Brain Function In Schizophrenia Research Articles

S40-04 - Neural correlates of cognitive behavioural therapy in patients with schizophrenia

Cognitive behavioural therapy (CBT) is an important treatment in conjunction with psychopharmacotherapy in schizophrenia. However, there is only very little research on the effects of such interventions on brain function.Recent studies have suggested that jumping to conclusions and a specific attributional bias is a predominant cognitive style in patients which might lead to the development of delusions. In this multi-centre fMRI trial, we investigated the effect of nine months of CBT on neural correlates of “jumping to conclusions” and the “attributional style” in patients with psychosis. Eighty patients and 80 control subjects were recruited in six centres and measured with 3-Tesla functional magnetic imaging (fMRI) before and after CBT.It could be shown that CBT ameliorates differences in brain activations between patients and controls after nine months.These results support the feasibility of fMRI multicenter trials and sheds further light into the mechanisms relating psychotherapy to brain function in Schizophrenia.

S34-04 - Genetic and non-genetic influences on brain function in schizophrenia: an fMRI study in twins

IntroductionAltered neurocognitive function in schizophrenia could reflect both genetic and illness-specific effects.ObjectivesTo use functional magnetic resonance imaging to discriminate between the influences of the genetic risk for schizophrenia and environmental factors on the neural substrate of verbal fluency, a candidate schizophrenia endophenotype using a case control twin design.MethodsWe studied 23 monozygotic twin pairs: 13 pairs discordant for schizophrenia and 10 pairs of healthy volunteer twins. Groups were matched for age, gender, handedness, level of education, parental socio-economic status, and ethnicity. Behavioural performance and regional brain activation during a phonological verbal fluency task were assessed.ResultsRelative to healthy control twins, both patients and their non-psychotic co-twins produced fewer correct responses and showed less activation in the medial temporal region and inferior frontal gyrus. Twins with schizophrenia showed greater activation than both their non-psychotic co-twins and controls in right lateral temporal cortex, reflecting reduced deactivation during word generation while their non-psychotic co-twins showed greater activation in the left temporal cortex.ConclusionsBoth genetic vulnerability to schizophrenia and schizophrenia were associated with impaired verbal fluency performance, reduced engagement of the medial temporal region and dorsal inferior frontal gyrus. Schizophrenia was specifically associated with an additional reduction in deactivation in the right temporal cortex.

Mathematical Modeling of Schizophrenia

Abnormal brain function in schizophrenia involves an extended network of brain structures. In schizophrenia, an abnormal dopamine activity in accordance with altered GABA and glutamate transmission appears to interfere with this process. In this study, we have examined the effect of dopamine hyperactivity on CA3 pyramidal cells using a mathematical model. Our simulation results show that while normal activity of dopamine system causes the membrane potential of pyramidal cell to display a periodic bursting behavior, hyperactivity of this system brings about irregular and aperiodic patterns of activity. In addition, it is suggested that hypo-glutamatergic conditions result in reduced activation of the striatal complex and may induce psychotic symptoms. Thus, we also investigated the role of glutamate level in postsynaptic cell activity. Simulation results indicate that hypo-glutamatergic condition has the same effect on the membrane potential of pyramidal cells, i.e. aperiodic and irregular firing patterns. Based on these results, we hypothesize that glutamate receptor activation may have good therapeutic results in schizophrenia.

Association between sigma-1 receptor gene polymorphism and prefrontal hemodynamic response induced by cognitive activation in schizophrenia

The molecular biological role of the sigma-1 receptor (Sig-1R) has attracted much attention. Evidence suggests that the Sig-1R engaged in modulating NMDA and dopamine receptors is involved in the pathophysiology of schizophrenia and the mechanism of psychotropic drug efficacy. However, whether the Sig-1R genotype affects brain function in schizophrenia in vivo remains unknown. We investigated the association between Sig-1R functional polymorphism (Gln2Pro) and brain function in schizophrenia. The subjects were 40 patients with schizophrenia and 60 healthy controls, all right-handed, who gave written informed consent to participate. Signals, detected from prefrontal regions by 52-channel near-infrared spectroscopy (NIRS) during cognitive activation, were compared between two Sig1-R genotype subgroups (Gln/Gln individuals and Pro carriers) matched for age, gender, premorbid IQ and task performance. The prefrontal hemodynamic response of healthy controls during the verbal fluency task was higher than that of patients with schizophrenia. For the patients with schizophrenia, even after controlling the effect of medication, the [oxy-Hb] increase in the prefrontal cortex of the Gln/Gln genotype group was significantly greater than that of the Pro carriers (false discovery rate corrected p < 0.05). Clinical symptoms were not significantly different between the two Sig-1R genotype subgroups. These differences were not significant in the healthy controls. This is the first functional imaging genetics study that implicated the association between Sig-1R genotype and prefrontal cortical function in schizophrenia in vivo. Our findings also suggest that the prefrontal hemodynamic response assessed by noninvasive and less demanding NIRS is a useful intermediate phenotype for translational research in schizophrenia.

MTHFR 677C → T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val → Met

Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val --> Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val --> Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C --> T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR x COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.

Altered Center-Surround Motion Inhibition in Schizophrenia

Schizophrenia is a brain disorder that spans across biological and behavioral levels. The links between altered neural circuitry and abnormal behaviors are yet to be understood. Visual motion perception has been established in basic neuroscience and may provide an opportunity to link different levels of brain functions in schizophrenia. Center-surround interaction is a ubiquitous neural mechanism underlying the organization of visual information over different spatial locations. We applied a psychophysical paradigm to examine center-surround interaction in schizophrenia. Patients (n = 24) and control subjects (n = 33) judged the direction of a moving random dot pattern (RDP, center) with and without the presence of another concentric surrounding RDP (surround). The presence of a moving surround shifted the perceptual judgments of center motion in the opposite direction from the surround in both subject groups but the magnitude of the perceptual shift was significantly larger in patients. The increased perceptual shift was not correlated with psychotic symptoms, which were mild in this patient sample, or antipsychotic medication. The increased perceptual shift suggests that the putative surround suppression on visual motion perception is abnormally increased in schizophrenia. This result provides perceptual evidence for altered basic inhibitory control of visual motion context in schizophrenia.

Native EEG and treatment effects in neuroleptic-naïve schizophrenic patients: Time and frequency domain approaches

Time domain analysis of electroencephalography (EEG) can identify subsecond periods of quasi-stable brain states. These so-called microstates assumingly correspond to basic units of cognition and emotion. On the other hand, Global Field Synchronization (GFS) is a frequency domain measure to estimate functional synchronization of brain processes on a global level for each EEG frequency band [Koenig, T., Lehmann, D., Saito, N., Kuginuki, T., Kinoshita, T., Koukkou, M., 2001. Decreased functional connectivity of EEG theta-frequency activity in first-episode, neuroleptic-naive patients with schizophrenia: preliminary results. Schizophr Res. 50, 55-60.]. Using these time and frequency domain analyzes, several previous studies reported shortened microstate duration in specific microstate classes and decreased GFS in theta band in drug naïve schizophrenia compared to controls. The purpose of this study was to investigate changes of these EEG parameters after drug treatment in drug naïve schizophrenia. EEG analysis was performed in 21 drug-naive patients and 21 healthy controls. 14 patients were reevaluated 2–8 weeks (mean 4.3) after the initiation of drug administration. The results extended findings of treatment effect on brain functions in schizophrenia, and imply that shortened duration of specific microstate classes seems a state marker especially in patients with later neuroleptic responsive, while lower theta GFS seems a state-related phenomenon and that higher gamma GFS is a trait like phenomenon.

Application of electroencephalography to the study of cognitive and brain functions in schizophrenia.

The electroencephalogram (EEG) recorded from the human scalp is widely used to study cognitive and brain functions in schizophrenia. Current research efforts are primarily devoted to the assessment of event-related potentials (ERPs) and event-related oscillations (EROs), extracted from the ongoing EEG, in patients with schizophrenia and in clinically unaffected individuals who, due to their family history and current mental status, are at high risk for developing schizophrenia. In this article, we discuss the potential usefulness of ERPs and EROs as genetic vulnerability markers, as pathophysiological markers, and as markers of possible ongoing progressive cognitive and cortical deterioration in schizophrenia. Our main purpose is to illustrate that these neurophysiological measures can offer valuable quantitative biological markers of basic pathophysiological mechanisms and cognitive dysfunctions in schizophrenia, yet they may not be specific to current psychiatry's diagnosis and classification. These biological markers can provide unique information on the nature and extent of cognitive and brain dysfunction in schizophrenia. Moreover, they can be utilized to gain deeper theoretical insights into illness etiology and pathophysiology and may lead to improvements in early detection and more effective and targeted treatment of schizophrenia. We conclude by addressing several key methodological, conceptual, and interpretative issues involved in this research field and by suggesting future research directions.

Improvement of prefrontal brain function in schizophrenia under atypical neuroleptic treatment

Background and AimsVarious cognitive activation tasks in schizophrenic patients have demonstrated an altered function of the anterior cingulate cortex (ACC) interconnecting the prefrontal cortex with limbic areas. This prefrontal dysfunction is a main target of antipsychotic treatment, as it is considered to be involved in both negative symptoms and cognitive dysfunction.MethodsTwo- (NoGo-anteriorization; NGA) and three-dimensional topographical measures (source locations with the Low Resolution Electromagnetic Tomography; LORETA) of the event-related potentials elicited during the execution (Go) and the inhibition (NoGo) condition of the Continuous Performance Test allow an assessment of anterior cingulate function with extraordinary high interindividual stability and retest reliability.ResultsThese methods revealed a significant brain electrical hypoactivity in the ACC of schizophrenic patients as compared to age- and gender-matched controls. Both a neuropsychological index of ACC performance and the proposed electrophysiological measure of this region have been shown to be improved in patients treated with atypical but not with typical antipsychotics.ConclusionsThese results support the notion that a functional deficit of the ACC during response control is a core feature in schizophrenias, which can be improved by atypical antipsychotic treatment.

Effects of γ-Aminobutyric Acid–Modulating Drugs on Working Memory and Brain Function in Patients With Schizophrenia

Cognitive impairment causes morbidity in schizophrenia and could be due to abnormalities of cortical interneurons using the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). To test the predictions that cognitive and brain functional responses to GABA-modulating drugs are correlated and abnormal in schizophrenia. Pharmacological functional magnetic resonance imaging study of 2 groups, each undergoing scanning 3 times, using an N-back working memory task, after placebo, lorazepam, or flumazenil administration. Eleven patients with chronic schizophrenia were recruited from a rehabilitation service, and 11 healthy volunteers matched for age, sex, and premorbid IQ were recruited from the local community. Intervention Participants received 2 mg of oral lorazepam, a 0.9-mg intravenous flumazenil bolus followed by a flumazenil infusion of 0.0102 mg/min, or oral and intravenous placebo. Working memory performance was summarized by the target discrimination index at several levels of difficulty. Increasing (or decreasing) brain functional activation in response to increasing task difficulty was summarized by the positive (or negative) load response. Lorazepam impaired performance and flumazenil enhanced it; these cognitive effects were more salient in schizophrenic patients. Functional magnetic resonance imaging demonstrated positive load response in a frontoparietal system and negative load response in the temporal and posterior cingulate regions; activation of the frontoparietal cortex was positively correlated with deactivation of the temporocingulate cortex. After placebo administration, schizophrenic patients had abnormally attenuated activation of the frontoparietal cortex and deactivation of the temporocingulate cortex; this pattern was mimicked in healthy volunteers and exacerbated in schizophrenic patients by lorazepam. However, in schizophrenic patients, flumazenil enhanced deactivation of the temporocingulate and activation of the anterior cingulate cortices. The GABA-modulating drugs differentially affect working memory performance and brain function in schizophrenia. Cognitive impairment in schizophrenia may reflect abnormal inhibitory function and could be treated by drugs targeting GABA neurotransmission.

Improvement of Prefrontal Brain Function in Endogenous Psychoses Under Atypical Antipsychotic Treatment

Typical and atypical antipsychotics are thought to exert their effects on different neurotransmitter pathways with specific action of atypical compounds on the prefrontal cortex, but studies directly investigating the effect of those drugs on neurophysiological measures of prefrontal brain function are sparse. We therefore investigated the influence of different antipsychotics on an electrophysiological marker of prefrontal brain function (NoGo anteriorization, NGA) and neuropsychological test scores. For this purpose, 38 patients with endogenous psychoses were investigated at the beginning of a stationary psychiatric treatment and at a 6-week-follow-up. Patients were treated with typical or atypical antipsychotics, or a combination of both. They underwent psychopathological diagnostic and neuropsychological testing, as well as electrophysiological investigations during a Continuous Performance Test. The results indicate that typical and atypical antipsychotics differentially affected the development of the NGA over the course of the treatment, typical antipsychotics tending to result in decreased values at follow-up, and atypical antipsychotics stabilizing, or increasing this parameter. Performance in tests of frontal lobe function generally declined under typical antipsychotics and improved with atypical compounds, changes in Stroop interference correlated with changes in the NGA. We conclude that typical and atypical antipsychotics differ regarding their effect on prefrontal brain function in schizophrenia, atypical neuroleptics often showing a more favorable impact than conventional antipsychotics on respective parameters.

Application of Electroencephalography to the Study of Cognitive and Brain Functions in Schizophrenia

Application of Electroencephalography to the Study of Cognitive and Brain Functions in Schizophrenia

A fMRI investigation of startle gating deficits in schizophrenia patients treated with typical or atypical antipsychotics

A key feature of schizophrenia is the inability to screen out irrelevant sensory input. Prepulse inhibition (PPI) of the startle response, a cross-species measure of sensorimotor gating, provides a valuable opportunity to study this feature. PPI is reliably impaired in schizophrenia. Animal models of disrupted PPI have proved valuable for the evaluation of antipsychotic substances. The cortico-striato-pallido-thalamic circuitry is primarily responsible for modulation of PPI in animals. We examined PPI and its brain correlates, using functional magnetic resonance imaging (fMRI), in men with schizophrenia treated with typical or atypical antipsychotics. Thirty men with schizophrenia on stable doses of typical antipsychotics (n=10), risperidone (n=10) or olanzapine (n=10; 9 with usable fMRI data) and 12 healthy men underwent psychophysiological testing and fMRI during a tactile PPI paradigm. The results showed reduced PPI of the eye-blink startle response in patients compared with healthy controls. Within the patient group, those on typical antipsychotics showed significantly impaired PPI but risperidone- or olanzapine-treated patients showed a milder (non-significant) deficit. Increased activity in the striatum, thalamus, insula, hippocampal, temporal, inferior frontal and inferior parietal regions occurred in association with PPI in controls. Patients treated with risperidone or olanzapine, but not with typical antipsychotics, showed significant activation in PPI-relevant regions. Our findings provide preliminary evidence that atypical antipsychotics positively influence PPI and partially restore associated brain functions in schizophrenia. Imaging data buttress the validity of PPI as a useful animal model of schizophrenia.

Auditory P300 latency prolongation with age in schizophrenia: Gender and subcomponent effects

Previous studies showing prolongation of auditory P300b latency with increasing age provided support for post-onset progressive change in schizophrenia. We sought to extend the findings by evaluating the effects of gender and the subcomponents (P3b versus P3a) in schizophrenia ( N = 108) and controls ( N = 70). P3b latency significantly correlated with age in schizophrenia (Spearman's rho = 0.214, P = 0.026) and in male patients with schizophrenia (rho = 0.260, P = 0.049) whereas, it did not reach significance in female patients with schizophrenia (rho = 0.174, P = 0.23). P3a latency showed no correlation. Our findings may provide evidence for progressive change in the brain function in schizophrenia, and this change may be slower in female than male patients. P3b may serve as a more sensitive index for cognitive decline than P3a.

Closing in on Schizophrenia

Closing in on Schizophrenia

Eye movement disturbances in schizophrenia and a polymorphism of catechol- O-methyltransferase gene

Previous studies suggested an association between the catechol- O-methyltransferase (COMT) Val/Met polymorphism and the performance on neuropsychological tests, measuring prefrontal function in schizophrenia. The aim of this study was to examine the relationship between this polymorphism and performance on oculomotoric tests in schizophrenic patients. The intensity of eye movement disturbances on fixation and smooth pursuit tests and the Val/Met polymorphism of COMT gene were studied in 117 schizophrenic patients (74 male and 43 female). In male schizophrenic patients, the mean intensity of both kinds of eye movement disturbances was lower in subjects who had the Met/Met genotype, with significant difference compared to other genotypes. Also, a significantly higher frequency of the Met allele and the Met/Met genotype was found in male schizophrenic patients exhibiting a lower intensity of smooth pursuit disturbances, and a trend in this direction was observed for the intensity of fixation disturbances. No such relationship was found in female schizophrenic patients. The results obtained suggest that, in male schizophrenic patients the Met allele of the COMT Val/Met polymorphism may have an alleviating effect on eye movement disturbances. They also point to possible gender differences as to the role of COMT in brain function in schizophrenia.

An estimation of the first positive Lyapunov exponent of the EEG in patients with schizophrenia

We studied the complexity of the electroencephalogram (EEG) in schizophrenic patients by estimating the first Lyapunov exponent (L1), which might serve as an indicator of the specific brain function in schizophrenia. We recorded the EEG from 25 schizophrenic patients (12 male, 13 female; age=25.1±7.0 years) fulfilling DSM-IV criteria and 15 healthy controls (9 male, 6 female; age=27.8±4.2 years) at 16 electrodes, different from previous studies which recorded the EEGs at limited electrodes. We employed a method with an optimal embedding dimension to calculate the L1s. For limited noisy data, this algorithm was strikingly faster and more accurate than previous ones. Our results showed that the schizophrenic patients had lower values of the L1 at the left inferior frontal and anterior temporal regions compared with normal controls. These results for L1 in non-linear analysis have some differences from those for power ratios in linear analysis. These suggest that the non-linear analysis of the EEGs such as the estimation of the L1 might be a useful tool in analyzing EEG data to explore the neurodynamics of the brains of schizophrenic patients.

Local and Distributed Effects of Apomorphine on Fronto-Temporal Function in Acute Unmedicated Schizophrenia

We used positron emission tomography (PET) to measure brain activity in healthy control subjects and unmedicated patients with schizophrenia. Subjects were scanned in the context of a combined psychological and pharmacological challenge, and we examined the effects of apomorphine, a drug acting on dopamine receptors, on brain systems engaged by a paced verbal fluency task. This factorial design enabled comparison of control subjects and schizophrenics in terms of the activations engendered by the cognitive task and the pharmacological challenge and the interaction of the two. We report a failure of cognitive task-related activation in anterior cingulate cortex and of task-related deactivation in the left superior temporal gyrus in the schizophrenic subjects. Compared with controls, the impaired cingulate activation was significantly reversed by apomorphine. Additionally, there was a trend for the abnormal fronto-temporal pattern of activation in schizophrenic subjects to be normalized by the drug. Overall, in schizophrenic subjects the effect of apomorphine, which we interpret in terms of a net dopaminergic antagonism, was to modify the brain activity, making the pattern more akin to that seen in control subjects. The results indicate both a regionally specific abnormality of brain function in schizophrenia and an abnormal pattern of fronto-temporal interactions.

Functional imaging--schizophrenia.

Evidence from recent studies of brain function in schizophrenia confirms that the frontal underactivity reported in earlier studies is a feature only of cases with decreased psychomotor activity, while patients with different symptom profile have different patterns of cerebral activity. Each of the three major groups of schizophrenic symptoms reflects a specific pattern of aberrant cerebral activity in association cortex of frontal, parietal and temporal lobes, and in related subcortical nuclei. These patterns indicate imbalances between neuronal activity at diverse interconnected brain sites, rather than abnormal function at a single location. Furthermore, during the performance of executive tasks, schizophrenic subjects exhibit impaired frontal activation, while during memory tasks there a tendency towards impaired temporal lobe activation. The difficulty activating a particular region does not reflect fixed loss of function. Rather the evidence indicates that the characteristic feature of schizophrenia is disturbed connectivity between cerebral areas.

Electrical brain activity in schizophrenia described by equivalent dipoles of FFT-data

Since results of conventional FFT-power-analysis are reference-dependent, only unambiguous neurophysiological data should be used for a functional physiological interpretation of EEG-data. FFT-approximation with successive center-of-gravity-dipole calculation gives unambiguous EEG-data with regard to recording reference. In the present investigation 22 medicated schizophrenic patients were compared with 22 healthy age- and sex-matched controls with regard to spontaneous resting EEG. More anterior and superficial equivalent-dipoles were found in the beta-bands for schizophrenic patients compared to healthy control subjects. There was a tendency of increased beta-activity in schizophrenic subjects. With more severe schizophrenic symptoms (higher BPRS-score), the more anterior was the equivalent-dipole localization in the betal-band, and the deeper in the theta-band. The different locations of the betaband dipoles in schizophrenic patients suggest that different neuronal populations generate beta-activity in schizophrenia compared to healthy controls. FFT-approximation allows a substantial and meaningful data reduction in multichannel recordings and will hopefully help in understanding pathological brain functions in schizophrenia.