Comparisons of verbal fluency brain correlates between adults and adolescents suffering from schizophrenia spectrum disorders: A pilot study

Background and Objectives: Prefrontal cortex (PFC) dysfunctions leading to cognitive deficits refer to a core feature of schizophrenia spectrum disorders (SSD). This exploratory study compares the effect of SSD on two stages of maturation of PFC. Methods: Using functional magnetic resonance imaging (fMRI), we measured the brain correlates related to a verbal fluency task (a hallmark executive function test) in 12 patients with SSD: 6 adolescents (SSD-ado) and 6 adults (SSD-adu). Results: SSD-ado showed greater activation in insula, thalamus and hIP1 whereas SSDadu recruited more intensively precentral gyrus and temporal pole to resolve the task. Thus, adolescents with SSD seem to adopt less frontal mediated strategic processes. In contrast, adults seem to be able to use PFC mediated strategy despite the well-known deleterious effect of SSD on the PFC. Conclusions: This first exploratory study revealed that adults and adolescents with SSD seemed not to use the same strategy to resolve a verbal fluency task. Thus, despite the illness, which is known to have a deleterious influence on PFC, adult patients seem to be able to recruit these resources to perform an executive function task. Further studies are needed in order to confirm and extend these new and preliminary results (AU)

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Computerized Exercises to Promote Transfer of Cognitive Skills to Everyday Life.

In recent years, computerized and non-computerized cognitive remediation programs have been designed for both individual and group settings. We believe, however, that a common misconception lies in considering the efficiency of a cognitive remediation therapy as resulting from the sole use of a computer. This omits that metacognitive skills need also to be trained throughout the remediation phase. RECOS is a theory-based therapeutic approach designed to promote the transfer of cognitive skills to functional improvements. It involves working with one person at a time using both paper/pencil tasks and a set of interactive computer exercises. Paper/pencil exercises are used to promote problem-solving techniques and to help patients to find appropriate suitable strategies. During the following computerized 1-h session, therapists guide participants to the procedural dimension of the action, which refers to knowledge about doing things and relies on retrospective introspection. We assume that each patient has a rich and underestimated procedural knowledge he/she is not aware of. By providing complex and interactive environments, computerized exercises are recommended to bring this knowledge to light. When strategies used by the participant become conscious, conditional knowledge determines when and why to use them in real-life situations.

Increased activation in Broca's area after cognitive remediation in schizophrenia.

Functional magnetic resonance imaging (fMRI) was used to measure changes in cerebral activity in patients with schizophrenia after participation in the Cognitive Remediation Program for Schizophrenia and other related disorders (RECOS). As RECOS therapists make use of problem-solving and verbal mediation techniques, known to be beneficial in the rehabilitation of dysexecutive syndromes, we expected an increased activation of frontal areas after remediation. Executive functioning and cerebral activation during a covert verbal fluency task were measured in eight patients with schizophrenia before (T1) and after (T2) 14 weeks of RECOS therapy. The same measures were recorded in eight patients with schizophrenia who did not participate in RECOS at the same intervals of time (TAU group). Increased activation in Broca's area, as well as improvements in performance of executive/frontal tasks, was observed after cognitive training. Metacognitive techniques of verbalization are hypothesized to be the main factor underlying the brain changes observed in the present study.

Specific vs general cognitive remediation for executive functioning in schizophrenia: a multicenter randomized trial.

BACKGROUND: This study assesses the benefits of an individualized therapy (RECOS program) compared with the more general cognitive remediation therapy (CRT). METHODS: 138 participants took part with 65 randomized to CRT and 73 to RECOS. In the RECOS group, participants were directed towards one of five training modules (verbal memory, visuo-spatial memory and attention, working memory, selective attention or reasoning) corresponding to their key cognitive concern whereas the CRT group received a standard program. The main outcome was the total score on BADS (Behavioural Assessment of Dysexecutive Syndrome) and the secondary outcomes were: cognition (executive functions; selective attention; visuospatial memory and attention; verbal memory; working memory) and clinical measures (symptoms; insight; neurocognitive complaints; self-esteem). All outcomes were assessed at baseline (T1), week 12 (posttherapy, T2), and follow-up (week 36, i.e., 6months posttherapy, T3). RESULTS: No difference was shown for the main outcome. A significant improvement was found for BADS' profile score for RECOS at T2 and T3, and for CRT at T3. Change in BADS in the RECOS and CRT arms were not significantly different between T1 and T2 (+0.86, p=0.108), or between T1 and T3 (+0.36, p=0.540). Significant improvements were found in several secondary outcomes including cognition (executive functions, selective attention, verbal memory, and visuospatial abilities) and clinician measures (symptoms and awareness to be hampered by cognitive deficits in everyday) in both treatment arms following treatment. Self-esteem improved only in RECOS arm at T3, and working memory improved only in CRT arm at T2 and T3, but there were no differences in changes between arms. CONCLUSIONS: RECOS (specific remediation) and CRT (general remediation) globally showed similar efficacy in the present trial.

Encoding dysfunctions in a dynamic-static paradigm for visuospatial working memory in first-episode psychosis patients: a 2-year follow-up study.

AIM: To investigate static and dynamic visuospatial working memory (VSWM) processes in first-episode psychosis (FEP) patients and explore the validity of such measures as specific trait markers of schizophrenia. METHODS: Twenty FEP patients and 20 age-, sex-, laterality- and education-matched controls carried out a dynamic and static VSWM paradigm. At 2-year follow up 13 patients met Diagnostic and Statistical Manual (of Mental Health Disorders)--Fourth Edition (DSM-IV) criteria for schizophrenia, 1 for bipolar disorder, 1 for brief psychotic episode and 5 for schizotypal personality disorder. RESULTS: Compared with controls, the 20 FEP patients showed severe impairment in the dynamic VSWM condition but much less impairment in the static condition. No specific bias in stimulus selection was detected in the two tasks. Two-year follow-up evaluations suggested poorer baseline scores on the dynamic task clearly differentiated the 13 FEP patients who developed schizophrenia from the seven who did not. CONCLUSIONS: Results suggest deficits in VSWM in FEP patients. Specific exploratory analyses further suggest that deficit in monitoring-manipulation VSWM processes, especially involved in our dynamic VSWM task, can be a reliable marker of schizophrenia.

Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients.

In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2 g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex- and age- matched healthy controls (p=0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p=0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

Visuo-spatial processing in a dynamic and a static working memory paradigm in schizophrenia.

Recent findings suggest that the visuo-spatial sketchpad (VSSP) may be divided into two sub-components processing dynamic or static visual information. This model may be useful to elucidate the confusion of data concerning the functioning of the VSSP in schizophrenia. The present study examined patients with schizophrenia and matched controls in a new working memory paradigm involving dynamic (the Ball Flight Task - BFT) or static (the Static Pattern Task - SPT) visual stimuli. In the BFT, the responses of the patients were apparently based on the retention of the last set of segments of the perceived trajectory, whereas control subjects relied on a more global strategy. We assume that the patients' performances are the result of a reduced capacity in chunking visual information since they relied mainly on the retention of the last set of segments. This assumption is confirmed by the poor performance of the patients in the static task (SPT), which requires a combination of stimulus components into object representations. We assume that the static/dynamic distinction may help us to understand the VSSP deficits in schizophrenia. This distinction also raises questions about the hypothesis that visuo-spatial working memory can simply be dissociated into visual and spatial sub-components.

A first step toward cognitive remediation of voices: a case study.

Several studies have shown that source-monitoring errors are related to verbal hallucinations in schizophrenia. An exploratory pilot study has been carried out to investigate the possibility of training patients in how to avoid errors in source-monitoring. One patient with paranoid schizophrenia and persistent thought insertions was trained for 6 hours to use mnemonic techniques to compensate specific deficits in source-monitoring. Results show that the patient was able to improve his performance and maintain the acquired progress at a 1-month follow-up assessment. These preliminary results are interesting for developing a larger controlled study of cognitive remediation of source-monitoring deficits.

Event-related potentials during rule processing in schizophrenia.

Several studies have shown that schizophrenia is characterized by impaired frontal lobe functions, functions that are responsible, for example, for the management of rules, strategic reasoning, and selective attention. Using event-related potentials (ERP), we assessed the brain's electrical activity in a group of patients with schizophrenia (n=11) and a healthy control group (n=14) during a reaction time task requiring the use of a rule. ERP waves were compared with those elicited in a similar task based on a direct sensory association. In the control group, ERP analyses showed a negative wave moving from the posterior to the anterior regions of the scalp in a latency range of 250-400 ms. Then, the negativity remained at the frontal scalp region in a latency range of 400-800 ms. In this group, the amplitude was higher during the rule operation than during the sensory association task. In schizophrenic patients, the anteroposterior component of the negative wave was totally absent in both tasks, and we did not find a modulation of the ERP by the task. Frontal scalp negativity was observed, but its latency was longer and its amplitude lower than in the control group. We discuss these findings in terms of the frontoposterior disconnection hypothesis.

Distance estimation in a dynamic simulated environment: a visual field dependence problem?

Egocentric distance estimation implies that the subject perceives his own location in the environment. In a simulated environment, subjects have to transpose perceptively their own observation point in order to assume their virtual body position. As only visual information specifies this position, their ability to perceive the camera viewpoint should be linked to the field dependence independence factor (FDI). Field-independent subjects underestimated the mid-distance between their own virtual body position and a far-located target; their bisection was located between the projective (2-D) and the simulated (3-D) mid-distance which indicates their difficulty in considering the in-depth simulated spatial references. High correlations between the vertical estimation in the rod-and-frame test and the egocentric-distance-estimation task (with shifted camera) suggest a similar perceptive process in both tasks. This result is confirmed by the better performances of the field-dependent subjects in this condition. In conclusion, we discuss the relationship between FDI and the sense of presence in virtual environments.

[Cognitive remediation: a new approach for treating schizophrenia]. / La remédiation cognitive: une nouvelle approache pour le traitement de la schizophrénie.

Two years ago, the "E. Minkowski" section of the "Département Universitaire de Psychiatrie Adulte" in Lausanne (DUPA) developed a cognitive remediation program for young schizophrenic patients. Preliminary results indicate a significant improvement in cognitive performance in most patients. Despite encouraging results, cognitive remediation therapies for patients with schizophrenia are rarely used in our country. The importance of cognitive deficits contrasts with the lack of resources engaged for their remediation. Some hypotheses are discussed for understanding why the treatment of cognitive deficits in schizophrenia has been delayed.

Augmentation of induced visual gamma activity by increased task complexity.

Recently the study of induced gamma band oscillations has focused on their modulation by top-down processes, mainly attention. Numerous studies have observed an increase in induced gamma band energy with increases in covert selective attention and visual perception. The current study investigated the modulation of visually induced gamma band oscillations by top-down processes associated with task complexity. Fourteen human subjects performed a reaction time task under two experimental conditions that differed in task complexity. In one, subjects simply had to press one of four buttons that corresponded to a colour stimulus shown to the subject. In the second, the stimulus response mapping was altered by the implementation of a rule, thus increasing task complexity. Cortical electrical activity was recorded using a 65 electrode whole scalp electroencephalographic (EEG) net. The EEG activity was analysed using Morlet wavelets to produce time-frequency maps. Although induced gamma band activity was observed in both conditions, there was significantly greater energy during the rule-operation condition at approximately 276 ms after the appearance of the stimulus. This increase was localized to electrodes overlying the right-central parietal scalp. The results of this study show that top-down processes modulate the level of induced gamma band activity. We discuss these findings in terms of the role of gamma oscillations in the construction of a sensory representation useful for a correct motor response.

Stimulus and response ERP analyses of a two-level reaction time task.

Higher cognitive processes include the ability to reliably transform sensory or mnemonic information. These processes either occur automatically or they are consciously controlled. To compare these two types of information processing, we developed a reaction time task that requires either a rule operation or else a direct sensory association. We were interested in evaluating the brain's electrical activity corresponding to both tasks, using event-related potentials (ERPs). In order to gain complete insight into the electrical activity of a stimulus-response segment, we analyzed the ERPs corresponding to the processing of the stimulus and the ERPs corresponding to the preparation of the response. To complete the analysis, we also evaluated the lateralized readiness potential (LRP) matched to the stimulus and to the response onset. Compared with the sensory association task, rule operation generated a higher negative potential field at frontocentral scalp areas in a latency range of 312-512 ms after the stimulus. In contrast, the LRP showed a negative component in the sensory association task which was absent during the rule operation; the latency of the difference was in the range 374-532 ms after the stimulus. The ERP component obtained by the response onset analysis was more negative in the rule condition up to a latency of -214 ms before the generation of the movement; the effect was localized at frontal and central scalp regions. We failed to find any significant difference in the LRP matched to the response onset. These results suggest that the brain computation of the rule operation takes place approximately in the middle of the stimulus-response time interval and that it is an additive process to the sensory association response.

Reduced P300 amplitude in a visual recognition task in patients with schizophrenia.

We studied top-down visual processes in schizophrenia by analyzing visual event-related potentials (ERPs) during a gestalt recognition task, after subjects (patients with schizophrenia, n = 10; controls, n = 14) were trained to perceive three different geometrical shapes. Recognition performance of patients was poorer under both the figure and the nonfigure conditions then that of normal controls. ERPs analysis indicated that P300 amplitudes of the patients were significantly smaller than those of controls during correct figure detection trials. Moreover, topographical analysis of the differences in ERPs during the figure vs the nonfigure condition showed an earlier, more positive and more widely distributed P300 in controls than in patients with schizophrenia. Our study supports the misconnection hypothesis of schizophrenia and highlights the difficulty of the patients to refer to previous experience in order to filter incoming information. In a visual recognition task, this misconnection syndrome might induce a failure to integrate information stored in the frontal and prefrontal sites with incoming stimuli.