Faculty Bibliography

Long-term morphological synaptic changes associated with homosynaptic long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) in vivo, in awake adult rats were analyzed using three-dimensional (3-D) reconstructions of electron microscope images of ultrathin serial sections from the molecular layer of the dentate gyrus. For the first time in morphological studies, the specificity of the effects of LTP and LTD on both spine and synapse ultrastructure was determined using an N-methyl-d-aspartate (NMDA) receptor antagonist CPP (3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid). There were no differences in synaptic density 24 h after LTP or LTD induction, and CPP alone had no effect on synaptic density. LTP increased significantly the proportion of mushroom spines, whereas LTD increased the proportion of thin spines, and both LTP and LTD decreased stubby spine number. Both LTP and LTD increased significantly spine head evaginations (spinules) into synaptic boutons and CPP blocked these changes. Synaptic boutons were smaller after LTD, indicating a pre-synaptic effect. Interestingly, CPP alone decreased bouton and mushroom spine volumes, as well as post-synaptic density (PSD) volume of mushroom spines.These data show similarities, but also some clear differences, between the effects of LTP and LTD on spine and synaptic morphology. Although CPP blocks both LTP and LTD, and impairs most morphological changes in spines and synapses, CPP alone was shown to exert effects on aspects of spine and synaptic structure.

Recently, resting state functional connectivity (RSFC) studies based on fMRI and EEG/MEG have provided valuable insight into the intrinsic functional architecture of the human brain. However, whether functional near infrared spectroscopy (fNIRS), a suitable imaging method for infant and patient populations, can be used to examine RSFC remains elusive. Using an ETG-4000 Optical Topography System, the present study measured 29 adult subjects (14 females) over the sensorimotor and auditory cortexes during a resting session and a motor-localizer task session. The RSFC maps were computed by seed-based correlation analysis and data-driven cluster analysis. The results from both analyses showed robust RSFC maps, which were not only consistent with the localizer task-related activation results, but also those of previous fMRI findings. Moreover, the strong consistency between the seed-based correlation analysis and the data-driven cluster analysis further validated the use of fNIRS to assess RSFC. The potential influence of a specific low-frequency filtering range (0.04-0.15 Hz and 0.01-0.08 Hz) and three fNIRS parameters (oxy-Hb, deoxy-Hb, and total-Hb) on RSFC results were also examined.

Autism spectrum disorders (ASD) are associated with disturbances of neural connectivity. Functional connectivity between neural structures is typically examined within the context of a cognitive task, but also exists in the absence of a task (i.e., 'rest'). Connectivity during rest is particularly active in a set of structures called the default network, which includes the posterior cingulate cortex (PCC), retrosplenial cortex, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus. We previously reported that adults with ASD relative to controls show areas of stronger and weaker connectivity within the default network. The objective of the present study was to examine the default network in adolescents with ASD. Sixteen adolescents with ASD and 15 controls participated in a functional MRI study. Functional connectivity was examined between a PCC seed and other areas of the default network. Both groups showed connectivity in the default network. Relative to controls, adolescents with ASD showed widespread weaker connectivity in nine of the eleven areas of the default network. Moreover, an analysis of symptom severity indicated that poorer social skills and increases in restricted and repetitive behaviors and interests correlated with weaker connectivity, whereas poorer verbal and non-verbal communication correlated with stronger connectivity in multiple areas of the default network. These findings indicate that adolescents with ASD show weaker connectivity in the default network than previously reported in adults with ASD. The findings also show that weaker connectivity within the default network is associated with specific impairments in ASD

Memory and its underlying neural plasticity play important roles in sensory discrimination and cortical pattern recognition in olfaction. Given the reported function of slow-wave sleep states in neocortical and hippocampal memory consolidation, we hypothesized that activity during slow-wave states within the piriform cortex may be shaped by recent olfactory experience. Rats were anesthetized with urethane and allowed to spontaneously shift between slow-wave and fast-wave states as recorded in local field potentials within the anterior piriform cortex. Single-unit activity of piriform cortical layer II/III neurons was recorded simultaneously. The results suggest that piriform cortical activity during slow-wave states is shaped by recent (several minutes) odor experience. The temporal structure of single-unit activity during slow waves was modified if the animal had been stimulated with an odor within the receptive field of that cell. If no odor had been delivered, the activity of the cell during slow-wave activity was stable across the two periods. The results demonstrate that piriform cortical activity during slow-wave state is shaped by recent odor experience, which could contribute to odor memory consolidation

Principal points are cluster means for theoretical distributions. A discriminant methodology based on principal points is introduced. The principal point classification method is useful in clinical trials where the goal is to distinguish and differentiate between different treatment effects. Particularly, in psychiatric studies where placebo response rates can be very high, the principal point classification is illustrated to distinguish specific drug responders from non-specific placebo responders

Functional connectivity magnetic resonance imaging (fcMRI) studies in rat brain show brain reorganization following peripheral nerve injury. Subacute neuroplasticity was observed 2 weeks following transection of the four major nerves of the brachial plexus. Direct stimulation of the intact radial nerve reveals a functional magnetic resonance imaging (fMRI) activation pattern in the forelimb regions of the sensory and motor cortices that is significantly different from that observed in normal rats. Results of this fMRI experiment were used to determine seed voxel regions for fcMRI analysis. Intrahemispheric connectivities in the sensorimotor forelimb representations in both hemispheres are largely unaffected by deafferentation, whereas substantial disruption of interhemispheric sensorimotor cortical connectivity occurs. In addition, significant intra- and interhemispheric changes in connectivities of thalamic nuclei were found. These are the central findings of the study. They could not have been obtained from fMRI studies alone-both fMRI and fcMRI are needed. The combination provides a general marker for brain plasticity. The rat visual system was studied in the same animals as a control. No neuroplastic changes in connectivities were found in the primary visual cortex upon forelimb deafferentation. Differences were noted in regions responsible for processing multisensory visual-motor information. This incidental discovery is considered to be significant. It may provide insight into phantom limb epiphenomena.

Functional connectivity analyses of resting-state fMRI data are rapidly emerging as highly efficient and powerful tools for in vivo mapping of functional networks in the brain, referred to as intrinsic connectivity networks (ICNs). Despite a burgeoning literature, researchers continue to struggle with the challenge of defining computationally efficient and reliable approaches for identifying and characterizing ICNs. Independent component analysis (ICA) has emerged as a powerful tool for exploring ICNs in both healthy and clinical populations. In particular, temporal concatenation group ICA (TC-GICA) coupled with a back-reconstruction step produces participant-level resting state functional connectivity maps for each group-level component. The present work systematically evaluated the test-retest reliability of TC-GICA derived RSFC measures over the short-term (<45 min) and long-term (5-16 months). Additionally, to investigate the degree to which the components revealed by TC-GICA are detectable via single-session ICA, we investigated the reproducibility of TC-GICA findings. First, we found moderate-to-high short- and long-term test-retest reliability for ICNs derived by combining TC-GICA and dual regression. Exceptions to this finding were limited to physiological- and imaging-related artifacts. Second, our reproducibility analyses revealed notable limitations for template matching procedures to accurately detect TC-GICA based components at the individual scan level. Third, we found that TC-GICA component's reliability and reproducibility ranks are highly consistent. In summary, TC-GICA combined with dual regression is an effective and reliable approach to exploratory analyses of resting state fMRI data

BACKGROUND: Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins. The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho; and, ii) the anticipated correlations would be more pronounced in the melancholic subtype group. METHODS: Fourteen adolescents with MDD (seven with melancholic features) and six healthy controls were enrolled. Minimums of 6 weeks MDD duration and a severity score of 40 on the Children's Depression Rating Scale-Revised were required. All were scanned at 3T with MRI, multi-voxel 3-dimensional, high, 0.75 cm(3), spatial resolution proton magnetic resonance spectroscopic imaging. Striatal tCho concentrations were assessed using phantom replacement. Spearman correlation coefficients were Bonferroni-corrected. RESULTS: Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate (r=0.93, p=0.03) and the left putamen (r=0.96, p=.006), respectively. CONCLUSIONS: These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD. Larger studies should follow

OBJECTIVE: Advanced paternal age is consistently associated with an increased risk for schizophrenia, accounting for up to a quarter of cases in some populations. If paternal age-related schizophrenia (PARS) involves a distinct etiopathology, then PARS cases may show specific characteristics, vis-a-vis other schizophrenia cases. This study examined if PARS exhibits the symptom profile and sex differences that are consistently observed for schizophrenia in general, wherein males have an earlier onset age and more severe negative symptoms than females. METHOD: Symptoms were assessed at baseline (admission) and during medication-free and treatment phases for 153 inpatients on a schizophrenia research unit, 38 of whom fulfilled operationally defined criteria for PARS (sporadic cases with paternal age > or = 35). RESULTS: Males and females with PARS had the same age at onset and a similar preponderance of negative symptoms, whereas the other (non-PARS) cases showed the typical earlier onset age and more severe negative symptoms in males. When medications were withdrawn, PARS cases showed significantly worse symptoms than non-PARS cases (higher total PANSS scores and positive, activation, and autistic preoccupation scores). However these symptoms globally improved with antipsychotic treatment, such that the differences between the PARS and other schizophrenia cases receded. CONCLUSION: The lack of sex differences in the age at onset and the greater severity of medication-free symptoms bolster the hypothesis that PARS has a distinct etiopathology. It also suggests that female sex does not exert a protective effect on the course of PARS, as it may in other forms of schizophrenia