1. Dr. Maria Karayiorgou (Rockefeller)
   
   
   1. She summarized previous genetic research on other psychiatric disorders (schizophrenia and bipolar) which have 1% and above prevalence rates. These disorders have common alleles with low penetrance and have combination of various alleles; no gene is necessary or sufficient for these disorders, and they have more than one allelic combination; adding to the complexities, there are gene-environment interactions. Psychiatric disorders are genetically similar to obesity, diabetes, and Alzheimer's in terms of polygenic complexity. In psychiatric disorders, including BPD, an added complication is clinical heterogeneity.
      
      
   2. Large sample sizes help with these complexities, along with well characterized patients across sites; this can lead to phenotypic stratification.
      
      
   3. She recommended the use of isolated, "founder" populations, rather than using outbred populations, which can be useful in isolating genes. This lesson has been learned from research in schizophrenia.
      
      
   4. She recommended the approaches of linkage mapping (utilizing extended pedigrees) or linkage disequilibrium mapping (similar to candidate gene approach). Most scientists study the same 20 genes out of a possible 50,000+ genes. This can be too limiting. She recommended searching for "conditional" candidate genes based on more educated guesses. She recommended comparing allele frequencies between families of disordered with matched (ethnically homogeneous) controls.
      
      
   5. Current possibilities for samples and projects: Torgersen twin sample in Norway. Or, use BPD sample in Freiburg to do family based association studies to identify candidate regions, which can then be tested on the Norwegian sample.
   
   
2. Discussants:
   
   
   1. Dr. Svenn Torgersen summarized his research with twins with PDs. His major findings are that all PDs but passive aggressive are strongly influenced by genes; BPD evidenced 60% heritability which is "very high." PDs are more influenced by genes than traits. He recommended, looking not only at BPD features, but all kinds of PD features. He is now studying 3000 twins. He uses the SIDP-R for assessing Axis II, personality disorders, and the CIDI for Axis I, clinical conditions. In addition a personality questionnaire is used, especially suitable for Borderline Personality Disorder. Half of the twins were also interviewed 8 years ago with some other methods. He recommended that it is important to look at the number of criteria fulfilled rather than simply cutoff, which is artificial. He also is studying 3000 individuals from the common population and is re-interviewing them after 6 years. The same methods are used as the twin study. One result is that of all PDs, BPD is associated with lowest quality of life and social functioning. The reinterviewing makes it possible to study the course of BPD as well as the variables predicting new cases of BPD.
      
      
   2. Dr. Olpe summarized, briefly, Dr. Urs Meyer's proposal for the Swiss BioCenter genetics project, which will be done in collaboration with the Freiburg Team. Dr. Meyer's laboratory has longstanding experience in analyzing the diversity of human genes in regard to differences in drug responses. He proposes 2 projects:
      
      
      1. To develop an oligonucleotide microarray system that simultanously test for the genetic polymorphisms of candidate genes that have been associated with neuropsychiatric disorders, including mutations of tryptophan hydroxylase, dopamine receptors and transporter, serotonin receptors and transporter, and opioid receptors.
         
         
      2. To study additional candidate genes, for which polymorphisms have not been described yet, e.g. glucocorticoid receptor, corticotropin-releasing hormone receptor(s), etc. ESTs (expressed sequence tags) of these genes will be screened in databases available in the public domain (and through contracts). These databases contain sequence information on most human genes from several hundred unrelated individuals. Polymophisms (e.g. SNPs) of the genes analysed and their frequences in the population can thus be predicted.

      Both approaches will be tested in DNA from patients characterized by Drs. Bohus and Lieb in Freiburg and with patients from the Psychiatric University Clinics in Basel (Müüller-Spahn, Küchenhoff). These patients have been characterized and followed up as described in the respective sections.

   3. Dr. Siever argued for the importance of establishing the validity of the diagnosis to sustain research resources. He argued that personality traits have higher genetic components than states (e.g., depression). He stated there are likely to be configurations of allelic variance leading to the phenotype, and more than one pathway to the phenotype. He recommended investing in high quality genetic data for future use. He argued that case control methods are the least desirable, though they have some uses. He recommended the study of genotypic interactions and studies with chip array technology. He recommended studying families of genes in neurotransmitter systems, e.g., serotonin. He also recommended assessing genetic contributions to intermediate phenotypes (e.g., traits). He recommended using laboratory tests of aggression, impulsivity, affectivity, etc. He discussed animal models as important in investigating possible candidate gene systems.
      
      
   4. Dr. Kandel reminded the group that between 1980 to present, 100 genes have been identified and the genetics field has been revolutionized because of this. He predicted that in the next 20 years a comparable revolution will occur for polygenic disorders. He recommended that all Sites appoint a representative to work with Dr. Siever around how to standardize data collection across all clinical samples for genetic studies.
      
      
   5. Dr. Wiesel added that Drs. Kessler and Hyman (NIMH) will be looking to collaborate as well, in particular on epidemiological studies. He and Dr. Kandel already have had discussions with Drs. Kessler and Hyman. Dr. Hyman has already joined the Board of Trustees of the Foundation.
      
      
   6. Dr. Innis suggested collaboration between genetics and imaging, e.g., with twins. Dr. Bohus suggested recruitment on the internet chat rooms for BPD subjects.

   C. Imaging:

   1. Dr. David Silbersweig (Cornell) discussed their plan to image the anterior medial temporal lobe and ventromedial prefrontal cortex (a circuit theorized to integrate emotion with goal directed behavior) in BPD patients and controls. He and Dr. Posner have developed probes to assess cognitive control and emotion systems. The Cornell Team will conduct fMRI activation probes with 36 initial patients in three different treatments. The probes will include a BPD tailored Emotional Stroop Test (activates amygdala in normals) and Go-No Go Task. The Team will also work with Dr. McEwen on stress-cortisol interactions as they relate to hippocampal atrophy in BPD, and this will be related to childhood trauma. Salivary cortisol measures will be obtained, and hippocampal volume will possibly be measured. Appropriate controls are people high in negative affect and low in effortful control but non-BPD.
      
      
   2. Dr. Bruce Wexler (Yale) summarized their functional and structural MRI studies. The first study will research four different emotional perturbations for use during imaging. They will look at potentiation and habituation over time for emotional arousal with a focus on self-regulation across several disorders. Dr. Innis will conduct molecular imaging using PET and SPECT to study the serotonergic system. Dr. Innis encouraged the assessment of decreased hippocampal volume as it relates to memory in BPD.
      
      
   3. Dr. Mark George (MUSC) will integrate fMRI studies with TMS. TMS consists of a powerful handheld magnet which affects the cortex. It has been shown to induce motor changes. TMS shows evidence of an antidepressant effect in several randomized, controlled trials. Phase I of their research will investigate whether TMS can be applied to regions related to BPD (assessed through neuroimaging). In Phase II, the Team will apply TMS to those regions as a possible treatment.
      
      
   4. Dr. Erich Seifritz (Basel/Freiburg) and his group will address the interaction between prefrontal cortex and amygdala using volumetric MRI studies. Hypothesis: altered connectivity between these two regions in BPD patients. The team will also assess HPA function and glucocortisoid receptors in hippocampus in BPD patients and controls. The team will also study habituation time needed to neutralize a conditioned stimulus in BPD vs. controls. The team will also study HPA pharmacologically in humans and animals.
      
      
   5. Discussion:
      1. Dr. Stephen Kosslyn recommended being mindful of the difference between neural correlates vs. neural causes (circuits). The functional architecture is not the same as the circuit. A circuit mandates that there is a temporal, causal link between two imaging variables. The task (probe) is therefore critical, and based on the question one wants to answer, one should always select a relevant task. He encouraged measuring mechanisms based on theory and research using top down and bottom up hypothesis testing. He advocated that the imaging studies be closely integrated with the rest of the studies (e.g., diagnostics should clearly define the phenotype). He reminded the group that genes affect brain development, which in turn affects behavior; genes don't directly lead to behavior. Once mechanisms are clearer, we can move to animal models. He cited Baxter's OCD treatment study as an example of how to integrate imaging of theorized mechanisms into measuring outcome in treatment studies.
         
         
      2. Dr. Damasio noted that BPD seems to not always be in its active state, so he recommended provoking these states before imaging. He suggested expanding scope of imaging to other brain regions than those that are highlighted currently.
         
         
      3. Dr. Kandel emphasized need for rigor in presenting data with proper control groups. He invited Dr. Posner to help design tasks (probes). He encouraged the development of a plan to utilize imaging to assess therapy outcome.
         
         
      4. Dr. Seelig emphasized that imaging techniques require improvement and that they are not as developed as generally assumed.
         
         
      5. Dr. Lenzeweger recommended using psychiatric controls, not just normal controls. A cousin of BPD is schizotypic individuals.
         
         
      6. Dr. Gunderson recommended tying technology and tasks more to BPD issues, e.g., constructing tasks related to the phenomenology of BPD.

   D. Treatment:

   1. Dr. Otto Kernberg (Cornell) summarized the basics of borderline psychopathology. The essential characteristics are impulsivity, affective dysregulation, identity disturbance. In BPD, there is a pathological activation of intense negative affects that overrule cognitive control, leading to impulsivity. The biological factor (affect dysregulation) is linked to the psychological factor (identity diffusion). Affects are a signal to the caregiver. In peak affect states, two person relationships are internalized as affective memory. They lead to a psychological representation of self and other under the impact of an affect (dyadic unit). Positive (idealized) and negative (persecutory) affects are built up separately. These affects are integrated in normal identity. In BPD, because of excessive negative affect, splitting of positive and negative affects is maintained, leading to a severe disturbance in identity. The etiology of BPD is, therefore, biological and psychological. Treatment strategies can 1) reduce affect through medications, 2) reinforce the self (DBT or Supportive Psychotherapy), or 3) let peak positive and negative affect states emerge in treatment situation and the therapist can encourage cognitive integration of self-states (Transference Focused Psychotherapy; TFP). These are the treatments Cornell is comparing, not in terms of a "horse race," but to identify the subgroups of BPD that respond best to the different treatments.
      
      
   2. Dr. Nash Boutros (Yale) will apply TMS protocol to BPD patients comorbid for depression. Dr. Rasmusson (Yale) will conduct a risperdal trial with BPD, in particular targeting impulsive-aggression and affective dyscontrol.
      
      
   3. Dr. Martin Bohus (Basel/Freiberg) summarized Dialectical Behavior Therapy (DBT) as a principle-based, multi-modal therapy. It emphasizes a skills training approach. He critiqued the "power" (sample size) of the Cornell Randomized Clinical Trial.
      
      
   4. Dr. Gunderson (Discussant) noted a risk that clinical problems of these patients can be overlooked with an overly biological focus that he feels is exhibited in the Symposium. He emphasized that BPD is a major public health problem, and that the American Psychiatric Association has started a workgroup to develop treatment guidelines. He suggested stratifying treatment samples on key prognostic variables. He suggested common intervals of assessment and outcome measures across Sites and treatment studies. The first interval might need to be within one month. He highlighted need for equal time and attention to different treatment strategies to guard against bias for or against different therapeutic approaches, which has been shown to influence treatment outcome.
      
      
   5. Dr. Kandel emphasized how important the clinical aspects are to the Foundation. He invited Dr. Gunderson to help optimize the treatment studies with a team of advisors.
      
      
   6. Dr. Skodol stated that stratifying would decrease statistical power, and that the sample size was adequate to differentiate DBT/TFP from Supportive in terms of efficacy, but not to differentiate DBT and TFP.
      
      
   7. Dr. Kernberg emphasized that the three therapies in the Cornell study will be equally attended to, e.g., Dr. Barbara Stanley is supervising the DBT condition.
      
      
   8. Dr. Wiesel emphasized the important link between diagnosis and therapy.
      
      
   9. Dr. Stoffel recommended stepping back and realizing the impressive amount of work done rather than get to become too critical around the details at this point. He thanked all the participants for their efforts and commitment to help patients with this disorder. He reminded everybody that he and Dr. Pletscher had started this effort only about a year ago when they visited various Universities to recruit them for this Consortium. He emphasized, "Now we are talking already about common new diagnostic standards and the interdisciplinary cooperation through cross-Site workshops." He reported that the donor family, who mandated him to start this Borderline Research Institute, is extremely pleased and confident that with this joint effort of leading research centers a breakthrough for the understanding and treatment of BPD is possible.

   E. Psychobiology:

   1. Dr. Michael Posner (Cornell) summarized assays that will be used to test BPD patients pre- and post- treatment, and to compare BPD patients with controls (normal and schizotypic). Dr. Lenzenweger summarized his plan to demonstrate the linkages of BPD psychopathology to well understood neurobehavioral systems and memory systems.
      
      
   2. Dr. George Heninger (Yale) summarized his findings comparing physiologic data between PTSD and BPD; they appear to be different. Predicted that this Consortium will do for BPD what was done for Social Anxiety.
      
      
   3. Dr. Martin Bohus (Basel/Freiburg) summarized their hand-held computer-based study of affective arousal comparing BPD patients to controls.
      
      
   4. Dr. Larry Siever (Discussant) stated he would like to see commonality in measures and/or conceptualizations of BPD. He emphasized the importance of state inductions and defensive processes (as highlighted by Kernberg) in studying these patients. He reiterated that identity disturbance is an affect related trait. The Cornell Treatment study is not a horse race, so he recommended the use imaging paradigms to assess outcome. He recommended focusing on the biologic footprints of trauma. He argued that BPD not just a variant of PTSD, so we should look at the differences.
      
      
   5. Dr. Innis raised possible ethical issues in working with BPD subjects, there could be adverse events. Dr. Kernberg summarized Cornell's strategy regarding this.

   F. Animal Studies:

   1. Dr. Bruce McEwen (Rockefeller) stated that animal studies can contribute to the study of stress, anxiety, fear, aggression, sensory-motor gating, and substance self-administration, which are all related to aspects of BPD. The hippocampus, amygdala, and prefrontal cortex have a plasticity related to stress levels. He recommended studying the relationship between neurochemistry and brain structure. He summarized research demonstrating that dendrites are remodeled under the influence of stress. With psychosocial stress the HPA axis changes in rats and mice. Maternal care influences HPA and neurochemicals in animals, consistent with a stress-diathesis model. A promising finding from their lab is their demonstration of change in mouse gene expression (specifically in the prefrontal cortex) in a stress paradigm experiment (Dr. Brake).
      
      
   2. Dr. Andreas Luethi (Basel/Freiburg) summarized that childhood trauma is hypothesized to be causally linked to BPD. He highlighted that the prefrontal cortex and amygdala are mutually interactive regions related to emotion modulation. He outlined that in the team, Dr Isabelle Mansuy (Zürich) will work towards developing mouse models for BPD, initially using environmental manipulations including maternal separation, then producing genetically modified mice. She will examine the consequences of such manipulations with behavioral, biochemical and molecular methods and for this will collaborate with the group of Bruce McEwen at Rockefeller University. Dr Andreas Luthi (Basel) will initially focus on characterizing the electrophysiological properties of the prefrontal/amygdala axis in wild-type animals, then will examine these properties in the mouse models produced by Dr Mansuy. He will coordinate with Dr. Bohus in human studies.
      
      
   3. Dr. Michael Meaney (Discussant) suggested not moving forward with animal models until neuroimaging and psychobiology are clearer, except for perhaps maternal stress work. He highlighted the exciting potential for translation research in the Consortium. Trevor Robbins (?), for example, moves across rat, monkey, and human studies to study impulse control. A coherent understanding of neurobehavioral systems can lead to a knowledge of mechanisms in BPD. He emphasized also looking at hippocampus's connections to the prefrontal cortex, not just the amygdala's connections to this region. He argued that habituation is promising area than can be made richer. Finally, he advocated for using developmental manipulations in a well timed, rigorous way.

   G. General Discussion: Mechanisms to Facilitate Consortium and Team Collaboration

   1. Dr. Kandel expressed that it is clear the BPD is "coming of age." He clarified that the Board's current oversight is because of lack of previous peer review, and apologized for this. His "fantasy" experiment is a treatment outcome study using imaging, he feels that would greatly strengthen psychiatry as a discipline. He encouraged using animals to study a more diverse range of aspects of BPD. Finally, he emphasized that competition is not for three more years, and that Sites are not necessarily competing with one another.
      
      
   2. Dr. Wiesel conceptualized the current funds as "seed money." He argued that both collaboration and competition foster scientific innovation and progress. He would like a workshop organized for the Treatment area. The Consortium will get more support from NIH, and the current seed money will put Sites at an advantage in the future for both outside funding and continued Foundation funds.
      
      
   3. Dr. Kosslyn advocated for an integration across imaging, therapy, and animal models. Dr. Seelig suggested an imaging coordination meeting.
      
      
   4. Dr. Heninger recommended modeling the Foundation after PTSD and Panic Disorder Foundations, who developed a gold standard assessment instrument for their respective disorders, but who also retain flexibility around other aspects of study of these disorders.
      
      
   5. Dr. Skodol proposed a Consensus Meeting in early September to settle core instrumentation issues in the Diagnosis area.
      
      
   6. For imaging, with well a defined phenotype via a diagnostic instrument, a team was recommended to develop BPD-specific tasks, probes, and challenges (Dr. Kandel suggested a team of Drs. Kosslyn, Damasio, and Posner).
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