Tatiana Falcone

Brain Transcriptional and Epigenetic Associations with Autism

Background Autism is a common neurodevelopmental syndrome. Numerous rare genetic etiologies are reported; most cases are idiopathic. Methodology/Principal Findings To uncover important gene dysregulation in autism we analyzed carefully selected idiopathic autistic and control cerebellar and BA19 (occipital) brain tissues using high resolution whole genome gene expression and whole genome DNA methylation microarrays. No changes in DNA methylation were identified in autistic brain but gene expression abnormalities in two areas of metabolism were apparent: down-regulation of genes of mitochondrial oxidative phosphorylation and of protein translation. We also found associations between specific behavioral domains of autism and specific brain gene expression modules related to myelin/myelination, inflammation/immune response and purinergic signaling. Conclusions/Significance This work highlights two largely unrecognized molecular pathophysiological themes in autism and suggests differing molecular bases for autism behavioral endophenotypes.

A multisite controlled study of risk factors in pediatric psychogenic nonepileptic seizures

Psychogenic nonepileptic seizures (PNES) in youth are symptoms of a difficult to diagnose and treat conversion disorder. PNES is associated with high medical and psychiatric morbidity, but specific PNES risk factors in the pediatric population are not known. We examined if youth with PNES have a distinct biopsychosocial risk factor profile compared to their siblings and if the interrelationships between these risk factors differentiate the PNES probands from the sibling group.

Identifying, evaluating, diagnosing, and treating ADHD in minority youth.

Objective: This literature review describes evaluation and treatment of minority youth with ADHD. Method: A search of databases for reports of ADHD in minority children was conducted. Results: Interpretation of behavior varies among parents, as does their trust in health care providers and school personnel. Parents desire to avoid stigmatization of their children from diagnostic labels and medications. They may not understand the sequelae of inadequate treatment or fear side effects of treatment. Children respond to stimulant medication but fare better when it is combined with regularly scheduled psychosocial treatment, including education and support for parents. Financial struggles affect access, evaluation, and treatment. Community support is desperately needed to gain parental trust. Creative planning allows health care providers and neighborhood leaders to join in, benefiting the children. Conclusion: Quality evaluation by a competent provider, careful choice of assessment tools, clear communication with parents, and close follow-up of progress are all needed. (J. of Att. Dis. 2008; 11(5) 522-528)

Does Systemic Inflammation Play a Role in Pediatric Psychosis

CONTEXT Human and animal studies have suggested an underlying inflammatory mechanism for a variety of neuropsychiatric disorders, including schizophrenia. To date, most available reports focused on adult patients. OBJECTIVE We wished to test the hypothesis that the first psychotic episode in youth is associated with inflammation. PATIENTS We studied patients admitted to a pediatric inpatient psychiatric unit. Patients (n=80) had new-onset psychosis diagnosed using DSM-IV TR criteria for Psychosis NOS, Schizophreniform Disorder or Schizoaffective Disorder. Patients were matched for age, race and gender with inpatient controls without psychosis within the same unit (n=66). We also compared these values to normal pediatric hematologic values. To study the role of inflammation in youth with psychosis, we collected serum samples of 28 children presenting with first-episode psychosis and compared their serum cytokine and S100B levels to eight healthy controls. MAIN OUTCOME MEASURES In this study, we measured serum markers of systemic inflammation. RESULTS Leukocyte counts revealed a statistically significant increase in absolute monocytes compared to patients without psychosis (0.61 ± 0.282 k/ml vs. 0.496 ± 0.14 k/ml; p<0.01) and lymphocytes (2.51 ± 0.84 k/ml vs. 2.24 ± 0.72 k/ml; p<0.05) in patients with psychosis. All other hematologic values were similar between the groups. In addition, psychosis was characterized by increased serum levels of S100B, a peripheral marker of blood-brain barrier (BBB) damage. Several inflammatory mediators (e.g., TNF-α, IL-1β, IL-6, IL-5, IL-10, and IFN-γ) were elevated in children with psychosis. CONCLUSIONS These results strongly support a link between systemic inflammation, blood-brain barrier disruption and first-episode psychosis in pediatric patients.

Suicidal behavior in adolescents with first-episode psychosis.

BACKGROUND Studies have reported an increased risk for suicide in adults with schizophrenia, but limited data on younger populations are available. AIMS We hypothesize that first-episode psychosis is associated with an increased risk of suicidal behavior in adolescents. METHOD A retrospective study was conducted with patients (n=102) diagnosed with psychosis not otherwised specified (NOS), schizophreniform disorder, schizoaffective disorder or schizophrenia within six months prior to admission. A control group consisting of ninety-eight patients with other (nonpsychosis) psychiatric diagnoses admitted to the same unit was matched by age, gender and ethnicity. All patients and controls were administered the Brief Psychiatric Rating Scale-Children version to assess severity of psychiatric symptoms and suicidality, and medical records were used to assess suicidal behavior and possible risk factors. RESULTS When compared to controls, patients with psychosis had over twice as many suicide attempts overall (p<0.01). The 32% incidence of suicide attempts reported in this cohort is nearly double what is reported in adults with psychosis. Depressive symptoms were significantly correlated with increased suicide attempts (p<0.05). CONCLUSIONS There was no significant difference between the number of pediatric psychosis inpatients versus nonpsychotic psychiatric inpatients who attempted suicide. There was, however, a significant difference between the total number of attempts between groups, illustrating that children and adolescents with psychosis are more likely than nonpsychotic psychiatric inpatients to have repeat, or multiple, suicide attempts. Longer duration of untreated psychosis, ADHD and depressive symptoms were found to be the strongest risk factors for patients with psychosis.

Risk factors for learning problems in youth with psychogenic non-epileptic seizures

OBJECTIVES This study examined the risk factors for learning problems (LP) in pediatric psychogenic non-epileptic seizures (PNES) and their specificity by comparing psychopathology, medical, cognitive/linguistic/achievement, bullying history, and parent education variables between subjects with PNES with and without LP and between subjects with PNES and siblings with LP. METHODS 55 subjects with PNES and 35 siblings, aged 8-18years, underwent cognitive, linguistic, and achievement testing, and completed somatization and anxiety sensitivity questionnaires. A semi-structured psychiatric interview about the child was administered to each subject and parent. Child self-report and/or parent report provided information on the presence/absence of LP. Parents also provided each subjects medical, psychiatric, family, and bullying history information. RESULTS Sixty percent (33/55) of the PNES and 49% (17/35) of the sibling subjects had LP. A multivariable logistic regression demonstrated that bullying and impaired formulation of a sentence using a stimulus picture and stimulus word were significantly associated with increased likelihood of LP in the PNES youth. In terms of the specificity of the LP risk factors, a similar analysis comparing LP in the youth with PNES and sibling groups identified anxiety disorder diagnoses and bullying as the significant risk factors associated with LP in the PNES youth. CONCLUSIONS These findings emphasize the need to assess youth with PNES for LP, particularly if they have experienced bullying, have linguistic deficits, and meet criteria for anxiety disorder diagnoses.

Patients with challenging behaviors: Communication strategies

Some patients have behaviors that make interactions unpleasant, sometimes contributing to suboptimal outcomes and physician burnout. Understanding common difficult personality types can help doctors plan effective strategies for dealing with each, resulting in more effective communication, less stress, and better health outcomes. Having a plan to deal with difficult personality types leads to better communication and outcomes—and less stress.

Holding on and letting go: acculturation versus biculturalism among international medical graduates in residency training

Acculturation is perhaps the most difficult problem many international medical graduates (IMGs) face during their training in the USA. Yet little is known about how residents and fellows progress through this aspect in the adaptation process. This study is an attempt to understand the acculturation process in the USA for IMGs by using a demographic survey and the General Ethnicity Questionnaire. In our study, IMGs reported fewer struggles with general adaptation, perhaps due to pre-residency experience living in the USA. International medical graduates generally embrace a life blended from the best of their country of origin and appreciated qualities found in the USA. Training programs focusing on the celebration of diversity in communities may further enhance adaptation and acculturation to life in the USA.

Self-harm during first-episode psychosis

We thank Harvey et al for bringing our attention to the frequency of self-harm during first-episode psychosis.1 Our data (which we are submitting for publication) indicates an even greater concern in this population. A retrospective review of all psychotic patients admitted to a child and adolescent psychiatry unit from 2003 to 2006 showed that out of 1500 cases reviewed, 102 patients below the age of 18 years who were identified with first-episode psychosis between the ages of 8 and 18 carried a diagnosis of psychosis not otherwise specified, schizophreniform disorder or schizoid personality disorder. A total of 32% of patients had a recent history of self-harm (suicide attempt) just prior to their admission for initial psychosis. Contrary to Harvey et al we did not find male gender to be associated with a higher incidence of self-harm and violence against others, but it was associated with high severity of the attempt. Interestingly, 28.43% of our sample who had shown violence against others accessed the legal system first and the mental health system second. Poor insight psychosis may pre-dispose those affected to make wrong choices and end up in the legal system before entering the mental health system. Previous non-psychotic psychiatric history was reported by 74 patients. The most frequent comorbidity was attention-deficit hyperactivity disorder (ADHD) followed by intermittent explosive disorder, separation anxiety, oppositional defiant disorder and emotional instability manifested by depression, explosiveness, or violence against self or others. Labile affect is a key symptom when suspecting an organic brain disorder, as are poor attention and motor abnormalities. When psychosis presents earlier in life, are there more physiological factors at play than presented in the third or fourth decade? Future research is needed to detect any differences that trigger psychosis in childhood v. adulthood. Observations that children are often more disinhibited than adults is consistent with this higher percentage of 32% particularly from in-patient services. Our results are double those identified in adult studies. Major depressive disorder (n=36) and ADHD (n=49) were the two most frequent comorbidities in the group who attempted suicide. Patients with longer duration of untreated psychosis had more severe suicide attempts. Although the number of attempts made by females and males in our sample were similar, females were more likely to repeat an attempt and to use less severe methods, which is consistent with prior reports. Our patients more often carried a historical diagnosis for depression prior to admission for psychosis, which may account for our higher rate of suicidal behaviour prior to admission. Duration of untreated psychosis has been an independent indicator of self-harm.1 Our sample demonstrated an interesting pattern with patients with the highest suicidality having had 7 months or more of untreated psychosis. The immature brain continues to develop into young adulthood when myelination, pruning and other neuronal maturation remain incomplete. It is understandable then that there may be a difference in rates of self-harm with even a higher number of cases in children and adolescents. Male gender, negative symptoms and persecutory delusions are clearly linked to greater treatment delay; this could also explain the increased rate in males. The quality of the initial treatment intervention for the first psychotic episode is critical. Each progressive psychotic episode affects brain development, social and family relationships. Investing efforts in improving the approach to treatment of the first psychotic episode may improve the eventual life outcome. There should be a low threshold for hospitalisation of children with psychosis, since the suicide attempt rate was so high in this population. This further supports the importance of a strong psychosocial plan and close follow-up for both patient and family. Perhaps the most critical factor in the treatment of these children is engaging the family early enough to enhance their understanding of the role of medication in addition to close follow-up and the consequences of inadequate or partial treatment.

Neurobiology of Suicide

Over the last 20 years, suicide rates have been increasing worldwide. Although the prognosis of suicide is complex, key psychosocial factors have been recognized to help identify identify individuals who may be at high risk. Nevertheless, a gap in research still exists between identifying high risk individuals and predicting when suicidal ideation and behavior will evlolve into a suicide attempt. The focus of this chapter is place on the most recent, relevant studies concerning the neurobiological findings in patients with suicidal behavior or after a suicide attempt. The convergence evidence for the role of the blood-brain barrier in the pathophysiology of suicide is described, as well as the role of several inflammatory markers and neurotropic factors.