De Vries F.E.,VU University Amsterdam |
De Wit S.J.,VU University Amsterdam |
Cath D.C.,Altrecht Academic Anxiety Center |
Cath D.C.,University Utrecht |
And 8 more authors.
Biological Psychiatry | Year: 2014
Background: Subtle deficits in executive functioning are present in patients with obsessive-compulsive disorder (OCD) and their first-degree relatives, suggesting involvement of the frontoparietal circuits. The neural correlates of working memory may be a neurocognitive endophenotype of OCD.Methods: Forty-three unmedicated OCD patients, 17 unaffected siblings, and 37 matched comparison subjects performed a visuospatial n-back task, with a baseline condition (N0) and three working memory load levels (N1, N2, N3) during functional magnetic resonance imaging. Task-related brain activity was compared between groups in frontoparietal regions of interest. Generalized psychophysiological interaction analyses were used to study task-related changes in functional connectivity.Results: Obsessive-compulsive disorder patients, compared with comparison subjects and siblings, showed increased error rates at N3. Compared with comparison subjects, OCD patients showed task-related hyperactivation in left dorsal frontal areas and left precuneus associated with better task performance. Siblings exhibited hyperactivation in a bilateral frontoparietal network. Increased task load was associated with increased task-related brain activity, but in OCD patients and siblings this increase was smaller from load N2 to N3 than in comparison subjects. Obsessive-compulsive disorder patients, compared with siblings and comparison subjects, showed increased task-related functional connectivity between frontal regions and bilateral amygdala.Conclusions: These findings indicate that compensatory frontoparietal brain activity in OCD patients and their unaffected relatives preserves task performance at low task loads but is insufficient to maintain performance at high task loads. Frontoparietal dysfunction may constitute a neurocognitive endophenotype for OCD, possibly reflecting limbic interference with and neural inefficiency within the frontoparietal network. © 2014 Society of Biological Psychiatry.
Bao A.-M.,Zhejiang University |
Swaab D.F.,Academy of Arts and science
Neuroscientist | Year: 2010
Sex differences in the brain are reflected in behavior and in the risk for neuropsychiatric disorders. The fetal brain develops in the male direction due to a direct effect of testosterone on the developing neurons, or in the female direction due to the absence of such a testosterone surge. Because sexual differentiation of the genitals takes place earlier in intrauterine life than sexual differentiation of the brain, these two processes can be influenced independently of each other. Gender identity (the conviction of belonging to the male or female gender), sexual orientation (heterosexuality, homosexuality, or bisexuality), pedophilia, sex differences in cognition, and the risks for neuropsychiatric disorders are programmed into our brains during early development. There is no proof that postnatal social environment has any crucial effect on gender identity or sexual orientation. Structural and functional sex differences in brain areas, together with changes in sex hormone levels and their receptors in development and adulthood, are closely related to sex differences in behavior and neuropsychiatric disorders. Knowing that such a relationship exists may help bring about sex-specific therapeutic strategies. © The Author(s) 2010.
Most E.I.S.,Academy of Arts and science |
Aboudan S.,Academy of Arts and science |
Aboudan S.,University of Florence |
Scheltens P.,University Medical Center |
And 2 more authors.
American Journal of Geriatric Psychiatry | Year: 2012
Objective: Sleep disturbances such as nocturnal awakenings frequently occur in demented elderly persons and can contribute to depression, cognitive impairment, and caregiver burden. Recognizing sleep disturbances at an early stage of the disease progress is a first prerequisite of intervention and monitoring of progress. This study aimed to investigate the reliability of subjective sleep reports in early-and moderate-stage Alzheimer dementia (AD), by investigating whether they differ from matched healthy normal comparison groups with respect to the discrepancy of subjective and objective sleep estimates. Measurements: Subjective sleep was assessed using the Pittsburgh Sleep Quality Index, the Sleep Disorders Questionnaire, and the Athens Insomnia Scale. Objective sleep was estimated using actigraphy. Results: As compared with the normal comparison group (N = 26), AD patients (N = 55) complained less of insomnia, while their objective sleep estimates indicated, in fact, more disturbed sleep, including a longer sleep onset latency and a lower sleep efficiency. Regression analyses aimed at predicting actigraphic sleep parameter estimates from their subjective counterparts showed significant predictive value of only very few subjective sleep parameters. Subjective reports of both patients and the normal comparison group had significant value in predicting actigraphic indices of total sleep time and bedtime. In addition, subjective reports of the normal comparison group, but not of patients, were of value to predict actigraphic indices of sleep onset latency, average sleep bout duration, and sleep efficiency. Conclusion: The results show that the value of sleep questionnaires is limited in early-and moderate-stage AD. Actigraphy may be essential to ensure that sleep problems do not go undetected and untreated. © 2012 American Association for Geriatric Psychiatry.
Mason M.R.J.,Academy of Arts and science |
Ehlert E.M.E.,Academy of Arts and science |
Eggers R.,Academy of Arts and science |
Pool C.W.,Royal Academy of Arts and science |
And 6 more authors.
Molecular Therapy | Year: 2010
For many experiments in the study of the peripheral nervous system, it would be useful to genetically manipulate primary sensory neurons. We have compared vectors based on adeno-associated virus (AAV) serotypes 1, 2, 3, 4, 5, 6, and 8, and lentivirus (LV), all expressing green fluorescent protein (GFP), for efficiency of transduction of sensory neurons, expression level, cellular tropism, and persistence of transgene expression following direct injection into the dorsal root ganglia (DRG), using histological quantification and qPCR. Two weeks after injection, AAV1, AAV5, and AAV6 had transduced the most neurons. The time course of GFP expression from these three vectors was studied from 1 to 12 weeks after injection. AAV5 was the most effective serotype overall, followed by AAV1. Both these serotypes showed increasing neuronal transduction rates at later time points, with some injections of AAV5 yielding over 90% of DRG neurons GFP at 12 weeks. AAV6 performed well initially, but transduction rates declined dramatically between 4 and 12 weeks. AAV1 and AAV5 both transduced large-diameter neurons, IB4 neurons, and CGRP neurons. In conclusion, AAV5 is a highly effective gene therapy vector for primary sensory neurons following direct injection into the DRG. © The American Society of Gene and Cell Therapy.
Bergfeld I.O.,University of Amsterdam |
Mantione M.,University of Amsterdam |
Hoogendoorn M.L.C.,University of Amsterdam |
Denys D.,University of Amsterdam |
Denys D.,Academy of Arts and science
Brain Stimulation | Year: 2013
Background: Deep brain stimulation (DBS) is routinely used as a treatment for treatment-refractory Parkinson's disease and has recently been proposed for psychiatric disorders such as Tourette syndrome (TS), obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Although cognitive deterioration has repeatedly been shown in patients with Parkinson's disease following DBS, the impact of DBS on cognitive functioning in psychiatric patients has not yet been reviewed. Objective: Reviewing the available literature on cognitive functioning following DBS in psychiatric patients. Methods: A systematic literature search in PubMed, EMBASE and Web of Science, last updated in September 2012, found 1470 papers. Abstracts were scrutinized and 26 studies examining cognitive functioning of psychiatric patients following DBS were included on basis of predetermined inclusion criteria. Results: Twenty-six studies reported cognitive functioning of 130 psychiatric patients following DBS (37 TS patients, 56 OCD patients, 28 MDD patients, 6 patients with Alzheimer's disease, and 3 patients with other disorders). None of the studies reported substantial cognitive decline following DBS. On the contrary, 13 studies reported cognitive improvement following DBS. Conclusion: Preliminary results suggest that DBS in psychiatric disorders does not lead to cognitive decline. In selected cases cognitive functioning was improved following DBS. However, cognitive improvement cannot be conclusively attributed to DBS since studies are hampered by serious limitations. We discuss the outcomes in light of these limitations and offer suggestions for future work. © 2013 Elsevier Inc. All rights reserved.
Pooresmaeili A.,Academy of Arts and science |
Poort J.,Academy of Arts and science |
Thiele A.,Northumbria University |
Roelfsema P.R.,Academy of Arts and science |
Roelfsema P.R.,VU University Amsterdam
Journal of Neuroscience | Year: 2010
The visual system encodes the features of visual stimuli as well as their behavioral relevance. Stimuli with a high luminance contrast evoke more activity in the visual cortex than stimuli with a low contrast. At the same time, attended stimuli evoke more activity than nonattended stimuli. There is a debate about how visual features and attention jointly determine neuronal activity in the visual cortex. Some studies suggested that attention increases apparent contrast (Reynolds et al., 2000), others that attention amplifies responses by a constant factor (Williford and Maunsell, 2006), and yet others that attention and contrast have largely additive effects (Buracas and Boynton, 2007; Thiele et al., 2009). The influence of attention on contrast sensitivity differs between neurons, raising the possibility that attention and contrast could be coded conjointly in a population of neurons. Here we investigate this possibility by recording neuronal activity at multiple sites in the primary visual cortex of macaque monkeys using multielectrode recording techniques and support vector machines to decode attended stimuli as well as stimulus contrast. We find that many, but not all, V1 neurons are influenced by attention and that the effects of attention and contrast are additive on average. Stimulus contrast can be decoded from neuronal responses not strongly modulated by attention, whereas the attended stimulus can be decoded as the difference in activity of cells that are influenced by attention and cells that are not. The success of the approach suggests that visual attention and stimulus contrast are represented by largely separable codes. Copyright © 2010 the authors.
Korecka J.A.,Academy of Arts and science |
Eggers R.,Academy of Arts and science |
Swaab D.F.,Academy of Arts and science |
Bossers K.,Academy of Arts and science |
Verhaagen J.,Academy of Arts and science
Restorative Neurology and Neuroscience | Year: 2013
Purpose: Parkinson's disease (PD) is a movement disorder mainly characterized by progressive neurodegeneration of dopaminergic (DAergic) neurons in the substantia nigra (SN). As yet, unknown molecular changes contribute to the development of PD leading to a great need for in vivo models that herald this disorder. Here we characterize an animal model presenting early PD pathology. Methods: Young, adult C57/BL6 mice were treated for five weeks twice a week with 15 mg/kg 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) in combination with 250 mg/kg probenecid. During the treatment mice were tested on their dopamine dependent movement skills. The integrity of their nigrostriatal system was examined through immunohistochemical studies. Results: During the treatment, mice developed dopamine-dependent movement deficits induced by loss of tyrosine hydroxylase (TH) positive nigrostriatal axon terminals. Immunohistochemical study identified astrogliosis and microgliosis in the SN but no decrease of TH immunostaining, demonstrating lack of DAergic neuron degeneration. We also observed formation of α-synuclein inclusion bodies in the SN. Conclusions: The combined features of this MPTP model appear to represent an early neurotoxic cellular stress to the SN neurons bearing a striking resemblance to the early stages of PD neuropathology. This model might prove very useful to investigate early neurodegenerative events in the nigrostriatal DAergic system and to study the effects of potential treatment strategies counteracting the early PD cellular changes. © 2013 IOS Press and the authors. All rights reserved.
Zhao J.,Academy of Arts and science |
Zhao J.,Tianjin Medical University |
Bao A.-M.,Zhejiang University |
Qi X.-R.,Academy of Arts and science |
And 4 more authors.
Journal of Affective Disorders | Year: 2012
Background: The prefrontal cortex (PFC) is presumed to be involved in the pathogenesis of depression. Methods: We determined the gene expression of 32 markers of the pathways of the two main neurotransmitters of the PFC, gamma-aminobutyric acid (GABA) and l-glutamic acid (glutamate), by real-time quantitative PCR in human postmortem anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC) in elderly non-suicidal patients with major depressive disorder (MDD) or bipolar disorder (BD). Results: We found the transcript levels of GABAA receptor beta 2 (GABRB2) and post-synaptic density-95 (PSD-95) to be significantly decreased in the ACC in mood disorder. DLPFC mRNA expression of all the detected genes in the mood disorder group did not differ significantly from that of the non-psychiatric controls. Limitations: Several inherent and potentially confounding factors of a postmortem study, such as medication and cause of death, did not seem to affect the conclusions. The group size was relatively small but well documented, both clinically and neuropathologically. Conclusions: The observed alterations in the GABAergic and glutamatergic pathways indicate a diminished activity. These alterations were only present in the ACC and not in the DLPFC. © 2012 Elsevier B.V. All rights reserved.
Van Wamelen D.J.,Academy of Arts and science |
Van Wamelen D.J.,Leiden University |
Aziz N.A.,Leiden University |
Anink J.J.,Academy of Arts and science |
And 2 more authors.
Brain Pathology | Year: 2012
Neuroendocrine, metabolic and autonomic nervous system dysfunctions are prevalent among patients with Huntington's disease (HD) and may underlie symptoms such as depression, weight loss and autonomic failure. Using post-mortem paraffin-embedded tissue, we assessed the integrity of the major neuropeptide populations in the paraventricular nucleus (PVN)-the hypothalamic neuroendocrine and autonomic integration center-in HD patients. The number corticotropin-releasing hormone, cocaine- and amphetamine-regulated transcript, arginine vasopressin and oxytocin immunoreactive (ir) neurons did not differ between HD patients and control subjects. However, the significant positive correlation between arginine vasopressin and oxytocin ir neurons in control subjects (P = 0.036) was absent in patients. Corticotropin-releasing hormone mRNA levels were 68% higher in HD patients (P = 0.046). Thyrotropin-releasing hormone mRNA levels did not differ between HD patients and control subjects, although a negative correlation with disease duration was present in the former (P = 0.036). These findings indicate that the PVN is largely unaffected in HD patients. However, our findings suggest that hypothalamic-pituitary-thyroid axis activity may alter during the course of the disease and that autonomic nervous system dysfunction might partly arise from an imbalance between arginine vasopressin and oxytocin neurons in the PVN. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.
Ishunina T.A.,Academy of Arts and science |
Ishunina T.A.,Kursk State Medical University |
Sluiter A.A.,Academy of Arts and science |
Swaab D.F.,Academy of Arts and science |
Verwer R.W.H.,Academy of Arts and science
Brain Research | Year: 2013
Estrogen receptor α (ERα) isoforms with complex types of alternative splicing are naturally present in the human brain and may affect canonical receptor signaling. In the present study we investigated transcriptional activity of common ERα splice variants from this group with different molecular defects: MB1 (intron retention), TADDI (small deletion between exons 3 and 4 with an insert), the Δ (deletion) 3-7*/819 (complete skipping of exons 4, 5 and 6 and partial deletion of exons 3 and 7) and the Δ3-6 (lacking exons 3, 4, 5 and 6) in HeLa and M17 cells upon stimulation with (17β)estradiol or insulin-like growth factor 1 (IGF-1). In HeLa cells, all these splice variants showed the dominant negative function that was more pronounced for the TADDI. In M17 cells the dominant negative variants appeared to be the MB1 and the Δ3-6, whereas TADDI turned out to be a clearly dominant positive variant. In M17 cells mRNA levels of Δ3-6 and Δ3*-7 */819 variants increased following (17β)estradiol administration. In Hela cells (17β)estradiol up-regulated the IGF-1 receptor mRNA levels in cultures transfected with MB1, TADDI and Δ3 *-7*/819. Our data demonstrate that ERα splice variants show differential levels of the transcriptional activity in a cell type-specific way and that IGF-1 signaling pathways are differentially employed in a cell-type specific manner depending on the level of the discrete ERα splice variants expressed. Functional properties of various ERα splice variants and their cell type-specificity should, thus, be considered as potential confounders of estrogen therapy effects on the brain. © 2013 Elsevier B.V.