clinical predictor. Indeed, ‘limbic irritability’ emerged as a better predictor than symptoms of post-traumatic stress, depression, anxiety, or anger-hostility and was the only universal predictor of increasing use of alcohol, nicotine, cannabis, and other substances. ‘Limbic irritability’ refers to the relatively frequent occurrence of temporal lobe epilepsy-like symptoms in non-epileptic individuals and consists of paroxysmal somatic disturbances, brief hallucinatory events, sensory distortions, automatisms, and dissociative symptoms, which are assessed using the Limbic System Checklist-33, developed by Dr. Teicher.

Although childhood maltreatment is the most important risk factor for a host of different psychiatric disorders, individuals differ in their degree of susceptibility and there is a significant number of individuals who report experiencing moderate-to-severe abuse who have no history of or current symptoms of psychiatric illness.

Originally, Dr. Teicher and his collaborators thought that psychiatric and neurobiological vulnerability would go hand in hand and that the brains of resilient maltreated individuals would be relatively unaffected. This turned out not to be true and brains of psychiatrically resilient and susceptible individuals show the same array of alterations in morphology, connectivity, and functional activity. Hence, resilient individuals are not unaffected, but through some other mechanisms are effectively compensated.

To understand how this occurs, the lab used network analyses to study the interconnections between brain regions and found that there were additional alterations in the connectivity of a constellation of brain regions that specifically identified resilient participants. This work, which was led by Dr. Kyoko Ohashi, also opens up a new line of thinking as it suggests that effective treatments for maltreated individuals may work not by reversing the effects of maltreatment, but by moving the network architecture of susceptible individuals more into line with the atypical network architecture of resilient individuals.

The team is also interested in identifying potential protective factors that may enhance resiliency or mitigate outcomes. Krista Goldstein-Cole worked with Dr. Teicher to explore the importance of school connectedness as a protective factor and found that elementary school connected was particularly helpful. This work was a key part of her doctoral dissertation at the Harvard School of Education.

Dr. Khan, working with Dr. Teicher, is also in the process of developing the Chronology of Perceived Discrimination scale to assess whether exposure to various forms of discrimination, during specific stages of development, enhances risk for psychiatric disorders and affects trajectories of brain development. In addition to assessing effects of exposure to discrimination based on race/ancestry/skin color/national origin, the lab will also assess developmental effects of exposure to discrimination based on sexual orientation, physical disabilities, psychiatric or neurological disorder, stigma, physical attractiveness, and financial status.

Drs. Teicher and Jacqueline Samson formulated the ‘ecophenotype hypothesis’ which postulates that maltreated and non-maltreated individuals with the same primary DSM-5 diagnosis are clinically, neurobiologically, and genetically distinct. Individuals with the maltreated ecophenotype typically have an earlier age of onset, a more pernicious clinical course, more comorbid diagnoses, and have a less satisfactory response to first-line treatments. Moreover, the maltreated and non-maltreated subtypes have distinctly different neurobiological signatures.

Dr. Teicher’s team is currently testing this theory in individuals with opioid use disorder, with the hypothesis that maltreatment and attention-deficit hyperactivity disorder (ADHD) represent two distinctly different pathways to opioid use disorder. In addition to evaluation of clinical and neurobiological differences, the lab will also evaluate between group differences in sleep architecture, with McLean’s Dr. Scott Lukas, and inflammatory and epigenetic differences, in collaboration with Drs. Kerry Ressler and Torsten Klengel.

Dr. Ohashi in Dr. Teicher’s group and Dr. Kathryn Eve Lewendowski in the psychotic disorders division are also studying the ecophenotype hypothesis in previously admitted individuals with bipolar disorder. Dr. Teicher has recently written a review article with Professor Charles Nemeroff at University of Texas, Austin advocating changes to the DSM to recognize the important distinction between psychiatric disorders with and without histories of early adversity.

In terms of treatment, Dr. Diane Joss, working in Dr. Teicher’s laboratory on a research scientist development award and with Dr. Sara Lazar at Massachusetts General Hospital, has published a series of studies on the therapeutic benefits of mindfulness in individuals with histories of childhood maltreatment, as well as the potential effects of mindfulness training on corticolimbic structure and connectivity.

A secondary focus of Dr. Teicher’s research program has been on the assessment, neurobiology, and treatment of ADHD and other early onset psychiatric disorders.

The lab is currently exploring the hypothesis that there are three subtypes of ADHD. First, there is the classic or uncomplicated form of ADHD. Second, there are individuals with the classic form who subsequently experience childhood maltreatment. These individual share the same primary brain changes seen in classic cases but have additional alterations in stress-susceptible structures and high comorbidity rates. Third, there are individuals with very early exposure to abuse or neglect who subsequently develop ADHD. Many of these individuals have symptoms and brain changes due to early exposure to maltreatment and appear to have brain changes and neurocognitive abnormalities not seen in the other subtypes.

Dr. Teicher’s team has conducted an open study of the effects of ‘brain balance center’ and ‘interactive metronome’ exercises on youths with ADHD. This involved an extensive home treatment protocol, which took place five times per week for 15 weeks. The Quotient ADHD System developed in the laboratory to provide objective measures of hyperactivity, inattention, and impulsivity was used as a primary outcome measure, along with parent reports and neuroimaging to evaluate treatment effects on resting-state functional connectivity.

This preliminary open study revealed potential evidence of efficacy, but this needs to be evaluated in a randomized control trial. There is a pressing need to develop nonpharmacological treatments for ADHD that might exert enduring therapeutic benefits.

The team is also in the process of conducting a study, in collaboration with Blaise Aguirre, MD, and his team at 3East, to assess the effects of dialectical behavior therapy (DBT) in youths with severe psychiatric symptomatology. Participants are scanned immediately prior to admission and at the time of discharge.

The lab will assess the effects of DBT on brain network architecture, with the hypothesis that youths who experience marked benefits will have greater alterations in connectivity of specific brain regions, such as the inferior frontal gyrus, than individuals who have experienced less beneficial responses. Dr. Khan is leading this effort in Dr. Teicher’s lab and this work is conducted in collaboration with Drs. Daniel Dickstein and Marisa Silveri, and Jill Nowak, LICSW, at McLean.

Dr. Frederic Schiffer and Dr. Teicher conducted a multicenter trial of unilateral transcranial photobiomodulation (tcPBM) as a potential treatment for individuals with opioid use disorder. This treatment enhances activity in the frontal lobe and was applied to the hemisphere with the more positive emotional valance. The results of this randomized control trial showed large beneficial effects of tcPBM on craving. Dr. Schiffer at MindLight, along with Dr. Teicher at McLean, are applying for SBIR funding to conduct a larger trial to assess the safety and efficacy of tcPBM in reducing opioid use in participants with mild-to-moderate opioid use disorder who are not receiving medication management.

Dr. Teicher’s team is also completing a study on the neurobiological effects of ketamine in adolescents and young adults with what Dr. Demitri Papolos, of Albert Einstein Medical School, has labeled the ‘fear of harm’ phenotype of bipolar disorder. These individuals have a psychiatric disorder characterized by emergence of intense nightmares during childhood followed by the development of pervasive fearfulness, mood swings, aggression, and problems with thermoregulation.

Participants in this study had failed to adequately benefit from multiple psychiatric medications but are doing well on a combination of intranasal ketamine, taken every 2-4 days, and a mood stabilizer. They are being scanned after being partially withdrawn from ketamine and rescanned 2-3 hours after ketamine. Marked effects have been observed so far in the response of the insula to graded thermal stimulation and in a host of brain regions to supraliminal and subliminal threatening faces. Drs. Teicher and Papolos recently hosted a Radcliffe Accelerator Meeting to discuss strategies for including this disorder in DSM-5.

In collaboration with McLean’s Kwang-Soo Kim, PhD, Bruce M. Cohen, MD, PhD, and Debkanya Datta, PhD, the lab collected skin samples from adults with ADHD and from siblings without psychiatric disorders. These samples were transformed into induced pluripotent stem cells and Dr. Kim’s lab is comparing the rate of development, metabolic activity, and neurochemistry of the neurons derived from these stem cells, and in fused cortical and midbrain organoids, in subjects with ADHD versus their unaffected relatives to better understand early developmental differences in this highly heritable disorder. Similar work is also taking place in collaboration with Drs. Kim and Diego Pizzagalli to compare iPS from susceptible versus resilient maltreated individuals.