Faculty Bibliography

The paper here presented was motivated by a case study involving high-dimensional and high-frequency tidal volume traces measured during induced panic attacks. The focus was to develop a procedure to determine the significance of whether a mean curve dominates another one. The key idea of the suggested method relies on preserving the order in mean while reducing the dimension of the data. The observed data matrix is projected onto a set of lower rank matrices with a positive constraint. A multivariate testing procedure is then applied in the lower dimension. We use simulated data to illustrate the statistical properties of the proposed testing procedure. Results on the case study confirm the preliminary hypothesis of the investigators and provide critical support to their overall goal of creating an experimental model of the clinical panic attack in normal subjects

We previously reported that EMD (Enamel Matrix Derivative) induces proliferation of human gingival fibroblasts via activation of Extracellular Regulated Kinase (ERK), and this study assessed the possible mediatory role of EGFR (Epidermal Growth Factor Receptor) in this effect. Treatment of gingival fibroblasts with EMD resulted in tyrosine phosphorylation of the EGFR, as assessed by immunoblotting and ELISA, while EMD-induced ERK activation and thymidine incorporation were markedly inhibited (approximately 40-50%) by a specific EGFR tyrosine kinase inhibitor. Using appropriate inhibitors, we established that EMD-induced EGFR activation is largely due to shedding of HB-EGF (Heparin-binding EGF) from the cell membrane via a metalloproteinase-mediated process. Finally, the addition of PP1, a Src family inhibitor, abrogated both EGFR phosphorylation and ERK activation. Taken together, these results indicate that, at least in human gingival fibroblasts, EMD-induced ERK activation and proliferation are partially due to a Src-dependent, metalloproteinase-mediated transactivation of EGFR.

Institutional deprivation is multifaceted and includes adverse psychosocial and nutrition-related components. In this study we partitioned these risks in relation to cognitive impairment and mental ill health, and explored the mediating role of reduced head/brain size. There were 138 participants (61 males, 77 females) in the study. Participants were Romanian adoptees who had experienced at least 2 weeks of early institutional deprivation. The sample was stratified on the basis of duration of deprivation (high risk >6 mo in institutions) and sub-nutrition (i.e. 1.5 SD below UK age-related norms for weight at UK entry). UK children adopted before 6 months of age and a group of non-institutionally deprived Romanian children constituted the comparison groups. Duration of deprivation was associated with smaller head circumference, lowered IQ, and increased mental heath problems, independently of effects found for sub-nutrition on head circumference and IQ. The mediating role of head circumference was limited to either sub-nourished (IQ) or non-sub-nourished (inattention/overactivity and disinhibited attachment) subgroups. Many negative effects of early deprivation, including stunted brain growth, occur without sub-nutrition: psychosocial deprivation plays a major role in neurodevelopmental effects of deprivation. Further studies of functional and structural neuroanatomy following institutional deprivation are required to delineate the role of brain development in its effects

It has long been recognized that women are at a higher risk than men to develop depression and that such risk is particularly associated with reproductive cycle events. Recent long-term, prospective studies have demonstrated that the transition to menopause is associated with higher risk for new onset and recurrent depression. A number of biological and environmental factors are independent predictors for depression in this population, including the presence of hot flushes, sleep disturbance, history of severe premenstrual syndrome or postpartum blues, ethnicity, history of stressful life events, past history of depression, body mass index, socioeconomic status and the use of hormones and antidepressants. Accumulated evidence suggests that ovarian hormones modulate serotonin and noradrenaline neurotransmission, a process that may be associated with underlying pathophysiological processes involved in the emergence of depressive symptoms during periods of hormonal fluctuation in biologically predisposed subpopulations. Transdermal estradiol and serotonergic and noradrenergic antidepressants are efficacious in the treatment of depression and vasomotor symptoms in symptomatic, midlife women. The identification of individuals whom might be at a higher risk for depression during menopausal transition could guide preventive strategies for this population

Adult learning and memory functions are strongly dependent on neonatal experiences. We recently showed that neonatal odor-shock learning attenuates later life odor fear conditioning and amygdala activity. In the present work we investigated whether changes observed in adults can also be observed in other structures normally involved, namely olfactory cortical areas. For this, pups were trained daily from postnatal (PN) 8 to 12 in an odor-shock paradigm, and retrained at adulthood in the same task. (14)C 2-DG autoradiographic brain mapping was used to measure training-related activation in amygdala cortical nucleus (CoA), anterior (aPCx), and posterior (pPCx) piriform cortex. In addition, field potentials induced in the three sites in response to paired-pulse stimulation of the olfactory bulb were recorded in order to assess short-term inhibition and facilitation in these structures. Attenuated adult fear learning was accompanied by a deficit in 2-DG activation in CoA and pPCx. Moreover, electrophysiological recordings revealed that, in these sites, the level of inhibition was lower than in control animals. These data indicate that early life odor-shock learning produces changes throughout structures of the adult learning circuit that are independent, at least in part, from those involved in infant learning. Moreover, these enduring effects were influenced by the contingency of the infant experience since paired odor-shock produced greater disruption of adult learning and its supporting neural pathway than unpaired presentations. These results suggest that some enduring effects of early life experience are potentiated by contingency and extend beyond brain areas involved in infant learning

The lateral nucleus of the amygdala (LA) is a site of convergence for auditory (conditioned stimulus) and foot-shock (unconditioned stimulus) inputs during fear conditioning. The auditory pathways to LA are well characterized, but less is known about the pathways through which foot shock is transmitted. Anatomical tracing and physiological recording studies suggest that the posterior intralaminar thalamic nucleus, which projects to LA, receives both auditory and somatosensory inputs. In the present study we examined the expression of the immediate-early gene c-fos in the LA in rats in response to foot-shock stimulation. We then determined the effects of posterior intralaminar thalamic lesions on foot-shock-induced c-Fos expression in the LA. Foot-shock stimulation led to an increase in the density of c-Fos-positive cells in all LA subnuclei in comparison to controls exposed to the conditioning box but not shocked. However, some differences among the dorsolateral, ventrolateral and ventromedial subnuclei were observed. The ventrolateral subnucleus showed a homogeneous activation throughout its antero-posterior extension. In contrast, only the rostral aspect of the ventromedial subnucleus and the central aspect of the dorsolateral subnucleus showed a significant increment in c-Fos expression. The density of c-Fos-labeled cells in all LA subnuclei was also increased in animals placed in the box in comparison to untreated animals. Unilateral electrolytic lesions of the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body reduced foot-shock-induced c-Fos activation in the LA ipsilateral to the lesion. The number of c-Fos labeled cells on the lesioned side was reduced to the levels observed in the animals exposed only to the box. These results indicate that the LA is involved in processing information about the foot-shock unconditioned stimulus and receives this kind of somatosensory information from the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body

Schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine and major disasters. Recent evidence suggests that human vulnerability may be greatest in the first trimester of gestation and rodent experiments suggest sex specificity. We aimed to describe the consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli war of 1967. A priori, we focused on gestational month and offspring's sex. METHOD: In a pilot study linking birth records to Israel's Psychiatric Registry, we analyzed data from a cohort of 88,829 born in Jerusalem in 1964-76. Proportional hazards models were used to estimate the relative risk (RR) of schizophrenia, according to month of birth, gender and other variables, while controlling for father's age and other potential confounders. Other causes of hospitalized psychiatric morbidity (grouped together) were analyzed for comparison. RESULTS: There was a raised incidence of schizophrenia for those who were in the second month of fetal life in June 1967 (RR = 2.3, 1.1-4.7), seen more in females (4.3, 1.7-10.7) than in males (1.2, 0.4-3.8). Results were not explained by secular or seasonal variations, altered birth weight or gestational age. For other conditions, RRs were increased in offspring who had been in the third month of fetal life in June 1967 (2.5, 1.2-5.2), also seen more in females (3.6, 1.3-9.7) than males (1.8, 0.6-5.2). CONCLUSION: These findings add to a growing literature, in experimental animals and humans, attributing long term consequences for offspring of maternal gestational stress. They suggest both a sex-specificity and a relatively short gestational time-window for gestational effects on vulnerability to schizophrenia

In recent years, calls for the scaling-up, or more broad dissemination of evidence-based HIV prevention programmes, have increased. This paper responds to the call for increasing applicable knowledge about programme dissemination by reviewing the history of a major evidence-based human immunodeficiency virus (HIV) prevention and mental health promotion programme that has been adapted successfully and pilot-tested across four settings - including two major cities, as well as in the United States, Trinidad and Tobago and South Africa - to date. This programme, entitled CHAMP (the Collaborative HIV Prevention & Adolescent Mental Health Project), is distinctive primarily for its emphasis on community collaboration and power-sharing, and also its incorporation of individual, family and community-level interventions. The history of programme development, including theoretical foundations and results across sites, is discussed with a particular emphasis on the implications of CHAMP'S dissemination thus far.