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(searched for: doi:10.1111/j.1600-0447.1974.tb09707.x)
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, Toby Pillinger, Pierluigi Selvaggi, Mattia Veronese, Federico Turkheimer,
Psychological Medicine pp 1-18;

Background: Impaired brain metabolism may be central to schizophrenia pathophysiology, but the magnitude and consistency of metabolic dysfunction is unknown. Methods: We searched MEDLINE, PsychINFO and EMBASE between 01/01/1980 and 13/05/2021 for studies comparing regional brain glucose metabolism using 18FDG-PET, in schizophrenia/first-episode psychosis v. controls. Effect sizes (Hedges g) were pooled using a random-effects model. Primary measures were regional absolute and relative CMRGlu in frontal, temporal, parietal and occipital lobes, basal ganglia and thalamus. Results: Thirty-six studies (1335 subjects) were included. Frontal absolute glucose metabolism (Hedge's g = −0.74 ± 0.54, p = 0.01; I2 = 67%) and metabolism relative to whole brain (g = −0.44 ± 0.34, p = 0.01; I2 = 55%) were lower in schizophrenia v. controls with moderate heterogeneity. Absolute frontal metabolism was lower in chronic (g = −1.18 ± 0.73) v. first-episode patients (g = −0.09 ± 0.88) and controls. Medicated patients showed frontal hypometabolism relative to controls (−1.04 ± 0.26) while metabolism in drug-free patients did not differ significantly from controls. There were no differences in parietal, temporal or occipital lobe or thalamic metabolism in schizophrenia v. controls. Excluding outliers, absolute basal ganglia metabolism was lower in schizophrenia v. controls (−0.25 ± 0.24, p = 0.049; I2 = 5%). Studies identified reporting voxel-based morphometry measures of absolute 18FDG uptake (eight studies) were also analysed using signed differential mapping analysis, finding lower 18FDG uptake in the left anterior cingulate gyrus (Z = −4.143; p = 0.007) and the left inferior orbital frontal gyrus (Z = −4.239; p = 0.02) in schizophrenia. Conclusions: We report evidence for hypometabolism with large effect sizes in the frontal cortex in schizophrenia without consistent evidence for alterations in other brain regions. Our findings support the hypothesis of hypofrontality in schizophrenia.
Katheron Intson, Salma Geissah, Robert E. McCullumsmith,
Published: 11 November 2020
Numerous genetic and postmortem studies link N-methyl-d-aspartate receptor (NMDAR) dysfunction with schizophrenia, forming the basis of the popular glutamate hypothesis. Neuronal NMDAR abnormalities are consistently reported from both basic and clinical experiments, however, non-neuronal cells also contain NMDARs, and are rarely, if ever, considered in the discussion of glutamate action in schizophrenia. We offer an examination of recent discoveries elucidating the actions and consequences of NMDAR activation in the neuroendothelium. While there has been mixed literature regarding blood flow alterations in the schizophrenia brain, in this review, we posit that some common findings may be explained by neuroendothelial NMDAR dysfunction. In particular, we emphasize that endothelial NMDARs are key mediators of neurovascular coupling, where increased neuronal activity leads to increased blood flow. Based on the broad conclusions that hypoperfusion is a neuroanatomical finding in schizophrenia, we discuss potential mechanisms by which endothelial NMDARs contribute to this disorder. We propose that endothelial NMDAR dysfunction can be a primary cause of neurovascular abnormalities in schizophrenia. Importantly, functional MRI studies using BOLD signal as a proxy for neuron activity should be considered in a new light if neurovascular coupling is impaired in schizophrenia. This review is the first to propose that NMDARs in non-excitable cells play a role in schizophrenia.
Published: 5 June 2020
Electroencephalography (EEG) based biomarkers have been shown to correlated with the presence of psychotic disorders. Increased delta and decreased alpha power in psychosis indicate an abnormal arousal state. We investigated brain activity across the basic EEG frequencies and also dynamic functional connectivity of both intra and cross-frequency coupling that could reveal a neurophysiological biomarker linked to an aberrant modulating role of alpha frequency in adolescents with schizophrenia spectrum disorders (SSDs).A dynamic functional connectivity graph (DFCG) has been estimated using the imaginary part of phase lag value (iPLV) and correlation of the envelope (corrEnv). We analyzed DFCG profiles of electroencephalographic resting state (eyes closed) recordings of healthy controls (HC) (n=39) and SSDs subjects (n=45) in basic frequency bands {δ,θ,α1212,γ}. In our analysis, we incorporated both intra and cross-frequency coupling modes. Adopting our recent Dominant Coupling Mode (DoCM) model leads to the construction of an integrated DFCG (iDFCG) that encapsulates the functional strength and the DoCM of every pair of brain areas.We revealed significantly higher ratios of delta/alpha1,2 power spectrum in SSDs subjects versus HC. The probability distribution (PD) of amplitude driven DoCM mediated by alpha frequency differentiated SSDs from HC with absolute accuracy (100%). The network Flexibility Index (FI) was significantly lower for subjects with SSDs compared to the HC group.Our analysis supports a central role of alpha frequency alterations in the neurophysiological mechanisms of SSDs. Currents findings open up new diagnostic pathways to clinical detection of SSDs and supports the design of rational neurofeedback training.Highlights: Ratios of delta/alpha1,2 relative power spectrum were significant higher in SSDs subjects compared to HC Probability distribution (PD) of amplitude driven DoCM mediated by alpha frequency differentiated SSDs from HC with 100% Network Flexibility index (FI) was significant lower for subjects with SSDs compared to HC group.
, Arne Nagels, Gebhard Sammer,
Published: 6 March 2020
Frontiers in Psychiatry, Volume 11;

Dysfunctional social communication is one of the most stable characteristics in patients with schizophrenia that also affects quality of life. Interpreting abstract speech and integrating nonverbal modalities is particularly affected. Considering the impact of communication on social life but failure to treat communication dysfunctions with usual treatment, we will investigate the possibility to improve verbal and non-verbal communication in schizophrenia by applying a multimodal speech-gesture training (MSG training). Here we describe the newly developed MSG training program and the study design for the first clinical investigation. The intervention contains perceptive rating (match/mismatch of sentence and gesture) and memory tasks (n-back tasks), imitation and productive tasks (e.g., SG fluency—similar to verbal fluency where words are accompanied by gesture). In addition, we offer information about gesture as meta-learning element as well as homework for reasons of transfer to everyday life as part of every session. In the MSG training intervention, we offer eight sessions (60 min each) of training. The first pilot study is currently conducted as a single-center, randomized controlled trial of speech-gesture intervention versus wait-list control with a follow-up. Outcomes are measured through pre-post-fMRI and standardized psychological questionnaires comparing two subject groups (30 patients with schizophrenia and 30 healthy controls). Patients and healthy controls are randomized in two intervention groups (with 20 being in the wait-training group and 10 in the training-follow-up group). With our study design we will be able to demonstrate the beneficial effect of the MSG training intervention on behavioral and neural levels. Clinical Trial Registration:, identifier DRKS00015118.
Aleksandra Aleksandrowicz, Florence Hagenmuller, Helene Haker, , Anastasia Theodoridou, , , Andreas Fallgatter, ,
Published: 2 March 2020
NeuroImage: Clinical, Volume 26;

The publisher has not yet granted permission to display this abstract.
, Guusje Collin, Synthia Guimond, Sinead Kelly, Konasale M. Prasad, Paulo Lizano
Published: 11 November 2019
Neuroimaging Clinics of North America, Volume 30, pp 73-83;

Schizophrenia is a chronic psychotic disorder with a lifetime prevalence of about 1%. Onset is typically in adolescence or early adulthood; characteristic symptoms include positive symptoms, negative symptoms, and impairments in cognition. Neuroimaging studies have shown substantive evidence of brain structural, functional, and neurochemical alterations that are more pronounced in the association cortex and subcortical regions. These abnormalities are not sufficiently specific to be of diagnostic value, but there may be a role for imaging techniques to provide predictions of outcome. Incorporating multimodal imaging datasets using machine learning approaches may offer better diagnostic and predictive value in schizophrenia.
Gloria Lee,
Frontiers in Molecular Neuroscience, Volume 12;

The N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis has been proposed to help understand the etiology and pathophysiology of schizophrenia. This hypothesis was based on early observations that NMDAR antagonists could induce a full range of symptoms of schizophrenia in normal human subjects. Accumulating evidence in humans and animal studies points to NMDAR hypofunctionality as a convergence point for various symptoms of schizophrenia. Here we review animal models of NMDAR hypofunction generated by pharmacological and genetic approaches, and how they relate to the pathophysiology of schizophrenia. In addition, we discuss the limitations of animal models of NMDAR hypofunction and their potential utility for therapeutic applications.
, Daniel H. Vaccaro, M. Mehmet Haznedar, Kim E. Goldstein
Published: 20 June 2019
Psychiatry Research, Volume 277, pp 39-44;

The publisher has not yet granted permission to display this abstract.
, Granville J Matheson, Christer Halldin, Simon Cervenka, Lars Farde
International Journal of Neuropsychopharmacology, Volume 22, pp 415-425;

Background Positron emission tomography studies examining differences in D1-dopamine receptor binding between control subjects and patients with schizophrenia have been inconsistent, reporting higher, lower, and no difference in the frontal cortex. Exposure to antipsychotic medication has been suggested to be a likely source of this heterogeneity, and thus there is a need for studies of patients at early stages of the disorder who have not been exposed to such drugs. Methods Here, we compared 17 healthy control subjects and 18 first-episode neuroleptic naive patients with schizophrenia or schizophreniform psychosis using positron emission tomography and the D1-dopamine receptor radioligand [11C]SCH23390. Results We observed a statistically significant difference in the dorsolateral prefrontal cortex. Contrary to our expectations, patients had less D1-dopamine receptor availability with a moderate effect size. In a Bayesian analysis, we show that the data are over 50 times more likely to have occurred under the decrease as opposed to the increase hypothesis. This effect was not global, as our analysis showed that the null hypothesis was preferred over either hypothesis in the striatum. Conclusions This investigation represents the largest single sample of neuroleptic-naive patients examined for D1-dopamine receptor availability using PET and suggests a reduction of prefrontal D1-dopamine receptor density in the pathophysiology of schizophrenia. However, further work will be required to reach a consensus.
Published: 15 February 2019
Conventional static or dynamic functional connectivity graph (FCG/DFCG) referred to as low-order FCG focusing on temporal correlation estimates of the resting-state electroencephalography (rs-EEG) time series between any potential pair of brain areas. A DFCG is first constructed from multichannel recordings by adopting the methodology of sliding-window and a proper functional connectivity estimator. However, low-order FC ignores the high-level inter-relationship of brain areas. Recently, a high-order version of FCG has emerged by estimating the correlations of the time series that describe the fluctuations of the functional strength of every pair of ROIs across experimental time.In the present study, a dynamic functional connectivity graph (DFCG) has been estimated using the imaginary part of phase lag value (iPLV). We analyzed DFCG profiles of electroencephalographic resting state (eyes-closed) recordings of healthy controls subjects (n=39) and subjects with symptoms of schizophrenia (n=45) in basic frequency bands {δ,θ,α1212,γ}. In our analysis, we incorporated both intra and cross-frequency coupling modes. Adopting our recent Dominant Intrinsic Coupling Mode (DICM) model leads to the construction of an integrated DFCG (iDFCG) that encapsulates both the functional strength but also the DICM of every pair of brain areas. Based on the LO - IDFCG, we constructed the HO- IDFCG by adopting the cosine similarity between the time-series derived from the LO-DIFCG. At a second level, we estimated the laplacian transformations of both LO and HO-IDFCG and by calculating the temporal evolution of Synchronizability (Syn), four network metric time series (NMTSSyn) were produced. Following, a machine learning approach based on multi-kernel SVM with the four NMTSSynused as potential features and appropriate kernels, we succeeded a superior classification accuracy (∼98%). DICM and flexibility index (FI) achieved a classification with absolute performance (100 %)Schizophrenic subjects demonstrated a hypo-synchronization compared to healthy control group which can be interpreted as a low global synchronization of co-fluctuate functional patterns. Our analytic pathway could be helpful both for the design of reliable biomarkers and also for evaluating non-intervention treatments tailored to schizophrenia. EEG offers a low-cost environment for applied neuroscience and the transfer of research knowledge from neuroimaging labs to daily clinical practice.
, Daniel H. Vaccaro, M. Mehmet Haznedar, Kim E. Goldstein
Published: 7 December 2018
Psychiatry Research, Volume 271, pp 535-540;

This is a selective review of the work of Buchsbaum and colleagues. It revisits and pays tribute to four decades of publications employing positron emission tomography (PET) with F-18fluorodeoxyglucose (FDG) to examine the neurobiology of schizophrenia-spectrum disorders (including schizotypal personality disorder (SPD) and schizophrenia). Beginning with a landmark FDG-PET study in 1982 reporting hypofrontality in unmedicated schizophrenia patients, Buchsbaum and colleagues published high-impact work on regional glucose metabolic rate (GMR) abnormalities in the spectrum. Several key discoveries were made, including the delineation of schizophrenia-spectrum abnormalities in frontal and temporal lobe, cingulate, thalamus, and striatal regions using three-dimensional mapping with coregistered MRI and PET. These findings indicated that SPD patients have less marked frontal lobe and striatal dysfunction compared with schizophrenia patients, possibly mitigating frank psychosis. Additionally, these investigations were among the first to conduct early seed-based functional connectivity analyses with FDG-PET, showing aberrant cortical-subcortical circuitry and, in particular, revealing a thalamocortical circuitry abnormality in schizophrenia. Finally, pioneering work employing the first double-blind randomized antipsychotic (haloperidol) vs. placebo FDG-PET study design in schizophrenia indicated that GMR in the striatum, more than in any other region, was related to clinical response.
Published: 25 June 2018
Schizophrenia Research, Volume 201, pp 224-230;

Brain functional changes reported in schizophrenia include reduced prefrontal cortex activation (hypofrontality), increased frontal activation (hyperfrontality) and failure of de-activation in the medial frontal cortex. The relative importance of these changes is unestablished. A ‘discovery’ sample of 32 schizophrenic patients and 32 controls was used to establish regions of altered activation and de-activation in the patients. The discriminatory power of these regions was examined using receiver-operator characteristics (ROC) analysis in two ‘test’ samples, one of 83 patients with chronic schizophrenia and 83 healthy controls, and the other of 31 first-episode patients and 31 healthy controls. The discovery sample revealed reduced activation in the prefrontal cortex and other regions, and failure of de-activation in the medial frontal cortex. Failure of de-activation had significantly greater power to distinguish the chronic patients from the healthy controls than hypoactivation. The pattern was similar in the first-episode patients, where additionally the discriminatory power of hypoactivation was poor. Controlling for the effects of n-back task performance tended to reduce discriminatory power overall, but this persisted for failure of de-activation in the chronic test sample. Both hypoactivation and failure of de-activation can distinguish patients with chronic schizophrenia from healthy subjects, but the latter abnormality has more power. Failure of de-activation cannot be construed simply as a passive consequence of reduced prefrontal activation in the disorder.
, Fay Y Womer, Miao Chang, Yue Zhu, Qian Zhou, Elliot Kale Edmiston, Xiaowei Jiang, Shengnan Wei, , Ke Xu, et al.
Schizophrenia Bulletin, Volume 45, pp 450-463;

Brain network alterations have increasingly been implicated in schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). However, little is known about the similarities and differences in functional brain networks among patients with SCZ, BD, and MDD. A total of 512 participants (121 with SCZ, 100 with BD, 108 with MDD, and 183 healthy controls, matched for age and sex) completed resting-state functional magnetic resonance imaging at a single site. Four global measures (the clustering coefficient, the characteristic shortest path length, the normalized clustering coefficient, and the normalized characteristic path length) were computed at a voxel level to quantify segregated and integrated configurations. Inter-regional functional associations were examined based on the Euclidean distance between regions. Distance strength maps were used to localize regions with altered distances based on functional connectivity. Patient groups exhibited shifts in their network architectures toward randomized configurations, with SCZ>BD>MDD in the degree of randomization. Patient groups displayed significantly decreased short-range connectivity and increased medium-/long-range connectivity. Decreases in short-range connectivity were similar across the SZ, BD, and MDD groups and were primarily distributed in the primary sensory and association cortices and the thalamus. Increases in medium-/long-range connectivity were differentially localized within the prefrontal cortices among the patient groups. We highlight shared and distinct connectivity features in functional brain networks among patients with SCZ, BD, and MDD, which expands our understanding of the common and distinct pathophysiological mechanisms and provides crucial insights into neuroimaging-based methods for the early diagnosis of and interventions for psychiatric disorders.
Sébastien Parnaudeau, Scott S. Bolkan,
Published: 1 April 2018
Biological Psychiatry, Volume 83, pp 648-656;

Deficits in cognition are a core feature of many psychiatric conditions, including schizophrenia, where the severity of such deficits is a strong predictor of long-term outcome. Impairment in cognitive domains such as working memory and behavioral flexibility has typically been associated with prefrontal cortex (PFC) dysfunction. However, there is increasing evidence that the PFC cannot be dissociated from its main thalamic counterpart, the mediodorsal thalamus (MD). Since the causal relationships between MD-PFC abnormalities and cognitive impairment, as well as the neuronal mechanisms underlying them, are difficult to address in humans, animal models have been employed for mechanistic insight. In this review, we discuss anatomical, behavioral, and electrophysiological findings from animal studies that provide a new understanding on how MD-PFC circuits support higher-order cognitive function. We argue that the MD may be required for amplifying and sustaining cortical representations under different behavioral conditions. These findings advance a new framework for the broader involvement of distributed thalamo-frontal circuits in cognition and point to the MD as a potential therapeutic target for improving cognitive deficits in schizophrenia and other disorders.
Frontiers in Behavioral Neuroscience, Volume 12;

While the causes of myriad medical and infectious illnesses have been identified, the etiologies of neuropsychiatric illnesses remain elusive. This is due to two major obstacles. First, the risk for neuropsychiatric disorders, such as schizophrenia, is determined by both genetic and environmental factors. Second, numerous genes influence susceptibility for these illnesses. Genome-wide association studies have identified at least 108 genomic loci for schizophrenia, and more are expected to be published shortly. In addition, numerous biological processes contribute to the neuropathology underlying schizophrenia. These include immune dysfunction, synaptic and myelination deficits, vascular abnormalities, growth factor disruption, and N-methyl-D-aspartate receptor (NMDAR) hypofunction. However, the field of psychiatric genetics lacks a unifying model to explain how environment may interact with numerous genes to influence these various biological processes and cause schizophrenia. Here we describe a biological cascade of proteins that are activated in response to environmental stimuli such as stress, a schizophrenia risk factor. The central proteins in this pathway are critical mediators of memory formation and a particular form of hippocampal synaptic plasticity, long-term depression (LTD). Each of these proteins is also implicated in schizophrenia risk. In fact, the pathway includes four genes that map to the 108 loci associated with schizophrenia: GRIN2A, nuclear factor of activated T-cells (NFATc3), early growth response 1 (EGR1) and NGFI-A Binding Protein 2 (NAB2); each of which contains the “Index single nucleotide polymorphism (SNP)” (most SNP) at its respective locus. Environmental stimuli activate this biological pathway in neurons, resulting in induction of EGR immediate early genes: EGR1, EGR3 and NAB2. We hypothesize that dysfunction in any of the genes in this pathway disrupts the normal activation of Egrs in response to stress. This may result in insufficient electrophysiologic, immunologic, and neuroprotective, processes that these genes normally mediate. Continued adverse environmental experiences, over time, may thereby result in neuropathology that gives rise to the symptoms of schizophrenia. By combining multiple genes associated with schizophrenia susceptibility, in a functional cascade triggered by neuronal activity, the proposed biological pathway provides an explanation for both the polygenic and environmental influences that determine the complex etiology of this mental illness.
, , Mark E. Schweitzer
Published: 7 January 2018
Magnetic Resonance in Medicine, Volume 80, pp 736-747;

The publisher has not yet granted permission to display this abstract.
, Wojciech Jernajczyk
Published: 30 November 2017
The present study evaluated brain connectivity using electroencephalography (EEG) data from 14 patients with schizophrenia and 14 healthy controls. Phase-Locking Value (PLV), Phase-Lag Index (PLI) and Directed Transfer Function (DTF) were calculated for the original EEG data and following current source density (CSD) transformation, re-referencing using the average reference electrode (AVERAGE) and reference electrode standardization techniques (REST). The statistical analysis of adjacency matrices was carried out using indices based on graph theory. Both CSD and REST reduced the influence of volume conducted currents. The largest group differences in connectivity were observed for the alpha band. Schizophrenic patients showed reduced connectivity strength, as well as a lower clustering coefficient and shorter characteristic path length for both measures of phase synchronization following CSD transformation or REST re-referencing. Reduced synchronization was accompanied by increased directional flow from the occipital region for the alpha band. Following the REST re-referencing, the sources of alpha activity were located at parietal rather than occipital derivations. The results of PLV and DTF demonstrated group differences in fronto-posterior asymmetry following CSD transformation, while for PLI the differences were significant only using REST. The only analysis that identified group differences in inter-hemispheric asymmetry was DTF calculated for REST. Our results suggest that a comparison of different connectivity measures using graph-based indices for each frequency band, separately, may be a useful tool in the study of disconnectivity disorders such as schizophrenia.
Rujuta Parlikar, Damodharan Dinakaran, Anushree Bose, ,
Journal of the Indian Institute of Science, Volume 97, pp 583-590;

The publisher has not yet granted permission to display this abstract.
, Tomohiro Umemura, Masahiro Matsunaga, Takayoshi Hirai
Published: 13 November 2017
Hypofrontality is a state of decreased cerebral blood flow in the prefrontal cortex during executive function performance; it is commonly observed in patients with schizophrenia. Cognitive dysfunction, as well as the psychological symptoms of schizophrenia, influences the ability of patients to reintegrate into society. The current study investigated the effects of an interactive sports video game (IVG; Nintendo Wii™ Sports Resort) on frontal lobe function of patients with schizophrenia. A sample of eight patients (6 male and 2 female; mean age = 46.7 years, standard deviation (SD) = 13.7) engaged in an IVG every week for 3 months in a controlled, single-blind, crossover study. Before and after the intervention we examined frontal lobe blood-flow volume using functional near-infrared spectroscopy (fNIRS), and assessed functional changes using the Frontal Assessment Battery, Health-Related Quality of Life scale, and behaviorally-assessed physical function tests. fNIRS revealed that prefrontal activity during IVG performance significantly increased in the IVG period compared with the control period. Furthermore, significant correlations between cerebral blood flow changes in different channels were observed during IVG performance. In addition, we observed intervention-related improvement in health-related quality of life following IVG. IVG intervention was associated with increased prefrontal cortex activation and improved health-related quality of life performance in patients with schizophrenia. Patients with chronic schizophrenia are characterized by withdrawal and a lack of social responsiveness or interest in others. Interventions using IVG may provide a useful low-cost rehabilitation method for such patients, without the need for specialized equipment.
Michael W. Best,
Expert Review of Neurotherapeutics, Volume 17, pp 713-723;

Introduction: Individuals with psychotic disorders experience profound impairment in neurocognition, which is consistently found to be the best predictor of independent community functioning. Several diverse behavioural treatments designed to enhance neurocognitive abilities have been developed, with subtle to stark differences among them. Various approaches, to varying degrees, have demonstrated success across diffuse outcomes: improved brain structure and function, performance on neuropsychological tests, and community activities associated with daily living. Areas covered: This paper reviews the different approaches to cognitive remediation and the differential effects these approaches have on neurophysiological function, neurocognitive abilities, and real-world community functioning. Cognitive remediation approaches can be broadly classified along two dimensions: 1) treatment target, and 2) treatment modality. Some approaches target more basic perceptual skills, some target higher level executive processes, while some are non-targeted and seek to improve general cognitive ability. With regard to modality, approaches might have little/no therapist involvement and rely exclusively on computerized practice or they may include intensive therapist involvment to generalize neurocognitive change to community functioning. Expert commentary: Compared to other widely implemented treatments for schizophrenia, cognitive remediation produces better effects on outcome measures. It is time for cognitive remediation to be adopted as a best practice in the treatment of schizophrenia.
Jane R. Garrison, Emilio Fernandez-Egea, Rashid Zaman, Mark Agius,
Published: 25 January 2017
NeuroImage: Clinical, Volume 14, pp 260-268;

The publisher has not yet granted permission to display this abstract.
, Hans-Peter Volz, Franziska Dorn
Published: 1 January 2017
The publisher has not yet granted permission to display this abstract.
, , Yu. I. Poliakov, A. Yu. Mitrofanov, J. D. Kropotov
Published: 1 November 2016
Human Physiology, Volume 42, pp 606-614;

The article analyzes event-related potentials in the Go/NoGo test of patients with schizophrenia and schizotypal personality disorder in relation to healthy subjects. Differences identified in the group of patients with schizophrenia are consistent with previous studies and indicate disruption in processes associated with different stages of visual information processing and executive functions. Specific features of brain activity in patients with schizotypal personality disorder were significantly less pronounced and presumably pointed to changes in the processes of attention redistribution and action monitoring. The results agree well with the clinical symptoms of schizophrenia and schizotypal personality disorder, so that this technique can be considered a possible additional diagnostic criterion for these disorders.
, Laurent Boyer, Raphaëlle Richieri, Pascal Auquier, Christophe Lançon, Eric Guedj
Published: 12 February 2016
Psychiatry Research: Neuroimaging, Volume 249, pp 67-75;

The aim of this study was to investigate the functional brain substrate of quality of life (QoL) in patients with schizophrenia. Participants comprised 130 right-handed patients with schizophrenia who underwent whole-brain single photon emission computed tomography (SPECT) with (99m)Tc-labeled ethylcysteinate dimer ((99m)Tc-ECD) for exploring correlations of regional cerebral blood flow (rCBF) with the eight dimensions score of the Schizophrenia Quality of Life questionnaire (S-QoL 18). A significant positive correlation was found between the global index of the S-QoL 18 and rCBF in the right superior temporal sulcus and between psychological well-being dimension and rCBF in Brodmann area (BA)6, BA8, BA9, and BA10 and between self-esteem dimension and rCBF in striatum and between family relationship dimension and rCBF in BA1, BA2, BA3, BA4, BA8, BA22, BA40, BA42 and BA44 and between relationship with friends dimension and rCBF in BA44 and between physical well-being dimension and rCBF in parahippocampal gyrus, and finally between autonomy dimension and rCBF in cuneus and precuneus. A significant negative correlation was found between resilience dimension and rCBF in precuneus and between sentimental life dimension and rCBF in BA10. Our findings provide neural correlates of QoL. Brain regions involved in cognitions, emotional information processing and social cognition underlie the different QoL dimensions.
, Hans-Peter Volz, Franziska Dorn
Published: 1 January 2016
The publisher has not yet granted permission to display this abstract.
, C. Quiles, R. Belzeaux, , J.-M. Azorin
Published: 1 December 2015
L'Encéphale, Volume 41, pp 6S50-6S56;

The aim of this review of the literature is to summarize the state of the knowledge concerning the relationship between negative symptoms in schizophrenia, electrophysiology and electrotherapy. The scientific literature search of international articles was performed during August and September 2015 using the PubMed electronic database. We used the following MeSH terms: "Negative symptoms", "Schizophrenia", "Electrophysiology", "Neurophysiology", "EEG power", "Alpha rhythm", "Transcranial magnetic stimulation", "Transcranial direct current stimulation", "Electroconvulsive therapy", "Neurofeedback", "Vagus Nerve Stimulation", "Deep Brain Stimulation", and "State dependent". Negative symptoms in schizophrenia are associated with altered activity in prefrontal cortex in functional neuroimaging studies. This is in line with electrophysiological measurements that found a change in EEG spectral power in the alpha frequency band over prefrontal brain regions. The notion of functional hypofrontality has led to hypotheses that electrotherapy applied to the prefrontal cortex may be an effective treatment of negative symptoms in schizophrenia. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) were used to increase cortical activity in schizophrenia and achieve a clinical effect on negative symptoms. Three meta-analyses confirmed, with a moderate effect size, that rTMS is an effective treatment option for negative symptoms in schizophrenia. The two subsequently published prospective multicenter studies, however, found opposite results from each other. Two randomized controlled studies suggested that tDCS is an effective treatment option for negative symptoms. There is no study on the efficacy of neurofeedback, vagal nerve stimulation or deep brain stimulation on negative symptoms in schizophrenia. Additional studies are needed to confirm the efficacy of rTMS and tDCS on negative symptoms in schizophrenia. Influencing factors, related to clinical and stimulation parameters, of rTMS and tDCS on negative symptoms should be better investigated. Effects related to electrophysiological brain activity of the patient, especially in the alpha band, during the stimulation should also be better investigated. The action of electrotherapy may be state dependent, and a better understanding of electrophysiological effects of electrotherapy techniques could enable their optimization.
Published: 17 November 2015
Frontiers in Psychiatry, Volume 6;

Schizophrenia is a mental disorder that is characterized by various abnormal symptoms. Previous studies indicate decreased expression of Phospholipase C-β1 (PLC-β1) in the brains of patients with schizophrenia. PLC-β1-null (PLC-β1-/-) mice exhibit multiple endophenotypes of schizophrenia. Furthermore, a study of PLC-β1 knockdown in the medial prefrontal cortex (mPFC) of mice has shown a specific behavioral deficit, impaired working memory. These results support the notion that disruption of PLC-β1-linked signaling in the brain is strongly involved in the pathogenesis of schizophrenia. In this review, we broadly investigate recent studies regarding schizophrenia-related behaviors as well as their various clinical and biological correlates in PLC-β1-/- and knockdown mouse models. This will provide a better understanding of the pathological relevance of the altered expression of PLC-β1 in the brains of patients with schizophrenia. Evidence accumulated will shed light on future in-depth studies, possibly in human subjects.
, Andrea Mechelli, , Mikail Rubinov, Edward T. Bullmore,
Schizophrenia Bulletin, Volume 42, pp 434-442;

Functional neuroimaging studies of schizophrenia have identified abnormal activations in many brain regions. In an effort to interpret these findings from a network perspective, we carried out a meta-analysis of this literature, mapping anatomical locations of under- and over-activation to the topology of a normative human functional connectome. We included 314 task-based functional neuroimaging studies including more than 5000 patients with schizophrenia and over 5000 controls. Coordinates of significant under- or over-activations in patients relative to controls were mapped to nodes of a normative connectome defined by a prior meta-analysis of 1641 functional neuroimaging studies of task-related activation in healthy volunteers. Under-activations and over-activations were reported in a wide diversity of brain regions. Both under- and over-activations were significantly more likely to be located in hub nodes that constitute the “rich club” or core of the normative connectome. In a subset of 121 studies that reported both under- and over-activations in the same patients, we found that, in network terms, these abnormalities were located in close topological proximity to each other. Under-activation in a peripheral node was more frequently associated specifically with over-activation of core nodes than with over-activation of another peripheral node. Although schizophrenia is associated with altered brain functional activation in a wide variety of regions, abnormal responses are concentrated in hubs of the normative connectome. Task-specific under-activation in schizophrenia is accompanied by over-activation of topologically central, less functionally specialized network nodes, which may represent a compensatory response.
Shyamalagauri Jadhav,
Published: 1 October 2014
Clinical Lipidology, Volume 9, pp 533-551;

The development of therapies for neuropsychiatric disorders is hampered by the lack of understanding of the mechanisms underlying their pathologies. While aberrant sphingolipid metabolism is associated with psychiatric illness, the role of sphingolipids in these disorders is not understood. The genetically tractable yeast model can be exploited in order to elucidate the cellular consequences of sphingolipid perturbation. Hypotheses generated from studies in yeast and tested in mammalian cells may contribute to our understanding of the role of sphingolipids in psychiatric disorders and to the development of new treatments. Here, we compare sphingolipid metabolism in yeast and mammalian cells, discuss studies implicating sphingolipids in psychiatric disorders and propose approaches that utilize yeast in order to elucidate sphingolipid function and identify drugs that target sphingolipid synthesis.
, Yoko Mori, Shinichiro Ochi, Shusuke Numata, Takashi Ishimaru, Kiyohiro Yamazaki, , Shu-Ichi Ueno
Published: 13 August 2014
Journal of Neural Transmission, Volume 122, pp 731-732;

Abnormal hexanucleotide repeat expansion of C9ORF72 is known to cause neurodegenerative disorders such as frontotemporal dementia. Additionally, patients with psychotic symptoms are more likely to have abnormal hexanucleotide repeat expansion than are patients without them. We investigated the hexanucleotide repeat sizes of C9ORF72 in 466 Japanese schizophrenia patients. We found no abnormal hexanucleotide repeat expansion. In conclusion, C9ORF72 may not be responsible for schizophrenia susceptibility in the Japanese population.
Frontiers in Neural Circuits, Volume 8;

In this review, we provide a brief overview over the current knowledge about the role of dopamine transmission in the prefrontal cortex during learning and memory. We discuss work in humans, monkeys, rats, and birds in order to provide a basis for comparison across species that might help identify crucial features and constraints of the dopaminergic system in executive function. Computational models of dopamine function are introduced to provide a framework for such a comparison. We also provide a brief evolutionary perspective showing that the dopaminergic system is highly preserved across mammals. Even birds, following a largely independent evolution of higher cognitive abilities, have evolved a comparable dopaminergic system. Finally, we discuss the unique advantages and challenges of using different animal models for advancing our understanding of dopamine function in the healthy and diseased brain.
Annya M, Annya M. Smyth, Stephen M,
Clinical Psychopharmacology and Neuroscience, Volume 11, pp 107-117;

Schizophrenia (SCZ) is a polygenic, multi-factorial disorder and a definitive understanding of its pathophysiology has been lacking since it was first described more than a century ago. The predominant pharmacological approach used to treat SCZ is the use of dopamine receptor antagonists. The fact that many patients remain symptomatic, despite complying with medication regimens, emphasises the need for a more encompassing explanation for both the causes and treatment of SCZ. Recent neuroanatomical, neurobiological, environmental and genetic studies have revived the idea that inflammatory pathways are involved in the pathogenesis of SCZ. These new insights have emerged from multiple lines of evidence, including the levels of inflammatory proteins in the central nervous system of patients with SCZ and animal models. This review focuses on aberrant inflammatory mechanisms present both before and during the onset of the psychotic symptoms that characterise SCZ and discusses recent research into adjunctive immune system modulating therapies for its more effective treatment.
, Thomas Juergen Bahmer, Florian Gerhard Metzger, , , Bruno Pfuhlmann, , Mark-Christian Eberle, Lena Helene Ernst, Andreas Jochen Fallgatter, et al.
International Journal of Neuropsychopharmacology, Volume 16, pp 1911-1925;

Atypical antipsychotic agents are a frequently and effectively used treatment in schizophrenia and psychotic disorders. Other than conventional antipsychotics, which mainly exert their pharmacological effect in subcortical dopaminergic systems, atypical antipsychotics additionally affect partly serotonergically innervated structures within prefrontal areas, such as the anterior cingulate cortex (ACC). However, only few controlled, randomized studies have so far investigated direct and indirect effects of atypical antipsychotics on the ACC and, up until now, no clinical investigation has exclusively addressed the specific effects of quetiapine on ACC function. The present study assessed ACC function in 18 quetiapine-medicated patients and 13 flupentixol-treated patients suffering from schizophrenia by means of the error-related negativity (ERN), a neurophysiological marker of ACC function, in a pre-post design. Between-group comparisons revealed different effects of quetiapine and flupentixol on ACC function despite similar improvement in psychopathology, cognitive performance and quality of life. Whereas atypical treatment was associated with an increase in amplitudes over time, there were prolonged ERN peak latencies in patients treated with the typical agent. Moreover, treatment effects depended on baseline prefrontal cortex function in both groups. We conclude that both flupentixol and quetiapine improve prefrontal function especially in patients with weak initial ACC function which might be due to their shared affinity for serotonin receptors in frontal brain regions. However, since this affinity is more pronounced for quetiapine, patients treated with quetiapine seemed to profit more evidently concerning their prefrontal cortex function compared to patients of the flupentixol group, who exhibited a compensatory prolongation of processes.
Published: 1 September 2013
Dialogues in Clinical Neuroscience, Volume 15, pp 315-328

Molecular imaging techniques have a number of advantages for research into the pathophysiology and treatment of central nervous system (CNS) disorders. Firstly, they provide a noninvasive means of characterizing physiological processes in the living brain, enabling molecular alterations to be linked to clinical changes. Secondly, the pathophysiological target in a given CNS disorder can be measured in animal models and in experimental human models in the same way, which enables translational research. Moreover, as molecular imaging facilitates the detection of functional change which precedes gross pathology, it is particularly useful for the early diagnosis and treatment of CNS disorders.
Niall J. Finnerty, Fiachra B. Bolger, Erik Pålsson,
ACS Chemical Neuroscience, Volume 4, pp 825-831;

Glucose, O2, and nitric oxide (NO) were monitored in real time in the prefrontal cortex of freely moving animals using microelectrochemical sensors following phencyclidine (PCP) administration. Injection of saline controls produced a decrease in glucose and increases in both O2 and NO. These changes were short-lived and typical of injection stress, lasting ca. 30 s for glucose and between 2 and 6 min for O2 and NO, respectively. Subchronic PCP (10 mg/kg) resulted in increased motor activity and increases in all three analytes lasting several hours: O2 and glucose were uncoupled with O2 increasing rapidly following injection reaching a maximum of 70% (ca. 62 μM) after ca. 15 min and then slowly returning to baseline over a period of ca. 3 h. The time course of changes in glucose and NO were similar; both signals increased gradually over the first hour post injection reaching maxima of 55% (ca. 982 μM) and 8% (ca. 31 nM), respectively, and remaining elevated to within 1 h of returning to baseline levels (after ca. 5 and 7 h, respectively). While supporting increased utilization of glucose and O2 and suggesting overcompensating supply mechanisms, this neurochemical data indicates a hyperfrontal effect following acute PCP administration which is potentially mediated by NO. It also confirms that long-term in vivo electrochemical sensors and data offer a real-time biochemical perspective of the underlying mechanisms.
, Michael J. Minzenberg, Sherief Raouf, Mark D’Esposito, Cameron S. Carter
Published: 7 January 2013
Biological Psychiatry, Volume 74, pp 122-129;

Background The theory that prefrontal cortex (PFC) dysfunction in schizophrenia leads to excess subcortical dopamine has generated widespread interest because it provides a parsimonious account for two core features of schizophrenia, cognitive deficits and psychosis, respectively. However, there has been limited empirical validation of this model. Moreover, the identity of the specific subcortical brain regions and circuits that may be impaired as a result of PFC dysfunction and mediate its link to psychosis in schizophrenia remains unclear. We undertook this event-related functional magnetic resonance imaging study to test the hypothesis that PFC dysfunction is associated with altered function of and connectivity with dopamine regulating regions of the basal ganglia. Methods Eighteen individuals with schizophrenia or schizoaffective disorder and 19 healthy control participants completed event-related functional magnetic resonance imaging during working memory. We conducted between-group contrasts of task-evoked, univariate activation maps to identify regions of altered function in schizophrenia. We also compared the groups on the level of functional connectivity between a priori identified PFC and basal ganglia regions to determine if prefrontal disconnectivity in patients was present. Results We observed task-evoked hyperactivity of the substantia nigra that occurred in association with prefrontal and striatal hypoactivity in the schizophrenia group. The magnitude of prefrontal functional connectivity with these dysfunctional basal ganglia regions was decreased in the schizophrenia group. Additionally, the level of nigrostriatal functional connectivity predicted the level of psychosis. Conclusions These results suggest that functional impairments of the prefrontal striatonigral circuit may be a common pathway linking the pathogenesis of cognitive deficits and psychosis in schizophrenia.
Published: 1 January 2013
Frontiers in Psychiatry, Volume 4;

The executive function (EF) is a set of abilities, which allows us to invoke voluntary control of our behavioral responses. These functions enable human beings to develop and carry out plans, make up analogies, obey social rules, solve problems, adapt to unexpected circumstances, do many tasks simultaneously, and locate episodes in time and place. EF includes divided attention and sustained attention, working memory (WM), set-shifting, flexibility, planning, and the regulation of goal directed behavior and can be defined as a brain function underlying the human faculty to act or think not only in reaction to external events but also in relation with internal goals and states. EF is mostly associated with dorsolateral prefrontal cortex (PFC). Besides EF, PFC is involved in self-regulation of behavior, i.e., the ability to regulate behavior according to internal goals and constraints, particularly in less structured situations. Self-regulation of behavior is subtended by ventral medial/orbital PFC. Impairment of EF is one of the most commonly observed deficits in schizophrenia through the various disease stages. Impairment in tasks measuring conceptualization, planning, cognitive flexibility, verbal fluency, ability to solve complex problems, and WM occur in schizophrenia. Disorders detected by executive tests are consistent with evidence from functional neuroimaging, which have shown PFC dysfunction in patients while performing these kinds of tasks. Schizophrenics also exhibit deficit in odor identifying, decision-making, and self-regulation of behavior suggesting dysfunction of the orbital PFC. However, impairment in executive tests is explained by dysfunction of prefronto-striato-thalamic, prefronto-parietal, and prefronto-temporal neural networks mainly. Disorders in EFs may be considered central facts with respect to schizophrenia and it has been suggested that negative symptoms may be explained by that executive dysfunction.
, Bjorn H. Ebdrup, , Hartwig R. Siebner
Current Neuropharmacology, Volume 10, pp 219-230;

Impaired brain connectivity is a hallmark of schizophrenia brain dysfunction. However, the effect of drug treatment and challenges on the dysconnectivity of functional networks in schizophrenia is an understudied area. In this review, we provide an overview of functional magnetic resonance imaging studies examining dysconnectivity in schizophrenia and discuss the few studies which have also attempted to probe connectivity changes with antipsychotic drug treatment. We conclude with a discussion of possible avenues for further investigation.
Jiacheng Liu, Maolin Qiu, ,
Published: 11 July 2012
Schizophrenia Research, Volume 140, pp 143-148;

Experimental changes in resting cerebral blood flow (CBF) affect task-related blood oxygenation level dependent (BOLD) responses. Since patients with schizophrenia have been shown to have abnormal resting CBF, we sought to determine whether differences between patients and healthy controls in resting CBF contribute to group differences in BOLD response.
, Henderikus Knegtering, Hans C. Klein, Rudie Kortekaas, André Aleman
Published: 30 June 2012
European Neuropsychopharmacology, Volume 22, pp 387-400;

The publisher has not yet granted permission to display this abstract.
, Daniel Weisholtz, Nancy Isenberg, Elizabeth Harding, Jane Epstein, Emily Stern, David Silbersweig
Published: 29 February 2012
Epilepsy & Behavior, Volume 23, pp 113-122;

The publisher has not yet granted permission to display this abstract.
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