Faculty Bibliography

Emotion enhances our ability to form vivid memories of even trivial events. Norepinephrine (NE), a neuromodulator released during emotional arousal, plays a central role in the emotional regulation of memory. However, the underlying molecular mechanism remains elusive. Toward this aim, we have examined the role of NE in contextual memory formation and in the synaptic delivery of GluR1-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA)-type glutamate receptors during long-term potentiation (LTP), a candidate synaptic mechanism for learning. We found that NE, as well as emotional stress, induces phosphorylation of GluR1 at sites critical for its synaptic delivery. Phosphorylation at these sites is necessary and sufficient to lower the threshold for GluR1 synaptic incorporation during LTP. In behavioral experiments, NE can lower the threshold for memory formation in wild-type mice but not in mice carrying mutations in the GluR1 phosphorylation sites. Our results indicate that NE-driven phosphorylation of GluR1 facilitates the synaptic delivery of GluR1-containing AMPARs, lowering the threshold for LTP, thereby providing a molecular mechanism for how emotion enhances learning and memory

Exposure to traumatic stress is a requirement for the development of posttraumatic stress disorder (PTSD). However, because the majority of trauma-exposed persons do not develop PTSD, examination of the typical effects of a stressor will not identify the critical components of PTSD risk or pathogenesis. Rather, PTSD represents a specific phenotype associated with a failure to recover from the normal effects of trauma. Thus, research must focus on identifying pre- and posttraumatic risk factors that explain the development of the disorder and the failure to reinstate physiological homeostasis. In this review, we summarize what is known about the clinical and biological characteristics of PTSD and articulate some of the gaps in knowledge that can be addressed by basic neuroscience research. We emphasize how knowledge about individual differences related to genetic and epigenetic factors in behavioral and brain responses to stress offers the hope of a deeper understanding of PTSD

BACKGROUND: Deficits in backward masking have been variably reported in schizophrenia patients, but individual differences in the expression of these deficits have not been explicitly investigated. In addition, increased knowledge of the visual system has opened the door for new techniques such as transcranial magnetic stimulation (TMS) to explore these deficits physiologically. METHODS: Patients with schizophrenia and healthy controls were tested using a backward masking paradigm. In order to examine the functionality of visual pathways involved in backward masking, subjects were retested on a backward masking paradigm using single pulse TMS applied to occipital cortex in lieu of the masking stimuli. RESULTS: Compared with controls, patients had significantly delayed recovery from visual backward masking. However, 23.5% of patients (compared to 5% of controls) never recovered to levels approaching unmasked performance. When these subjects were segregated from the analysis, group differences vanished. In addition, stimulus masking with occipital TMS followed the same pattern in both patients and controls. CONCLUSIONS: Observations of individual differences in visual masking performance may identify a subgroup of schizophrenia patients. The TMS data suggest that this deficit may not localize to the occipital cortex. However, TMS can be a useful tool for localizing processing deficits in schizophrenia

OBJECTIVE: The aim of this study was to examine immediate-release methylphenidate effectiveness during the 10-month open-label continuation phase of the Preschoolers with Attention-Deficit/Hyperactivity Disorder (ADHD) Treatment Study (PATS). METHODS: One hundred and forty preschoolers with ADHD, who had improved with acute immediate-release methylphenidate (IR-MPH) treatment, entered a 10-month, open-label medication maintenance at six sites. Assessments included the Clinical Global Impression-Severity (CGI-S), CGI-Improvement (CGI-I), Children's Global Assessment Scale (C-GAS), Swanson, Nolan, and Pelham Questionnaire (SNAP), Scale Strengths and Weaknesses of ADHD-Symptoms and Normal Behaviors (SWAN), Social Competence Scale, Social Skills Rating System (SSRS), and Parenting Stress Index-Short Form (PSI-SF). RESULTS: For the 95 children who completed the 10-month treatment, improvement occurred on the CGI-S (p = 0.02), CGI-I (p < 0.01), C-GAS (p = 0.001), and SSRS (p = 0.01). SNAP and SWAN scores remained stable. Forty five children discontinued: 7 for adverse effects, 7 for behavior worsening, 7 for switching to long-acting stimulants, 3 for inadequate benefit, and 21 for other reasons. The mean MPH dose increased from 14.04 mg/day +/- SD 7.57 (0.71 +/- 0.38 mg/kg per day) at month 1 to 19.98 mg/day +/- 9.56 (0.92 +/- 0.40 mg/kg per day) at month 10. CONCLUSIONS: With careful monitoring and gradual medication dose increase, most preschoolers with ADHD maintained improvement during long-term IR-MPH treatment. There was substantial variability in effective and tolerated dosing

The field of neuroimaging of attention-deficit/hyperactivity disorder (ADHD) is now 30 years old. This brief selective review highlights the increasing sophistication of recent structural and functional neuroimaging studies of ADHD. In volumetric studies, investigators are examining extra-frontal, as well as frontal-striatal circuits and beginning to differentiate the potential effects of medication exposure. Functional MRI studies are focusing on familial/genetic influences and enrolling medication naive, as well as medicated children with ADHD. A promising trend is the application of resting state approaches to mapping functional connectivity, which provides unexpectedly detailed information about interregional relationships while bypassing potentially confounding issues related to task performance. These developments allow us to conclude that neuroimaging studies of ADHD will increasingly inform our understanding of the neuronal substrates of ADHD

BACKGROUND AND PURPOSE: The early postnatal period is perhaps the most dynamic phase of white matter development. We hypothesized that the early postnatal development of the corpus callosum and corticospinal tracts could be studied in unsedated healthy neonates by using novel approaches to diffusion tensor imaging (DTI) and quantitative tractography. MATERIALS AND METHODS: Isotropic 2 x 2 x 2 mm(3) DTI and structural images were acquired from 47 healthy neonates. DTI and structural images were coregistered and fractional anisotropy (FA), mean diffusivity (MD), and normalized T1-weighted (T1W) and T2-weighted (T2W) signal intensities were determined in central midline and peripheral cortical regions of the white matter tracts of the genu and splenium of the corpus callosum and the central midbrain and peripheral cortical regions of the corticospinal tracts by using quantitative tractography. RESULTS: We observed that central regions exhibited lower MD, higher FA values, higher T1W intensity, and lower T2W intensity than peripheral cortical regions. As expected, MD decreased, FA increased, and T2W signal intensity decreased with increasing age in the genu and corticospinal tract, whereas there was no significant change in T1W signal intensity. The central midline region of the splenium fiber tract has a unique pattern, with no change in MD, FA, or T2W signal intensity with age, suggesting different growth trajectory compared with the other tracts. FA seems to be more dependent on tract organization, whereas MD seems to be more sensitive to myelination. CONCLUSIONS: Our novel approach may detect small regional differences and age-related changes in the corpus callosum and corticospinal white matter tracts in unsedated healthy neonates and may be used for future studies of pediatric brain disorders that affect developing white matter.

The Child and Adolescent Trauma Treatments and Services Consortium (CATS) was the largest youth trauma project associated with the September 11 World Trade Center disaster. CATS was created as a collaborative project involving New York State policymakers; academic scientists; clinical treatment developers; and routine practicing clinicians, supervisors, and administrators. The CATS project was established to deliver evidence-based cognitive-behavioral trauma treatments for children and adolescents affected by the September 11 terrorist attack in New York City and to examine implementation processes and outcomes associated with delivery of these treatments. Referrals were obtained on 1,764 children and adolescents; of these, 1,387 were subsequently assessed with a standardized clinical battery and 704 found to be eligible for services. Ultimately 700 youth participated in the project. Treatments were delivered in either school or clinic settings by clinicians employed in 9 provider organizations in New York City. All participating clinicians were trained on the cognitive behavioral therapy models by the treatment developers and received case consultation for 18 months by expert clinician consultants and the treatment developers. The challenges of mounting a large trauma treatment project within routine clinical practices in the aftermath of a disaster and simultaneously evaluating the project have been significant. We outline the major challenges, describe strategies we employed to address them, and make recommendations based on critical lessons learned