[Show abstract][Hide abstract] ABSTRACT: Exploratory (i.e., voxelwise) spatial methods are commonly used in neuroimaging to identify areas that show an effect when a region-of-interest (ROI) analysis cannot be performed because no strong a priori anatomical hypothesis exists. However, noise at a single voxel is much higher than noise in a ROI making noise management critical to successful exploratory analysis. This work explores how preprocessing choices affect the bias and variability of voxelwise kinetic modeling analysis of brain positron emission tomography (PET) data. These choices include the use of volume- or cortical surface-based smoothing, level of smoothing, use of voxelwise partial volume correction (PVC), and PVC masking threshold. PVC was implemented using the Muller-Gartner method with the masking out of voxels with low gray matter (GM) partial volume fraction. Dynamic PET scans of an antagonist serotonin-4 receptor radioligand ([(11)C]SB2307145) were collected on sixteen healthy subjects using a Siemens HRRT PET scanner. Kinetic modeling was used to compute maps of non-displaceable binding potential (BPND) after preprocessing. The results showed a complicated interaction between smoothing, PVC, and masking on BPND estimates. Volume-based smoothing resulted in large bias and intersubject variance because it smears signal across tissue types. In some cases, PVC with volume smoothing paradoxically caused the estimated BPND to be less than when no PVC was used at all. When applied in the absence of PVC, cortical surface-based smoothing resulted in dramatically less bias and the least variance of the methods tested for smoothing levels 5mm and higher. When used in combination with PVC, surface-based smoothing minimized the bias without significantly increasing the variance. Surface-based smoothing resulted in 2-4 times less intersubject variance than when volume smoothing was used. This translates into more than 4 times fewer subjects needed in a group analysis to achieve similarly powered statistical tests. Surface-based smoothing has less bias and variance because it respects cortical geometry by smoothing the PET data only along the cortical ribbon and so does not contaminate the GM signal with that of white matter and cerebrospinal fluid. The use of surface-based analysis in PET should result in substantial improvements in the reliability and detectability of effects in exploratory PET analysis, with or without PVC.
[Show abstract][Hide abstract] ABSTRACT: Fiber tractography (FT), which aims to reconstruct the three-dimensional trajectories of white matter (WM) fibers non-invasively, is one of the most popular approaches for analyzing diffusion tensor imaging (DTI) data given its high inter- and intra-rater reliability and scan-rescan reproducibility. The major disadvantage of manual FT segmentations, unfortunately, is that placing regions-of-interest for tract selection can be very labor-intensive and time-consuming. Although there are several methods that can identify specific WM fiber bundles in an automated way, manual FT segmentations across multiple subjects performed by a trained rater with neuroanatomical expertise are generally assumed to be more accurate. However, for longitudinal DTI analyses it may still be beneficial to automate the FT segmentation across multiple time points, but then for each individual subject separately. Both the inter-subject and intra-subject automation in this situation are intended for subjects without gross pathology. In this work, we propose such an automated longitudinal intra-subject analysis (dubbed ALISA) approach, and assessed whether ALISA could preserve the same level of reliability as obtained with manual FT segmentations. In addition, we compared ALISA with an automated inter-subject analysis. Based on DTI data sets from (i) ten healthy subjects that were scanned five times (six-month intervals, aged 7.6-8.6years at the first scan) and (ii) one control subject that was scanned ten times (weekly intervals, 12.2years at the first scan), we demonstrate that the increased efficiency provided by ALISA does not compromise the high degrees of precision and accuracy that can be achieved with manual FT segmentations. Further automation for inter-subject analyses, however, did not provide similarly accurate FT segmentations.
[Show abstract][Hide abstract] ABSTRACT: Since working memory deficits in schizophrenia have been linked to negative symptoms, we tested whether features of the one could predict the treatment outcome in the other. Specifically, we hypothesized that working memory-related functional connectivity at pre-treatment can predict improvement of negative symptoms in antipsychotic-treated patients. Fourteen antipsychotic-naive patients with first-episode schizophrenia were clinically assessed before and after 7 months of quetiapine monotherapy. At baseline, patients underwent functional magnetic resonance imaging while performing a verbal n-back task. Spatial independent component analysis identified task-modulated brain networks. A linear support vector machine was trained with these components to discriminate six patients who showed improvement in negative symptoms from eight non-improvers. Classification accuracy and significance was estimated by leave-one-out cross-validation and permutation tests, respectively. Two frontoparietal and one default mode network components predicted negative symptom improvement with a classification accuracy of 79% (p = 0.003). Discriminating features were found in the frontoparietal networks but not the default mode network. These preliminary data suggest that functional patterns at baseline can predict negative symptom treatment-response in schizophrenia. This information may be used to stratify patients into subgroups thereby facilitating personalized treatment.
The International Journal of Neuropsychopharmacology 11/2012; 16(06):1-10. DOI:10.1017/S1461145712001253 · 5.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is well-established that prolonged high levels of cortisol have adverse effects on hippocampal neurons and glial cells. Morphometric studies linking hippocampus volume to basal HPA-axis activity, however, have yielded less consistent results. Asymmetry may also be considered, since there is growing evidence for hemispheric lateralization in brain systems regulating arousal and emotion. Here we tested the hypotheses that individual variations in basal morning and afternoon/evening cortisol levels would be associated with the degree of hemispheric asymmetry in hippocampal microstructure. Fifty healthy adults aged 19 to 86 years were included in the analyses. Diffusion-weighted imaging was acquired from all subjects. Hippocampal mean diffusivity (MD) and volume was extracted. Cortisol measures were based on 5 morning and 3 afternoon/evening saliva samples. Higher left relative to right hippocampus MD was associated with higher basal cortisol levels. Associations were anatomically specific and not attributable to hippocampal volume asymmetry. No correlation between hippocampal volume and MD was observed, suggesting that MD and volume index distinct biological properties of the hippocampus. Observed associations raise a number of possibilities, among them an asymmetric role of the hippocampus on HPA-axis regulation, or conversely, that individual variations in secreted cortisol, perhaps associated with stress, may have lateralized effects on hippocampal microstructure. Our results point to an important relationship between the limbic system and neuroendocrine function in terms of left-right asymmetries, raising additional questions about how the limbic system is related to neuroendocrine functions.
[Show abstract][Hide abstract] ABSTRACT: Stress sensitivity and serotonergic neurotransmission interact, e.g. individuals carrying the low-expressing variants (S and L(G)) of the 5-HTTLPR promoter polymorphism of the serotonin transporter (SERT) gene are at higher risk for developing mood disorders when exposed to severe stress and display higher cortisol responses when exposed to psychosocial stressors relative to high expressing 5-HTTLPR variants. However, it is not clear how the relation between SERT and cortisol output is reflected in the adult brain. We investigated the relation between cortisol response to awakening (CAR) and SERT binding in brain regions considered relevant to modify the cortisol awakening response. Methods: thirty-two healthy volunteers underwent in vivo SERT imaging with [(11)C]DASB-Positron Emission Tomography (PET), genotyping, and performed home-sampling of saliva to assess CAR. Results: CAR, defined as the area under curve with respect to increase from baseline, was positively coupled to prefrontal SERT binding (p=0.02), independent of adjustment for 5-HTTLPR genotype. Although S- and L(G)-allele carriers tended to show a larger CAR (p=0.07) than L(A) homozygous, 5-HTTLPR genotype did not modify the coupling between CAR and prefrontal SERT binding as tested by an interaction analysis (genotype×CAR). Conclusion: prefrontal SERT binding is positively associated with cortisol response to awakening. We speculate that in mentally healthy individuals prefrontal serotonergic neurotransmission may exert an inhibitory control on the cortisol awakening response.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2012; 23(4). DOI:10.1016/j.euroneuro.2012.05.013 · 5.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Prepulse inhibition (PPI) of the startle reflex is modulated by a complex neural network. Prepulse inhibition impairments are found at all stages of schizophrenia. Previous magnetic resonance imaging (MRI) studies suggest that brain correlates of PPI differ between patients with schizophrenia and healthy controls; however, these studies included only patients with chronic illness and medicated patients. Our aim was to examine the structural brain correlates of PPI in antipsychotic-naive patients with first-episode schizophrenia. Methods: We performed acoustic PPI assessment and structural MRI (1.5 and 3 T) in men with first-episode schizophrenia and age-matched controls. Voxel-based morphometry was used to investigate the association between PPI and grey matter volumes. Results: We included 27 patients and 38 controls in the study. Patients had lower PPI than controls. The brain areas in which PPI and grey matter volume correlated did not differ between the groups. Independent of group, PPI was significantly and positively associated with regional grey matter volume in the right superior parietal cortex. Prepulse inhibition and grey matter volume associations were also observed in the left rostral dorsal premotor cortex, the right presupplementary motor area and the anterior medial superior frontal gyrus bilaterally. Follow-up analyses suggested that the rostral dorsal premotor cortex and presupplementary motor area correlations were driven predominantly by the controls. Limitations: We used 2 different MRI scanners, which might have limited our ability to find subcortical associations since interscanner consistency is low for subcortical regions. Conclusion: The superior parietal cortex seems to be involved in the regulation of PPI in controls and antipsychotic-naive men with first-episode schizophrenia. Our observation that PPI deficits in schizophrenia may be related to the rostral dorsal premotor cortex and presupplementary motor area, brain areas involved in maintaining relevant sensory information and voluntary inhibition, warrants further study.
[Show abstract][Hide abstract] ABSTRACT: Serotonin (5-HT) is a neuromodulator affecting myriad aspects of personality and behavior and has been implicated in the pathophysiology of affective disorders including depression and anxiety. The 5-HTTLPR is a common genetic polymorphism within the promoter region of the gene coding for the serotonin transporter such that the S allele is associated with reduced transcriptional efficacy compared to the L allele, potentially contributing to increased serotonin levels. In humans, this genetic variant has been linked to inter-individual variability in risk for affective disorders, related aspects of personality and brain function including response to threat. However, its effects on aspects of serotonin signaling in humans are not fully understood. Studies in animals suggest that the 5-HT 4 receptor (5-HT(4)) shows a monotonic inverse association with long-term changes in serotonin levels indicating that it may be a useful measure for identifying differences in serotonergic neurotransmission. In 47 healthy adults we evaluated the association between 5-HTTLPR status and in vivo 5-HT(4) receptor binding assessed with [(11)C]SB207145 positron emission tomography (PET). We observed a significant association within the neocortex where [(11)C]SB207145 binding was 9% lower in S carriers compared to LL homozygotes. We did not find evidence for an effect of season or a season-by-5-HTTLPR interaction effect on regional [(11)C]SB207145 binding. Our findings are consistent with a model wherein the 5-HTTLPR S allele is associated with relatively increased serotonin levels. These findings provide novel evidence supporting an effect of 5-HTTLPR status on serotonergic neurotransmission in adult humans. There were no indications of seasonal effects on serotonergic neurotransmission.
[Show abstract][Hide abstract] ABSTRACT: In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [(18)F]altanserin and [(11)C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([(11)C]DASB). Overall [(18)F]altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [(11)C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [(11)C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT(2A) receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections.
Neurobiology of aging 03/2012; 33(3):479-87. DOI:10.1016/j.neurobiolaging.2010.03.023 · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Studies of in vivo dopamine receptors in schizophrenia have mostly focused on D2 receptors in striatal areas or on D1 receptors in cortex. No previous study has examined the correlation between cortical dopamine D2/3 receptor binding potentials and cognition in schizophrenia patients. The objective was to examine this relation in the frontal cortex in first-episode, drug-naive schizophrenia patients. Based on preclinical and pharmacological evidence, we specifically expected to find a relation between D2/3 receptor binding potentials and set shifting. This was a cross-sectional, case-control study using single-photon emission computerized tomography with the D2/3-receptor ligand [123I]epidepride, co-registered with structural magnetic resonance imaging and correlated to cognitive measures. Participants were 24 antipsychotic-naive, first-episode schizophrenia patients and 20 healthy controls matched for gender and age. For patients, a significant linear correlation between D2/3 BPND and set shifting was found, while significant quadratic associations were observed for verbal fluency, planning and attention. For controls, the only significant association with D2/3 BPND was a quadratic partial correlation for set shifting. The main findings indicated a relation between D2/3 receptor binding in the frontal cortex and set shifting, planning and attention, but also support a differential involvement of cortical dopamine D2/3 receptor binding in at least some cognitive functions, perhaps particularly attention, in schizophrenia patients compared to healthy people. The results suggest that cortical D2/3 receptor function may be more involved in some cognitive functions (i.e. attention, fluency and planning) in patients with schizophrenia than in healthy people, suggesting that information processing in schizophrenia may be characterized by lower signal:noise ratios.
The International Journal of Neuropsychopharmacology 02/2012; 16(1):1-14. DOI:10.1017/S146114571200003X · 5.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The limbic system plays an important role in regulating the hypothalamic-pituitary-adrenal (HPA) axis as well as aspects of emotion, and both neuroendocrine disturbance and increased negative emotionality are associated with risk for developing affective disorders. However, the extent to which the architecture of connections between limbic structures may be linked to individual differences in basal HPA-axis reactivity and negative emotionality is unknown. Here we tested the hypotheses that microstructural asymmetry of the major limbic fibre bundles would be associated with cortisol awakening response (CAR) and neuroticism, a personality trait associated with the tendency to experience negative emotions. Sixty-nine healthy adults were studied with diffusion-weighted imaging, and fractional anisotropy (FA) was extracted from the cingulum and uncinate fasciculus. Higher neuroticism scores, which were associated with higher CAR, were also correlated with higher right relative to left cingulum FA. Elevated CAR was associated with the degree of FA asymmetry within both the cingulum and the uncinate fasciculus, but in opposing directions. These results suggest that the balance between left- and right-sided limbic circuits may bear an important relationship to hypothalamic-pituitary-adrenal axis reactivity, and to the tendency to experience negative emotions, and they raise important questions about the significance of limbic system architecture.
Psychiatry Research 01/2012; 201(1):63-72. DOI:10.1016/j.pscychresns.2011.07.015 · 2.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent research on aging has established important links between the neurobiology of normal aging and age-related decline in episodic memory, yet the exact nature of this relationship is still unknown. Functional neuroimaging of regions such as the medial temporal lobe (MTL) have produced conflicting findings. Using functional magnetic resonance imaging (fMRI), we have recently shown that young healthy individuals show a stronger activation of the MTL during encoding of objects as compared with encoding of positions. Using the same encoding task, the present study addressed the question whether this greater MTL activation during encoding of objects varies with age. Fifty-four healthy individuals aged between 18 and 81 years underwent functional magnetic resonance imaging while they encoded and subsequently made new-old judgments on objects and positions. Region of interest (ROI) analysis of task related changes in the blood oxygen level-dependent (BOLD) signal was performed in native space after correction for gender effects and individual differences in cerebral blood flow. The hippocampus, amygdala, and parahippocampal, perirhinal, entorhinal, and temporopolar cortices of right and left hemisphere were defined as ROIs. Aging had an adverse effect on memory performance that was similar for memorizing objects or positions. In left and right MTL, relatively greater activation for object stimuli was attenuated in older individuals. Age-related attenuation in content specificity was most prominent in the recognition stage. During recognition, the larger response to objects gradually decreased with age in all ROIs apart from left temporopolar and entorhinal cortex. An age-related attenuation was also present during encoding, but only in right parahippocampus and amygdala. Our results suggest that memory-related processing in the MTL becomes gradually less sensitive to content during normal aging.
Neurobiology of aging 11/2011; 33(9):1874-89. DOI:10.1016/j.neurobiolaging.2011.09.032 · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The corticospinal tracts and the basal ganglia continue to develop during childhood and adolescence, and indices of their maturation can be obtained using diffusion-weighted imaging. Here we show that a simple measure of visuomotor function is correlated with diffusion parameters in the corticospinal tracts and neostriatum. In a cohort of 75 typically-developing children aged 7 to 13years, mean 5-choice reaction times (RTs) were assessed. We hypothesised that children with faster choice RTs would show lower mean diffusivity (MD) in the corticospinal tracts and neostriatum and higher fractional anisotropy (FA) in the corticospinal tracts, after controlling for age, gender, and handedness. Mean MD and/or FA were extracted from the right and left corticospinal tracts, putamen, and caudate nuclei. As predicted, faster 5-choice RTs were associated with lower MD in the corticospinal tracts, putamen, and caudate. MD effects on RT were bilateral in the corticospinal tracts and putamen, whilst right caudate MD was more strongly related to performance than was left caudate MD. Our results suggest a link between motor performance variability in children and diffusivity in the motor system, which may be related to: individual differences in the phase of fibre tract and neostriatal maturation in children of similar age, individual differences in motor experience during childhood (i.e., use-dependent plasticity), and/or more stable individual differences in the architecture of the motor system.
[Show abstract][Hide abstract] ABSTRACT: Several studies have found atrophy of the corpus callosum (CC) in patients with Alzheimer's disease (AD). However, it remains unclear whether callosal atrophy is already present in the early stages of AD, and to what extent it may be associated with other structural changes in the brain, such as age-related white matter changes (ARWMC) and progression of the disease.
Twenty-eight patients in the early stages of AD and 50 non-demented elderly subjects with varying degrees of ARWMC were investigated using MRI. The CC was assessed semi-automatically, and ARWMC were rated according to the Fazekas scale.
A significant difference in posterior CC size could be detected between non-demented elderly subjects and early stage AD patients. The sizes of the total CC, rostral body and splenium at baseline were correlated with change from baseline MMSE score after a 1-year follow-up in AD patients. There was no association between CC size and ARWMC.
The present findings indicate that posterior CC atrophy is present in mild AD independently of ARWMC. Furthermore, CC atrophy may be associated with cognitive deterioration.