Neurobiology of emotion And Mental Illnesses BIOS E 232 Sabina Berretta, MD

1. Neurobiology of emotion And Mental Illnesses BIOS E 232 Sabina Berretta, MD Harvard Medical School McLean Hospital

2. Plan for today’s class • Students’ introductions • Today’s seminary: “Clinical domains pertinent to major mental illnesses” • Example of paper presentation: Phillips ML, Drevets WC, Rauch SL, Lane R, 2003. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol Psychiatry 54, 515-528. • Students chose dates for their presentation and papers for February 14th. • Instructions for course assignments: • review paper • grant application

3. Categorical versus Dimensional Debate in Psychiatry DSM-IV is based on a categorical approach: Different aggregations of symptoms are considered to be distinct disorders Strengths of this approach are good reliability, straightforward decision making and implementation (e.g. treatment) Weaknesses are lack of validity • Dimensional Approach: Symptoms common to different disorders provide clinical dimensions Examples are psychoses, depression, anxiety, mania

4. Dementia praecox (schizophrenia) Manic depressive insanity (bipolar disorder) Kraepelin’s dichotomy Emil Kraepelin, 1856-1926

5. "No experienced psychiatrist will deny there is an alarmingly large number of cases in which it seems impossible, in spite of the most careful observation, to make a firm diagnosis... it is becoming increasingly clear that we cannot distinguish satisfactorily between these two illnesses and this brings home the suspicion that our formulation of the problem may be incorrect. " Kraepelin, 1920

6. The Dilemma: the extended transition between affective and schizophrenia disorder Möller, 2008

7. Psychoses Disturbances of thought content: Delusions Delusions are fixed, false beliefs, or misinterpretations of events and their significance. These beliefs are not part of the person's culture and do not change. The person believes delusions even after other people prove that the beliefs are not true or logical. People with schizophrenia can have delusions that seem bizarre, such as believing that neighbors can control their behavior with magnetic waves. They may also believe that people on television are directing special messages to them, or that radio stations are broadcasting their thoughts aloud to others. Sometimes they believe they are someone else, such as a famous historical figure. They may have paranoid delusions and believe that others are trying to harm them, such as by cheating, harassing, poisoning, spying on, or plotting against them or the people they care about. These beliefs are called "delusions of persecution."

8. Psychoses Disturbances of sensory perception: Hallucinations Hallucinations are things a person sees, hears, smells, or feels that no one else can see, hear, smell, or feel. "Voices" are the most common type of hallucination in schizophrenia. Many people with the disorder hear voices. The voices may talk to the person about his or her behavior, order the person to do things, or warn the person of danger. Sometimes the voices talk to each other.

9. Psychoses Thought disordersare unusual or dysfunctional ways of thinking. One form of thought disorder is called "disorganized thinking." This is when a person has trouble organizing his or her thoughts or connecting them logically. They may talk in a garbled way that is hard to understand. Another form is called "thought blocking." This is when a person stops speaking abruptly in the middle of a thought. When asked why he or she stopped talking, the person may say that it felt as if the thought had been taken out of his or her head. Finally, a person with a thought disorder might make up meaningless words, or "neologisms." Movement disordersmay appear as agitated body movements. A person with a movement disorder may repeat certain motions over and over. In the other extreme, a person may become catatonic. Catatonia is a state in which a person does not move and does not respond to others. Catatonia is rare today, but it was more common when treatment for schizophrenia was not available.

10. Mania or manic episode Mood Changes: • A long period of feeling "high," or an overly happy or outgoing mood • Extremely irritable mood, agitation, feeling "jumpy" or "wired" Behavioral Changes: • Talking very fast; flight of ideas or subjective experience that thoughts are racing • Being easily distracted • Increasing goal-directed activities, such as taking on new projects • Being restless • Decreased need for sleep • Inflated self-esteem and grandiosity • Behaving impulsively and taking part in a lot of pleasurable,high-risk behaviors, such as spending sprees, impulsive sex, impulsive business investments, excessive use of alcohol and/or drugs

11. Depression or depressive episode Mood Changes: • A long period of feeling worried or empty • Loss of interest in activities once enjoyed, including sex, social interactions, hobbies etc. Behavioral Changes: • Feeling tired or "slowed down" • Having problems concentrating, remembering, and making decisions • Being restless or irritable • Changing eating, sleeping, or other habits, e.g. insomnia or hypersomnia, significant weight loss when not dieting or weight gain • Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) • Thinking of death or suicide, or attempting suicide

12. Bipolar Disorder

13. Bipolar Disorder (Manic Depressive Illness) Bipolar disorder is a brain disorder that causes unusual shifts in mood, energy, activity levels, and the ability to carry out day-to-day tasks. Symptoms of bipolar disorder are severe. Bipolar disorder symptoms can result in damaged relationships, poor job or school performance, and even suicide. But bipolar disorder can be treated, and people with this illness can lead full and productive lives.

14. Bipolar disorder often develops in a person's late teens or early adult years. At least half of all cases start before age 25. Some people have their first symptoms during childhood, while others may develop symptoms late in life. Bipolar disorder is not easy to spot when it starts. The symptoms may seem like separate problems, not recognized as parts of a larger problem. Some people suffer for years before they are properly diagnosed and treated.

15. Symptoms People with bipolar disorder experience unusually intense emotional states that occur in distinct periods called "mood episodes." An overly joyful or overexcited state is called a manic episode An extremely sad or hopeless state is called a depressive episode A mood episode may include symptoms of both mania and depression. This is called a mixed state Irritability and extreme changes in energy, activity, sleep, and behavior go along with mood changes

16. One side of the scale includes severe depression, moderate depression, and mild low mood. Moderate depression may cause less extreme symptoms, and mild low mood is called dysthymia when it is chronic or long-term. In the middle of the scale is normal or balanced mood. At the other end of the scale: hypomania and severe mania. During hypomanic episodes, a person may have increased energy and activity levels that are not as severe as typical mania, and do not require emergency care. A person having a hypomanic episode may feel very good, be highly productive, and function well. Without proper treatment, however, people with hypomania may develop severe mania or depression.

17. Psychosis in Bipolar Disorder The psychotic symptoms tend to reflect the person's extreme mood. • Psychotic symptoms for a person having a manic episode may include believing he or she is famous, has a lot of money, or has special powers. • A person having a depressive episode may believe he or she is ruined and penniless, or has committed a crime • Hallucinations may also be observed in patients with Bipolar Disorder, but they may be less severe, more visual and less often auditory in comparison with patients with schizophrenia

18. Four basic types of Bipolar Disorder: Bipolar I Disorder The essential feature of Bipolar I Disorder is a clinical course that is characterized by the occurrence of one or more Manic Episodes or Mixed Episodes (lasting at least 7 days and/or severe enough to require hospitalization). Often individuals have also had one or more Major Depressive Episodes. Bipolar II Disorder The essential feature of Bipolar II Disorder is a clinical course that is characterized by the occurrence of one or more Major Depressive Episodes accompanied by at least one Hypomanic Episode.

19. Bipolar Disorder Not Otherwise Specified (BP-NOS) Symptoms of the illness do not meet diagnostic criteria for either bipolar I or II. The symptoms may not last long enough, or the person may have too few symptoms, to be diagnosed with bipolar I or II. However, the symptoms are clearly out of the person's normal range of behavior. Cyclothymic Disorder, or Cyclothymia A mild form of bipolar disorder. People who have cyclothymia have episodes of hypomania that shift back and forth with mild depression for at least two years. However, the symptoms do not meet the diagnostic requirements for any other type of bipolar disorder.

20. Rapid-cycling Bipolar Disorder Four or more episodes of major depression, mania, hypomania, or mixed symptoms within a year. Some people experience more than one episode in a week, or even within one day. Rapid cycling seems to be more common in people who have severe bipolar disorder and may be more common in people who have their first episode at a younger age.

21. Schizophrenia

22. What is NOT Schizophrenia It is NOT a split personality disorder (e.g. Dr Jekill and Mr Hyde) The term ‘schizophrenia’ was coined by Bleuler in 1911 to indicate a ‘schism within the mind’, i.e. a separation of thought from affect and behavior

23. What is Schizophrenia? Schizophrenia is a severe, lifelong brain disorder. In men, symptoms usually start in the late teens and early 20s. For women, they start in the mid-20s to early 30s. It’s main symptoms are generally grouped under ‘Positive’ and ‘Negative’ symptoms Negative symptoms Negative symptoms are associated with disruptions to normal emotions and behaviors. "Flat affect" (a person's face does not move or he or she talks in a dull or monotonous voice) Lack of pleasure in everyday life Lack of ability to begin and sustain planned activities Speaking little, even when forced to interact. People with negative symptoms need help with everyday tasks. They often neglect basic personal hygiene. This may make them seem lazy or unwilling to help themselves, but the problems are symptoms caused by the schizophrenia.

24. Cognitive symptoms Cognitive symptoms are subtle. Like negative symptoms, cognitive symptoms may be difficult to recognize as part of the disorder. Often, they are detected only when other tests are performed. Cognitive symptoms include the following: Poor "executive functioning" (the ability to understand information and use it to make decisions) Trouble focusing or paying attention Problems with "working memory" (the ability to use information immediately after learning it). Cognitive symptoms often make it hard to lead a normal life and earn a living. They can cause great emotional distress.

25. Diagnostic Criteria for Schizophrenia DSM-IV TR A.Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated): • delusions • hallucinations • disorganized speech (e.g., frequent derailment or incoherence) • grossly disorganized or catatonic behavior • negative symptoms, i.e., affective flattening, alogia, or avolition Only one Criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person's behavior or thoughts, or two or more voices conversing with each other.

26. B. Social/occupational dysfunction:For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement). C. Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).

27. Are Schizophrenia and Bipolar Disorder Different Manifestations of the Same Disease?

28. THE KRAEPELINIAN binary system, it may be said, is dead, but the tyranny of its influence lives on. Crow, 1998

29. “… nosological arguments should be put on hold until basic understanding is gained of the specific mechanisms of syndromogenesis across diagnostic boundaries” Jamblesky, 1999

30. Recent investigations on susceptibility genes suggest a continuum between the two diseases Modified from Craddock et al., 2006

32. How to prepare an R21 grant application In ‘real life’, an R21 is intended as an opportunity to test a novel idea, often a ‘high-risk-high-reward project, in order to obtain preliminary results to build a broader research program. Although established investigators often use it for this purpose, it is also an excellent way for junior investigator to get their own program started. The format is identical to that of an R01, the most commonly used research application, but it is shorter in format. A maximum of 2 years of funding can be requested.

33. How to choose a project for your grant For this course assignment … if you have an idea in mind, go for it! A perfectly acceptable alternative is to base your grant application on investigations described in an original paper you read. If you choose this option, do a literature search on a general topic you may be interested in (e.g. autism), chose a methodology (e.g. animal models, postmortem, imaging etc), select a paper that you find particularly interesting. Try to write the grant as if you were proposing to do that experiment. You may want to integrate it with experiments that could extend or further validate the main findings. Of course, this strategy would not be appropriate for a real application.

34. Cover page • Fill in title of the grant, and your name • Provide a Project Summary: (maximum of 400 words overall). Provide a brief background to support the main hypothesis tested in this project. Summarized Specific Aims. Emphasize significance of the project (e.g. in what ways the information obtained through these investigations may be useful)

35. Specific Aims • 1 page maximum • Describe main idea for this proposal (1-2 paragraphs) • State overarching hypothesis clearly. It has to be cohesive and internally consistent. Do not just list the specific working hypotheses tested in the specific aims. Specific working hypotheses need to be designed to test complementary aspects of one overarching hypothesis. • Describe each Specific Aim 1 to 3, each with a title, brief description of the goal of the aim, main method, working hypotheses.

36. } Significance Innovation Approach (6 pages maximum, including figures and tables)

37. Significance (approximately 2-3 pages) Discuss what is the significance of the research you are proposing. If it focuses on a specific disease, provide some context in terms of impact of this disease on our society (e.g. percentage of people affected, how does the disease impact their life and their family lives etc.). Provide the necessary background to understand the proposed research (e.g. if your grant were focused on the role of serotonin in major depression, you could discuss serotoninergic pathways in the brain, current knowledge on their potential role in major depression etc). Make sure that all information you provide is needed and relevant to your proposal.

38. Innovation • This component can be as short or long as you need it, it typically varies from one paragraph to approximately a page Describe how your proposal is novel. Novelty may be in one or more fields, such as novel information to be obtained, novel methods or application of these methods to a particular topic, translation of current knowledge from one domain to another (e.g. basic research to clinical; animal model to human investigations etc).

39. Approach Discuss the main goal of this proposal and reiterate overarching hypothesis. Discuss this latter in relationship to specific working hypotheses. Lay out your strategy in summary and discuss the main aspects in detail. For instance, if you are proposing to use an animal model, what is the rationale of your choice? What are the advantages of this model with respect to others? What are the potential pitfalls of this approach and how are you planning to address them? How does this model relate to the disease you are investigating? Discuss each Specific Aim individually. What is the main goal of this aim? What is the rationale behind your choice of method(s)? Specific hypothesis tested. Interpretation of results: how would you interpret your results if they correspond to what you expected? What if they do not? What would that tell you? Methods need to be described only very briefly. Depending on the structure of your grant, you can choose to include them in each specific aim (if different in each aim) or to add them at the end of the grant, if similar enough to be described together.

40. Tips Time table - R21s are for 1 to 2 years of funding. It is sometimes a good idea to provide a time table for these investigations. That is often a useful exercise, as it may help you understand whether you are proposing too much or too little work. Reference List - Reference List is not included in the page limit, but you do need to cite references appropriately within the text. The format is up to you (i.e. numbered, author name and year etc). Abbreviations – they are useful, but … find the right balance

41. How to write a review paper … • Abstract/Summary • Introduction State main question and its relevance to a particular field • Background Provide information necessary to understand and support your idea.