Current knowledge on the pathophysiology of autism (continued)

1. Current knowledge on the pathophysiology of autism (continued) How does current knowledge on the neurobiology of disrupted emotion regulation inform social dynamics? Mental Illnesses and the legal system BIOS E 232 Sabina Berretta, MD Harvard Medical School McLean Hospital

2. Sabina Berretta - Current knowledge on the pathophysiology of autism (continued) Rhiannon Luyster - Insel T.R. The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior.Neuron 2010 65:768 Gwendolyn Volmar Neuhaus E. et al., Neurobioilogical correlates of social functioning in autism. Clinical Psychology Review 2010 30:733-748 Sabina Berretta - Mental Illnesses and Criminal Justice

3. AUTISM (A) Persistent deficits in social communication and social interaction across contexts: • Deficits in social-emotional reciprocity • Deficits in verbal and nonverbal communicative behaviors • Deficits in developing and maintaining relationships (B) Restricted, repetitive patterns of behavior, interests, or activities • Stereotyped or repetitive speech, motor movements, or use of objects •Excessive adherence to routines, ritualized patterns of verbal or nonverbal behavior, or excessive resistance to change •Highly restricted, fixated interests • Hyper-or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment

4. Two aspects potentially contributing to impairment of social interaction and communication • Emotion perception and processing • Regulation of social/affiliative behavior

5. • Emotion perception and processing

6. SOCIAL PROCESSING / COMMUNICATION CIRCUITS Medial-orbital prefrontal cortex Emotion processing and regulation – evaluation of on-going strategy Amygdala Ventral striatum Superior temporal sulcus Fusiform gyrus Emotional and motivational values / reward Perceptual processing of socially-relevant information

7. Superior Temporal Sulcus (STS) Function: processes selectively socially-relevant information • Vocal and speech stimuli over non social auditory stimuli • Motion of hands, face, eyes, and body as it relates to emotional expression, eye gaze, and intentional inference In ADS: Reduced gray matter; cortical thinning correlated with social and communication impairment Fusiform Gyrus Function: selective responses to human faces In ADS: Reduced gray matter; cortical thinning correlated with social and communication impairment

8. Amygdala abnormalities in autism Number of neurons in the total amygdala by age in control and autistic subjects Total neuron numbers are reduced in the lateral nucleus of the amygdala

9. Prefrontal cortex in autism White matter of postmortem human brain tissue below the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and lateral prefrontal cortex (LPFC), which are associated with attention, social interactions, and emotions, and have been consistently implicated in the pathology of autism These findings suggest a mechanism for disconnection of long-distance pathways, excessive connections between neighboring areas, and inefficiency in pathways for emotions, and may help explain why individuals with autism do not adequately shift attention, engage in repetitive behavior, and avoid social interactions. ACC (area 32): decrease in the largest axons that communicate over long distances. Overexpression of the growth-associated protein 43 kDa accompanied by excessive number of thin axons that link neighboring areas. OFC (area 11), axons had decreased myelin thickness.

10. Meta-analysis: abnormal gray matter volume of the amygdala, parietal cortex, and frontal cortex in Asperger disorder and autism Comparisons between Asperger disorder and autism suggest that these disorders may have similar anatomical substrates. Via et al., AGP 2011

11. Heider and Simmel's paradigm (1944) Social Attribution Task What happened was that the larger triangle, which was like a bigger kid or a bully and he had isolated himself from everything else until two new kids come along and the little one was a bit more shy, scared, and the smaller triangle more like stood up for himself and protected the little one. The big triangle got jealous of them, came out, and started to pick on the smaller triangle. The little triangle got upset and said like ``what's up? '' ``Why are you doing this ? '' … The big triangle went into the rectangle. There were a small triangle and a circle. The big triangle went out. The shapes bounce off each other. The small circle went inside the rectangle. The big triangle was in the box with the circle. The small triangle and the circle went around each other a few times. They were kind of oscillating around each other, maybe because of a magnetic field. After that, they go off the screen. The big triangle turned like a star like a Star of David and broke the rectangle. Klin et al., 2000

12. Brain regions differentially involved during ToM in people with autism as compared to normal controls 3 1 2 PET study - Greater activation in control v/s autistic subjects in occipital and temporal pole/amygdaloid regions (1), superior temporal sulcus (2), and medial prefrontal cortex (3). Abbr. LO, lateral occipital cortex; IT, inferior temporal gyrus; V3, extrastriatal cortex Castelli et al., 2002

13. The mirror neuron hypothesis Cattaneo and Rizzolatti Some functional deficits typical of ASD, such as deficits in imitation, emotional empathy, and attributing intentions to others, have a clear counterpart in the function of the mirror system

14. • Regulation of social/affiliative behavior

15. Dopamine Oxytocin - Vasopressin Mu-opioid Beta-endorphin The development and maintenance of affiliative bonds across two phases of reward Depue and Morrone-Strupisky, 2005

16. Dopaminergic projections from the VTA to the ventral striatum may mediate the rewarding aspects of affiliative behavior, from subjective feelings of desire in anticipation of social interactions to engagement in social behaviors (e.g. courtship, mating, grooming, breastfeeding). Mu-opioids/beta endorphins are likely to be involved in the feeling of pleasure involved in these latter behaviors. Oxytocin and vasopressin, originating from the hypothalamus and critically involved in affiliative behavior, are involved in all phases of affiliative behavior and interact with dopamine and opioids.

17. Genetic findings are consistent with the hypothesis that oxytocin is involved in the pathophysiology of autism and represents a vulnerability factor

19. Mental Illnesses and Criminal Justice

20. Some statistics on the issue • 1 in 4 (26.2%) adults suffers from a diagnosable mental disorder (NIMH) • 1 in 17 (6%) suffers from a serious mental disorder (NIMH) • One third of homeless adults suffers from schizophrenia or bipolar disorder (NAMI - www.schizophrenia.com) • Adults in severe mental illnesses are 4 times as likely to be the victims of violent crime (Teplin et al., AGP 2005) • Factors contributing to victimization are: • symptoms: impaired reality testing, disorganized thought process, impulsivity, poor planning and problem solving • - other factors: substance abuse, conflicted social relationships, poverty, homelessness(Teplin et al., AGP 2005)

21. • Persons with schizophrenia or bipolar disorder are thought to be at increased risk of committing violent crime 4 to 6 times the level of general population individuals without this disorder. • This increase was found to depend on substance of abuse, rather than on the disorders themselves. Langstrom et al., JAMA 2009 Fazel et al., AGP 2010 • Persons with schizophrenia are far more likely to hurt themselves than to hurt others. • Approximately 1000 out 24,000 homicides a year committed by individuals with schizophrenia and bipolar disorder, almost all of whom were not taking medication at the time of the homicide F. Torrey, NAMI • At any given time, there are more people with untreated severe psychiatric illnesses living on America’s streets than are receiving care in hospitals. (NAMI)

22. • 40-60% of all inmates in US suffer from a severe mental disorder • Jails and their personnel are not equipped to serve as the facto psychiatric hospitals. Most have nominal assistance from psychiatrists. The majority of mentally ill inmates spend most of their time in isolation.

23. My boyfriend has been diagnosed with schizophrenia for probably six years or more. When on the outside he wasn't on medication. During the four years I have been with him, he has steadily gotten more ill. Last year, we had an incident occur after many other domestic violence incidences that I finally got the cops involved. I knew he was having an episode, and thought the cops would help by getting him to a mental hospital not jail. The cops ended up arresting him and the city wouldn't let me drop charges. However, they let me give a statement during his sentencing. I advised that he needed help for his mental illness. They ended up putting him on probation supposibly with support workers helping him with the illness. In addition to I believe he was supposed to be on medication. This didn't work either, never saw him take meds, and the case workers barely came around. Now, he is unfortunately in jail again because of new accusations. I'm not sure if he is guilty or not, but if he is guilty it likely stems once again from having a schizophrenic episode. Jail is not helping his schizophrenia, it is making him very paranoid. In fact he has already gone to the hole several times due to his illness and behavior. I don't believe they have put him on medicine in jail either. I guess I feel like the system has let him down because they don't seem to be trying to help with his illness, which is causing him to continue to find his way into trouble. What is the jails responsibility? Should they be providing counseling or medication?

24. The affected person becomes a non-person in the responses of family members and outsiders (including mental-health-care workers). No longer regarded as fully human, he or she becomes a target for abuse, discrimination, and ultimately rejection. The individual is no longer valued as an effective node in the network of connections that form social life. Social inefficacy means non-participation in social reciprocity, including gift exchange, the fundamental cultural process of living an ordinary life. It means non-participation in marriage, in work, in education, in celebrations, festivals, mourning rituals, and in ordinary experience in markets, in stores, and in other everyday activities. It is to be treated as if one didn't exist. Kleinman, 2009

25. Mental illness≠Criminal insanity Mental illness: A disorder of the brain that disrupt a person's thinking, feeling, moods and the ability to relate to others. Mental illnesses are characterized clinically, and found to be associated with brain abnormalities. “Criminal insanity”:A mental defect or disease that makes it impossible for a person to understand the wrongfulness of his acts or, even if he understands them, to distinguish right from wrong. Defendants who are criminally insane cannot be convicted of a crime, since criminal conduct involves the conscious intent to do wrong — a choice that the criminally insane cannot meaningfully make.

26. History of Insanity Defense 1843- The insanity plea was codified in English law with the M'Naghten Rules: "at the time of the commission of the acts constituting the offense, the defendant, due to a severe mental disease or defect, i) did not know that his/her act would be wrong; or ii) was unable to appreciate the nature and quality of the wrongfulness of his acts.” M'Naughten was a Scottish woodcutter who murdered the secretary to the prime minister, Edward Drummond, in a botched attempt to assassinate the prime minister himself. M'Naughten apparently believed that the prime minister was the architect of the myriad of personal and financial misfortunes that had befallen him. During his trial, nine witnesses testified to the fact that he was insane, and the jury acquitted him, finding him "not guilty by reason of insanity." The M'Naughten rule was embraced with almost no modification by American courts and legislatures for more than 100 years, until the mid-20th century.

27. Several modifications were made to the M'Naghten Rules from the mid-20th century • Irresistible Impulse–lacking "the ability to exercise will-power to control acts in accordance with [their] rational judgment (Would the defendant have committed the crime even if there were a policeman standing at his elbow?) The Durham/New Hampshire Test - In the Durham case, the court ruled that a defendant is entitled to acquittal if the crime was the product of his mental illness (i.e., crime would not have been committed but for the disease). American Law Institute Model - provided a standard for legal insanity that was a compromise between the strict M'Naghten Rule, the lenient Durham ruling, and the irresistible impulse test. A defendant is not responsible for criminal conduct "if at the time of such conduct as a result of mental disease or defect he lacks substantial capacity either to appreciate the criminality of his conduct or to conform his conduct to the requirements of the law." The test thus takes into account both the cognitive and volitional capacity of insanity.

28. The Insanity Defense Reform Act of 1984 The perpetrator of President Reagan’s assassination attempt, John Hinckley, Jr. was found not guilty by reason of insanity. The public was outraged by the jury verdict that seemed to excuse Hinckley because he wanted to impress the actress Jodi Foster with his bravado. Congress passed the Insanity Defense Reform Act of 1984. Under this act, the burden of proof was shifted from the prosecution to the defense and the standard of evidence was increased from a preponderance of evidence to clear and convincing evidence. Previous tests were discarded in favor of a new test that more closely resembled M'Naughten's. Under this new test only perpetrators suffering from severe mental illnesses at the time of the crime could successfully employ the insanity defense. The defendant's ability to control themselves was no longer a consideration. The Act also curbed the scope of expert psychiatric testimony and adopted stricter procedures regarding the hospitalization and release of those who found not guilty by reason of insanity.

29. Psychotic illness (schizophrenia, bipolar disorder, drug-induced psychosis) A break from reality associated with: • false beliefs • hallucinations • disturbance in the flow of thought

30. The standard in many states has become a simple cognitive test that has little relationship to the scientific or clinical knowledge regarding psychotic illness. Rather than state of mind and the defendant's understanding of his or her actions, the standard is close to simply whether the defendant knew the act was unlawful. Insanity acquittals, already rare, now face an almost impossible standard. William T. Carpenter Jr.; Professor of psychiatry and pharmacology and Director of the Maryland Psychiatric Research Center at the University of Maryland School of Medicine.

31. Can current knowledge on emotion/behavior regulation inform current insanity law?