Cognitive Disturbances In Schizophrenia Research Articles

Prospects for Neurotrophic Factor-Based Early Intervention in Schizophrenia: Lessons Learned from the Effects of Antipsychotic Drugs on Cognition, Neurogenesis, and Neurotrophic Factors.

Although reducing psychotic symptoms in schizophrenia has been a major focus of therapeutic interventions for decades, improving cognition is considered a better predictor of functional outcomes. However, the most commonly prescribed antipsychotic drugs (APDs) show only marginal beneficial effects on cognition in patients with schizophrenia. The neural mechanisms underlying cognitive disturbances in schizophrenia remain unknown that making drug development efforts very challenging. Since neurotrophic factors are the primary architects of neurogenesis, synaptic plasticity, learning, and memory, the findings from preclinical and clinical studies that assess changes in neurogenesis and neurotrophic factors and their relationship to cognitive performance in schizophrenia, and how these mechanisms might be impacted by APD treatment, may provide valuable clues in developing therapies to combat cognitive deficit in schizophrenia. Numerous evidence produced over the years suggests a deficit in a wide spectrum of neurotrophic factors in schizophrenia. Since schizophrenia is considered a neurodevelopmental disorder, early intervention with neurotrophic factors may be more effective in ameliorating the cognitive deficits and psychopathological symptoms associated with this pathology. In this context, results from initial clinical trials with neurotrophic factors and their future potential to improve cognition and psychosocial functioning in schizophrenia are discussed.

Impairments in Probabilistic Prediction and Bayesian Learning Can Explain Reduced Neural Semantic Priming in Schizophrenia.

It has been proposed that abnormalities in probabilistic prediction and dynamic belief updating explain the multiple features of schizophrenia. Here, we used electroencephalography (EEG) to ask whether these abnormalities can account for the well-established reduction in semantic priming observed in schizophrenia under nonautomatic conditions. We isolated predictive contributions to the neural semantic priming effect by manipulating the prime's predictive validity and minimizing retroactive semantic matching mechanisms. We additionally examined the link between prediction and learning using a Bayesian model that probed dynamic belief updating as participants adapted to the increase in predictive validity. We found that patients were less likely than healthy controls to use the prime to predictively facilitate semantic processing on the target, resulting in a reduced N400 effect. Moreover, the trial-by-trial output of our Bayesian computational model explained between-group differences in trial-by-trial N400 amplitudes as participants transitioned from conditions of lower to higher predictive validity. These findings suggest that, compared with healthy controls, people with schizophrenia are less able to mobilize predictive mechanisms to facilitate processing at the earliest stages of accessing the meanings of incoming words. This deficit may be linked to a failure to adapt to changes in the broader environment. This reciprocal relationship between impairments in probabilistic prediction and Bayesian learning/adaptation may drive a vicious cycle that maintains cognitive disturbances in schizophrenia.

Psychophysical assessment of koniocellular pathway in patients with schizophrenia versus healthy controls

This study was designed to perform psychophysical assessment of koniocellular pathway in patients with schizophrenia versus healthy controls. A total of 26 patients diagnosed with schizophrenia and 15 healthy controls were included. Snellen Visual Acuity Chart scores and Short Wavelength Automated Perimetry (SWAP) visual field testing including global visual field indices [mean deviation (MD), pattern standard deviation (PSD), test time (min)], reliability parameters [false negative responses (%), false positive responses (%) and fixed losses (%)] and average threshold sensitivity [central (parafovea), peripheral area, and four quadrants] were recorded in both groups. Significantly lower MD scores, higher PSD scores and lower average threshold sensitivity at each location across the visual field were noted in schizophrenia relative to control group. In conclusion, our findings revealed a deficit in koniocellular pathway with impaired SWAP global indices and lower threshold sensitivity at each location across the visual field among chronic schizophrenic patients as compared with control subjects. Our findings emphasize potential application of SWAP outside its original intended purpose as a glaucoma test, to provide deeper understanding of the specific contribution of lateral geniculate nucleus to the visual and cognitive disturbances of schizophrenia.

White Matter Integrity in Genetic High-Risk Individuals and First-Episode Schizophrenia Patients: Similarities and Disassociations.

White matter (WM) neuroimaging studies have shown varied findings at different stages of schizophrenia (SZ). Understanding these variations may elucidate distinct markers of genetic vulnerability and conversion to psychosis. To examine the similarities and differences in WM connectivity between those at-risk for and in early stages of SZ, a cross-sectional diffusion tensor imaging study of 48 individuals diagnosed with first-episode SZ (FE-SZ), 37 nonpsychotic individuals at a high genetic risk of SZ (GHR-SZ), and 67 healthy controls (HC) was conducted. Decreased fractional anisotropy (FA) in the corpus callosum (CC), anterior cingulum (AC), and uncinate fasciculus (UF) was observed in both the GHR-SZ and FE-SZ groups, while decreased FAs in the superior longitudinal fasciculus (SLF) and the fornix were only seen in the FE-SZ participants. Additionally, both GHR-SZ and FE-SZ showed worse executive performance than HC. The left SLF III FA was significantly positively correlated with hallucinations, and right SLF II was positively correlated with thought disorder. The presence of shared WM deficits in both FE-SZ and GHR-SZ individuals may reflect the genetic liability to SZ, while the disparate FA changes in the FE-SZ group may represent symptom-generating circuitry that mediates perceptual and cognitive disturbances of SZ and ultimately culminates in the onset of psychotic episodes.

Editorial: 5-HT2A/2B/2C Receptors, Memory, and Neuropsychiatric Disorders.

It is very well known that memory formation and forgetting represent important cognitive functions modulated by several neurotransmitters, including serotonin (5-hydroxytryptamine, 5-HT) (e.g., Fioravanti and Di Cesare, 1992; Wagner and Davachi, 2001; Wixted, 2004; Mansuy, 2005; Hardt et al., 2013; Hupbach; Callaghan et al., 2014; Li et al., 2015; Meneses), and memory dysfunction is present in several neuropsychiatric disorders (Meyer-Lindenberg et al., 2012; Millan et al., 2012, 2014). How does the brain become dysfunctional? Such a question has intrigued neuroscientists for many years. Over recent decades, neuroscience research has shed light on this complex issue and growing evidence is providing important insights. For instance, several lines of evidence demonstrate that dysfunctions in memory processes occur in several neuropsychiatric disorders, including Alzheimer's disease (AD), characterized by memory deficits and dementia; however, dysfunctional memory is observed in other age-related neurodegenerative disorders, such as schizophrenia, post-traumatic stress disorder, stroke, etc. (Millan et al., 2014; Hashimoto, 2015). So far, no effective treatment for dysfunctional memory exists (e.g., Millan et al., 2012, 2014; Sun et al., 2015); this area is hampered by the absence of neural markers associated to memory. Hence, progress in the fields relating to memory, amnesia, forgetting (e.g., Tellez et al., 2012) and AD (e.g., McConathy and Sheline, 2015; Muenchhoff et al., 2015; Scarr et al., 2015) as well as mild cognitive impairment (Eshkoor et al., 2015) would be facilitated considerably by identification of suitable neural markers. Serotonin is involved in several physiological and pathophysiological processes in mammals and in the treatment of psychiatric disorders (Meneses). It is very well known that 5-HT receptor heterogeneity allows for greater advances, and 5-HT 2A∕2B∕2C receptors are emerging as important tools for preclinical and clinical investigation. This special issue provides a deep overview of important advances on cerebral modifications associated with neuropsychiatric alterations, including dysfunctional memory. In particular, some papers analyse the role of serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia (Sumiyoshi et al.), while others are focused on the missing link of the central serotonin-2A 5-HT2A receptor dysfunction in depression and epilepsy (Guiard and Di Giovanni) and on the activity-regulated cytoskeleton-associated protein's putative role in regulating dendritic plasticity, cognitive processes, and mood in animal models of depression is presented (Li et al.). Moreover, a critical evaluation of serotonin mediation of early memory formation via 5-HT2B receptor-induced glycogenolysis in the day-old chick is provided (Gibbs and Hertz). An important subject is the neuronal localization of the 5-HT2 receptor family in the amygdaloid complex and emotion memories (Bombardi). Modeling dysfunctional memory, mitochondrial energy metabolism in different regions of the brain and potential treatments is illustrated (Singh and Kumar). In short, the translational feature of this special issue may expand our knowledge on brain dysfunctions and inspire further investigation, thus leading to a better management of psychiatric diseases.

EEG-Informed fMRI Reveals a Disturbed Gamma-Band-Specific Network in Subjects at High Risk for Psychosis.

Objectives. Abnormalities of oscillatory gamma activity are supposed to reflect a core pathophysiological mechanism underlying cognitive disturbances in schizophrenia. The auditory evoked gamma-band response (aeGBR) is known to be reduced across all stages of the disease. The present study aimed to elucidate alterations of an aeGBR-specific network mediated by gamma oscillations in the high-risk state of psychosis (HRP) by means of functional magnetic resonance imaging (fMRI) informed by electroencephalography (EEG). Methods. EEG and fMRI were simultaneously recorded from 27 HRP individuals and 26 healthy controls (HC) during performance of a cognitively demanding auditory reaction task. We used single trial coupling of the aeGBR with the corresponding blood oxygen level depending response (EEG-informed fMRI). Results. A gamma-band–specific network was significantly lower active in HRP subjects compared with HC (random effects analysis, P < .01, Bonferroni-corrected for multiple comparisons) accompanied by a worse task performance. This network involved the bilateral auditory cortices, the thalamus and frontal brain regions including the anterior cingulate cortex, as well as the bilateral dorsolateral prefrontal cortex. Conclusions. For the first time we report a reduced activation of an aeGBR-specific network in HRP subjects brought forward by EEG-informed fMRI. Because the HRP reflects the clinical risk for conversion to psychotic disorders including schizophrenia and the aeGBR has repeatedly been shown to be altered in patients with schizophrenia the results of our study point towards a potential applicability of aeGBR disturbances as a marker for the prediction of transition of HRP subjects to schizophrenia.

Compromised small-world efficiency of structural brain networks in schizophrenic patients and their unaffected parents.

Several lines of evidence suggest that efficient information integration between brain regions is disrupted in schizophrenia. Abnormalities in white matter tracts that interconnect brain regions may be directly relevant to this pathophysiological process. As a complex mental disorder with high heritability, mapping abnormalities in patients and their first-degree relatives may help to disentangle the risk factors for schizophrenia. We established a weighted network model of white matter connections using diffusion tensor imaging in 25 nuclear families with schizophrenic probands (19 patients and 41 unaffected parents) and two unrelated groups of normal controls (24 controls matched with patients and 26 controls matched with relatives). The patient group showed lower global efficiency and local efficiency. The decreased regional efficiency was localized in hubs such as the bilateral frontal cortices, bilateral anterior cingulate cortices, and left precuneus. The global efficiency was negatively correlated with cognition scores derived from a 5-factor model of schizophrenic psychopathology. We also found that unaffected parents displayed decreased regional efficiency in the right temporal cortices, left supplementary motor area, left superior temporal pole, and left thalamus. The global efficiency tended to be lower in unaffected parents. Our data suggest that (1) the global efficiency loss in neuroanatomical networks may be associated with the cognitive disturbances in schizophrenia; and (2) genetic vulnerability to schizophrenia may influence the anatomical organization of an individual's brain networks.

Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia.

Negative symptoms (e.g., decreased spontaneity, social withdrawal, blunt affect) and disturbances of cognitive function (e.g., several types of memory, attention, processing speed, executive function, fluency) provide a major determinant of long-term outcome in patients with schizophrenia. Specifically, motivation deficits, a type of negative symptoms, have been attracting interest as (1) a moderator of cognitive performance in schizophrenia and related disorders, and (2) a modulating factor of cognitive enhancers/remediation. These considerations suggest the need to clarify neurobiological substrates regulating motivation. Genetic studies indicate a role for the monoamine systems in motivation and key cognitive domains. For example, polymorphism of genes encoding catecholamine-O-methyltransferase, an enzyme catabolizing dopamine (DA), affects performance on tests of working memory and executive function in a phenotype (schizophrenia vs. healthy controls)-dependent fashion. On the other hand, motivation to maximize rewards has been shown to be influenced by other genes encoding DA-related substrates, such as DARPP-32 and DA-D2 receptors. Serotonin (5-HT) receptors may also play a significant role in cognitive and motivational disabilities in psychoses and mood disorders. For example, mutant mice over-expressing D2 receptors in the striatum, an animal model of schizophrenia, exhibit both decreased willingness to work for reward and up-regulation of 5-HT2C receptors. Taken together, genetic predisposition related to 5-HT receptors may mediate the diversity of incentive motivation that is impaired in patients receiving biological and/or psychosocial treatments. Thus, research into genetic and neurobiological measures of motivation, in association with 5-HT receptors, is likely to facilitate intervention into patients seeking better social consequences.

11C-NS14492 as a Novel PET Radioligand for Imaging Cerebral α7 Nicotinic Acetylcholine Receptors: In Vivo Evaluation and Drug Occupancy Measurements

Small-molecule α(7) nicotinic acetylcholine receptor (α(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled α(7)nAChR PET tracer would be important for in vivo quantification of α(7)nAChR binding in humans and to measure α(7)nAChR occupancy of α(7)nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of (11)C-NS14492 as a selective α(7)nAChR PET radioligand. The high-affinity α(7)nAChR-selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using (11)C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the α(7)nAChR partial agonist SSR180711 or the unlabeled NS14492. (11)C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; (11)C-NS14492 regional distribution volumes were calculated, and α(7)nAChR occupancy was determined using an occupancy plot. (11)C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with α(7)nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution volumes of (11)C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to α(7)nAChR in vivo. We report here that (11)C-NS14492 is the first, to our knowledge, PET radioligand for α(7)nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of α(7)nAChR binding in the human brain.

Cognitive impairment following prenatal immune challenge in mice correlates with prefrontal cortical AKT1 deficiency

Accumulating evidence indicates that genetically determined deficiency in the expression of the cytoplasmic serine-threonine protein kinase AKT1 may contribute to abnormal prefrontal cortical structure and function relevant to the cognitive disturbances in schizophrenia. However, it remains essentially unknown whether prefrontal AKT1 expression may also be influenced by environmental factors implicated in the aetiology of this mental illness. One of the relevant environmental risk factors of schizophrenia and related disorders is prenatal exposure to infection and/or immune activation. This study therefore explored whether prenatal immune challenge may lead to prefrontal AKT1 deficiency and associated changes in cognitive functions attributed to the prefrontal cortex. For these purposes, we used a well-established experimental mouse model of prenatal exposure to a viral-like acute phase response induced by the synthetic analogue of double-stranded RNA, polyriboinosinic-polyribocytidilic acid (PolyI:C). We found that adult offspring born to PolyI:C-treated mothers showed delay-dependent impairments in spatial working memory and recognition memory together with a marked reduction of AKT1-positive cells in the prefrontal cortex. These effects emerged in the absence of concomitant changes in prefrontal catechol-O-methyltransferase (COMT) density. Correlative analyses further demonstrated a significant positive correlation between the number of AKT1-positive cells in distinct prefrontal cortical subregions and cognitive performance under high storage load in the temporal domain. Our findings thus highlight that schizophrenia-related alterations in AKT1 signalling and associated cognitive dysfunctions may not only be precipitated by genetically determined factors, but may also be produced by (immune-associated) environmental insults implicated in the aetiology of this disabling brain disorder.

A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia.

BackgroundCognitive deficits in schizophrenia are associated with psychosocial deficits that are primarily responsible for the poor long-term outcome of this disease. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. Our studies suggest that the α7 nicotinic acetylcholine receptor (α7 nAChR) agonist tropisetron might be a potential therapeutic drug for cognitive deficits in schizophrenia. Therefore, it is of particular interest to investigate the effects of tropisetron on the cognitive deficits in patients with schizophrenia.MethodsA randomised, placebo-controlled trial of tropisetron in patients with schizophrenia was performed. A total of 40 patients with chronic schizophrenia who had taken risperidone (2 to 6 mg/day) were enrolled. Subjects were randomly assigned to a fixed titration of tropisetron (n = 20, 10 mg/day) or placebo (n = 20) in an 8-week double-blind trial. Auditory sensory gating P50 deficits and Quality of Life Scale (QLS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Positive and Negative Syndrome Scale (PANSS) scores were measured.ResultsIn all, 33 patients completed the trial. Tropisetron was well tolerated. Administration of tropisetron, but not placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. The score on the rapid visual information processing (sustained visual attention) task of CANTAB was significantly improved by tropisetron treatment. Total and subscale scores of PANSS were not changed by this trial. QLS scores in the all patients, but not non-smoking patients, were significantly improved by tropisetron trial.ConclusionsThis first randomised, double-blind, placebo-controlled trial supports the safety and efficacy of adjunctive tropisetron for treatment of cognitive deficits in schizophrenia.

A systematic fMRI investigation of the brain systems subserving different working memory components in schizophrenia

Working memory impairment is one of the cardinal cognitive disturbances in schizophrenia and considerable evidence suggests that it can be traced to functional alterations in the brain. The exact allocation of specific deficits to regional specific dysfunctions, however, remains elusive. The aim of this study was to examine the functional integrity of three distinguishable brain systems underlying maintenance-related subprocesses of working memory (articulatory rehearsal, non-articulatory maintenance of phonological information, maintenance of visuospatial information) in patients with schizophrenia. Using an experimental paradigm, which had been designed to selectively activate these different brain systems, we assessed the brain activation of patients and controls with functional magnetic resonance imaging. Compared with controls, patients showed reduced activation of the fronto-opercular, intraparietal and anterior cingulate cortex during the non-articulatory maintenance of phonological information, as well as attenuated deactivation of the hippocampus. Additionally, we found prefrontal activation to depend critically on the patients' current symptom status. During visuospatial maintenance, patients showed impaired activation of the superior parietal, temporal and occipital cortex, combined with enhanced activation of the frontal eye field and the inferior parietal cortex. No abnormal activations were observed during the articulatory rehearsal task. All activation differences were independent of group differences in task performance. Our fine-grained analysis of dysfunctions in particular aspects of working memory circuitry provides evidence for a differential impairment of the brain systems supporting working memory subcomponents in schizophrenia and extends knowledge of the relationship between cognitive deficits, brain activation abnormalities and symptoms in schizophrenia.

EEG phase synchronization in patients with paranoid schizophrenia

Recent findings suggest that specific deficits in neural synchrony and binding may underlie cognitive disturbances in schizophrenia and that key aspects of schizophrenia pathology involve discoordination and disconnection of distributed processes in multiple cortical areas associated with cognitive deficits. In the present study we aimed to investigate the underlying cortical mechanism of disturbed frontal-temporal-central-parietal connectivity in schizophrenia by examination of the synchronization patterns using wavelet phase synchronization index and coherence between all defined couples of 8 EEG signals recorded at different cortical sites in its relationship to positive and negative symptoms of schizophrenia. 31 adult schizophrenic outpatients with diagnosis of paranoid schizophrenia (mean age 27.4) were assessed in the study. The obtained results present the first quantitative evidence indicating direct relationship between wavelet phase synchronization and coherence in pairs of EEG signals recorded from frontal, temporal, central and parietal brain areas and positive and negative symptoms of schizophrenia. The performed analysis demonstrates that the level of phase synchronization and coherence in some pairs of EEG signals is inversely related to positive symptoms, negative symptoms and general psychopathology in temporal scales (frequency ranges) given by wavelet frequencies (WFs) equal to or higher than 7.56 Hz, and positively related to negative symptoms in wavelet frequencies equal to or lower than 5.35 Hz. This finding suggests that higher and lower frequencies may play a specific role in binding and connectivity and may be related to decreased or increased synchrony with specific manifestation in cognitive deficits of schizophrenia.

The selective α7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain: Differential effects in the juvenile and adult rat

Due to the cognitive-enhancing properties of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists, they have attracted interest for the treatment of cognitive disturbances in schizophrenia. Schizophrenia typically presents in late adolescence or early adulthood. It is therefore important to study whether alpha7 nAChR stimulation activates brain regions involved in cognition in juvenile as well as adult individuals. Here, we compared the effects of the novel and selective alpha7 nAChR agonist 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) in the juvenile and adult rat forebrain using two markers, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos, to map neuronal activity. Acute administration of A-582941 (1, 3, 10 mg/kg) induced a dose-dependent increase in Arc mRNA expression in the medial prefrontal cortex (mPFC) and the ventral/lateral orbitofrontal (VO/LO) cortex of juvenile, but not adult rats. This effect was mitigated by the alpha7 nAChR antagonist methyllycaconitine. A-582941 also increased c-Fos mRNA expression in the mPFC of juvenile, but not adult rats. Furthermore, A-582941 increased the number of Arc and c-Fos immunopositive cells in the mPFC, VO/LO, and shell of the nucleus accumbens, in both juvenile and adult rats. The A-582941-induced c-Fos protein expression was significantly greater in the mPFC and VO/LO of juvenile compared with adult rats. These data indicate that A-582941-induced alpha7 nAChR stimulation activates brain regions critically involved in working memory and attention. Furthermore, this effect is more pronounced in juvenile than adult rats, indicating that the juvenile forebrain is more responsive to alpha7 nAChR stimulation. This observation may be relevant in the treatment of juvenile-onset schizophrenia.

Serotonin-1A agonists as a cognitive enhancer in schizophrenia: Clinical evidence

Background and Aims:Postmortem and PET studies indicate increased serotonin (5-HT)-5-HT1A receptor density in frontal and temporal cortices in schizophrenia, suggesting up-regulation secondary to diminished 5-HT1A-receptor stimulation. We previously conducted a series of pilot studies of the effects of the addition of tandospirone, a 5-HT1A partial agonist and azapirone derivative, to ongoing treatment with small to moderate doses of typical antipsychotic drugs, on cognitive function in patients with schizophrenia. The addition of tandospirone (30 mg/day), but not placebo, for 4 to 6 weeks was found to improve executive function and verbal learning and memory.Methods and Results:We have conducted a randomly-assigned placebo-controlled double-blind study to investigate the ability of the addition of buspirone to enhance cognitive function in subjects with schizophrenia treated with atypical antipsychotic drugs (AAPDs). Buspirone, 30 mg/day, outperformed placebo in improving the performance on a measure of attention/speeded motor performance and index of general cognitive function. The distinct cognition-enhancing ability of buspirone suggests its usefulness for patients who have large deficits in attention in spite of treatment with AAPDs.Conclusions:The findings from these clinical studies indicate 5-HT1A receptors are a promising target for the management of psychotic symptoms and cognitive disturbances of schizophrenia. This concept has prompted the development of novel antipsychotic compounds with agonist actions at 5-HT1A receptors, e.g. F156063, SLV313, SSR181507, and bifeprunox. Evidence from basic studies with these drugs suggests an optimal balance of activity at 5-HT1A and dopamine-D2 receptors is required to gain cognitive benefits, which deserves further investigations.

The assessment of cognitive impairment would be a relevant addition to the criteria for diagnosing schizophrenia

The paper by Keefe reviews in a comprehensive and balanced way the findings on cognitive disturbances in schizophrenia. These disturbances are prevalent years before the psychotic breakdown, are only partially associated with acute psychotic symptoms, are more or less stable or can even increase over the longitudinal course of schizophrenia. In cross-sectional assessments, they are closely associated with social functioning and are more pronounced in patients diagnosed with schizophrenia than in those with (non-psychotic) affective disorders. All these are good reasons for Keefe to suggest that cognitive impairment should be included in the diagnostic criteria for schizophrenia. I fully agree with this suggestion. The inclusion of cognitive impairment would correspond very well to the traditional concept of dementia praecox/schizophrenia as proposed by Kraepelin and Bleuler. Kraepelin's term “dementia praecox” emphasized the importance of cognitive deterioration, although it alluded also to the change of personality in terms of negative symptoms. Similarly, Bleuler regarded cognitive alterations and negative symptoms as core symptoms of schizophrenia, while delusions and hallucinations were considered accessory symptoms. The predominance of positive symptoms in the concept of schizophrenia was established later on, especially with Schneider's concept of first-rank symptoms, and endorsed by our modern diagnostic systems, the DSM-IV and the ICD-10. The interest in the core symptoms of schizophrenia, including cognitive impairment, was revived by the introduction of second-generation antipsychotics, which are believed to have a somewhat stronger impact than older antipsychotics on both negative symptoms and cognitive disturbances 1. The focus on these core dimensions of schizophrenia could result in the development of drugs mainly targeted at cognitive deficit, but also able to treat positive symptoms. It is also important to stress that, in the context of the neurodevelopmental theory, cognitive disturbances are interpreted as being a vulnerability marker indicative of subtle brain alterations, and that modern neurogenetics applies cognitive impairment as an endophenotype 2–4. In the old days, the group of cognitive deficits consisted primarily of those disturbances which can be observed directly during psychiatric examination, such as deficits in attention and abstract thinking, thought blocking, incoherence, etc. These symptoms are still included in some schizophrenia rating scales, such as the Positive and Negative Syndrome Scale (PANSS). Nowadays, neurocognitive tests are able to assess cognitive impairment objectively and reliably and to describe the disturbances in verbal fluency, working memory, executive control, visual and verbal memory, and mental speed. There is no doubt that neurocognitive testing would be the proper way to diagnose cognitive deficits in schizophrenia. However, it should be kept in mind that, to my knowledge, thought disorders like thought blocking or incoherence are not covered by these tests. The question whether neurocognitive testing can be performed in the frame of routine care, as addressed by Keefe, is of course of great importance. Although several West European countries and the United States have a long tradition of psychological test assessments in the routine care of hospitalized patients, there are other regions of the world where this is not affordable. A categorical criterion, which is primarily based on clinical explorations of the patient and his relatives, might therefore be preferable. I think that a test battery specifically developed for the assessment of cognitive disturbances in schizophrenia, like the MATRICS 5, might complicate the test procedure in psychiatric hospitals or outpatient facilities. It seems more pragmatic to apply those neurocognitive test batteries which are used in the routine care of each facility. Of course, when it comes to research, an internationally standardized procedure like the MATRICS would be the best option. I definitely support Keefe's view that the inclusion of cognitive impairment in the diagnostic criteria for schizophrenia would enrich the diagnostic concept and hopefully contribute towards a better definition of a “point of rarity” between schizophrenia and affective psychosis. If DSM-V and ICD-11 follow a dimensional approach, including negative and cognitive symptoms as separate dimensions beside positive symptoms, it may be possible to achieve both a better differential diagnosis and a more powerful prognostic differentiation. I believe that such a dimensional approach, as an additional descriptive level to a categorical differentiation between schizophrenia and affective disorders or as a primarily syndromic classification of a broad psychosis category, could represent a fruitful improvement of our current diagnostic systems 6,7.

Decreased numerical density of CA3 hippocampal mossy fiber synapses in schizophrenia

The CA3 region of the hippocampus is unique in its connectivity, its role in cognitive maintenance, and its great vulnerability in schizophrenia. The down regulation of the expression and binding activity of glutamate receptors was revealed in the CA3 hippocampal region and may be attributed to cognitive disturbances in schizophrenia. Our previous study demonstrated that only schizophrenics with predominantly positive (but not predominantly negative) symptoms had smaller-sized branched spines (thorny excrescences) of CA3 pyramidal neurons and fewer synaptic contacts formed by dentate mossy fiber terminals (MFT-synapses). In the present study, we used an unbiased stereological physical dissector method to verify whether the numerical density of MFT-synapses is altered in schizophrenia. A morphometric study was performed in 10 normal controls and eight age-matched cases with chronic schizophrenia, including five cases with predominantly positive and three with predominantly negative symptoms. Schizophrenic cases had a significantly reduced numerical density of MFT-synapses (-25%, P < 0.01) compared with the control group. The decrease was similar in schizophrenic subgroups with predominantly positive and predominantly negative symptoms. No effects of postmortem delay, age, duration of disease, and neuroleptic exposure were found. Taken together with our previous results, the data suggest that the decrease of numerical density of MFT-synapses may be the result of different mechanisms in schizophrenics with predominantly positive and predominantly negative symptoms.

Alpha‐7 nicotinic acetylcholine receptor agonists selectively activate limbic regions of the rat forebrain: An effect similar to antipsychotics

It is considered that activation of nicotinic alpha7 receptors (alpha7 nAChR) is useful for the treatment of cognitive disturbances in schizophrenia and Alzheimer's disease. Recently, selective alpha7 nAChR agonists have been discovered and are used to validate the alpha7 nAChR as a drug target for the treatment of cognitive disturbances in schizophrenia. One important feature shared by all known antipsychotics is their capacity to induce expression of the neuronal immediate-early gene c-fos in the limbic forebrain. Using two novel and selective alpha7 nAChR agonists, PNU-282987 and SSR180711, we investigated their ability to induce c-Fos expression in the limbic forebrain with particular emphasis on the same regions reported to be activated by antipsychotics. Both alpha7 nAChR agonists increased c-Fos dose-dependently in the prefrontal cortex and the shell of nucleus accumbens, while leaving the core of nucleus accumbens and the dorsolateral striatum unaffected. The accumbal and cortical effect of SSR180711 was blocked completely by pre-administration of the alpha7 nAChR antagonist methyllycaconitine. Also, SSR180711 displayed no c-Fos-inducing effect in alpha7 nAChR knock-out mice. In conclusion, these results show that selective pharmacologic stimulation of alpha7 nAChR function results in activation of forebrain regions similar to conventional antipsychotics.

Habenula lesions alter synaptic plasticity within the fimbria–accumbens pathway in the rat

Both the habenula and the nucleus accumbens, and especially the glutamatergic innervation of the latter from the hippocampus, have been hypothesized to be involved, in different ways, in the pathophysiology of cognitive disturbances in schizophrenia. Lesions of the habenula produce disturbances of memory and attention in experimental animals. As the habenular nuclei have been shown to influence the release of many neurotransmitters, both in the hippocampus and the nucleus accumbens, we examined in this study the effects of bilateral habenula lesions on the plasticity of the fimbria–nucleus accumbens pathway, by means of the long-term depression phenomenon in freely moving rats. Long-term depression, induced within the shell region of the nucleus accumbens by low-frequency stimulation of the fimbria, was exaggerated and showed greater persistence in habenula-lesioned rats compared with sham-operated animals. These results indicate that plasticity in the fimbria–nucleus accumbens pathway is altered by habenula lesions in a way similar to previously-reported effects of stress and the psychosis-provoking agent ketamine. Moreover, they strengthen the views that the habenula belongs to systems, mediating higher cognitive functions, which involve the hippocampus and the nucleus accumbens. Finally, this study suggests that dysfunction of the habenula could contribute to cognitive alterations in diseases such as schizophrenia, where the habenula is reported to exhibit exaggerated calcification.

Lateralized cognitive dysfunction and psychotic symptoms in schizophrenia

Our understanding of hemispheric asymmetries in schizophrenia can be attributed to extensive neuropsychological and neuroimaging research on this topic; however, it has yet to be determined whether lateralized cognitive dysfunction represents a single core trait in schizophrenia or whether the lateralized impairments are domain specific. To test whether lateralized deficits are core features in schizophrenia we examined performance across a wide range of lateralized cognitive domains including attention, fluency, recognition memory, perception, and arousal. We also examined the relationship between lateralized impairments and psychotic and affective symptoms to determine whether abnormal hemispheric asymmetries were possibly state-related. The sample consisted of 43 subjects with schizophrenia and 66 normal healthy comparison subjects without psychiatric illness. Schizophrenia subjects exhibited abnormal right hemisphere performance on a test of recognition memory and abnormal left hemisphere performance on a measure of arousal. These findings suggest that lateralized cognitive disturbances in schizophrenia do not represent a single core lateralized deficit. Regarding the symptom analyses, severity of positive symptoms was related to right hemisphere cognitive impairment (including fluency and recognition memory), whereas severity of negative symptoms was related to left hemisphere cognitive impairment (including fluency). Overall, our findings suggest that lateralized dysfunction can occur in both hemispheres in schizophrenia, and that the positive psychotic symptoms may relate more to right hemisphere impairment, whereas negative psychotic symptoms may related more to left hemisphere impairment.