Saccadic Eye Movements in Elderly Depressed Patients With Suicidal Behaviors: An Exploratory Eye-Tracking Study.

Suicidal behaviors (SBs) are often associated with impaired performance on neuropsychological executive functioning (EF) measures that encourage the development of more specific and reliable tools. Recent evidence could suggest that saccadic movement using eye tracking can provide reliable information on EF in depressive elderly. The aim of this study was to describe oculomotor performances in elderly depressed patients with SB. To achieve this aim, we compared saccadic eye movement (SEM) performances in elderly depressed patients (N = 24) with SB and with no SB in prosaccade (PS) and antisaccade (AS) tasks under the gap, step, and overlap conditions. All participants also underwent a complete neuropsychological battery. Performances were impaired in patients with SB who exhibited less corrected AS errors and longer time to correct them than patients with no SB. Moreover, both groups had a similar performance for PS latencies and correct AS. These preliminary results suggested higher cognitive inflexibility in suicidal patients compared to non-suicidal. This inflexibility may explain the difficulty of the depressed elderly in generating solutions to the resurgence of suicidal ideation (SI) to respond adequately to stressful environments. The assessment of eye movement parameters in depressed elderly patients may be a first step in identifying high-risk patients for suicide.

Repetitive Transcranial Magnetic Stimulation as an Add-On Treatment for Cognitive Impairment in Alzheimer's Disease and Its Impact on Self-Rated Quality of Life and Caregiver's Burden.

Alzheimer's disease (AD) is associated with progressive memory loss and decline in executive functions, as well as neuropsychiatric symptoms. Patients usually consider quality of life (QoL) and mood as more important for their health status than disease-specific physical and mental symptoms. In this open-label uncontrolled trial, 12 subjects diagnosed with AD underwent 10 sessions of repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (10 Hz, 20 min, 2000 pulses/day, 110% MT). Outcomes were measured before and 30 days after treatment. Our primary objective was to test the efficacy of rTMS as an add-on treatment for AD on the global cognitive function, assessed through the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS). As secondary objectives, the detailed effect on cognitive functions, depression and anxiety symptoms, QoL, and functionality in daily life activities were evaluated, as well as correlations between QoL and cognition, depression and anxiety scores. The treatment significantly enhanced semantic memory and reduced anxiety. Improvement of these features in AD could become an important target for treatment strategies. Although limited by its design, this trial may contribute with another perspective on the analysis and the impact of rTMS on AD.

[Neurodevelopmental disorders modify neurodegenerative diseases: a medical history to screen in memory clinic]. / Les troubles neurodéveloppementaux miment ou influencent les pathologies neurodégénératives : prise en compte des antécédents neurodéveloppementaux en consultation mémoire.

Neurodevelopmental disorders are frequent in the general population and are often lifelong conditions despite sometimes being masked by conscious or unconscious compensation and avoidance mechanisms. These conditions are often unknown or underestimated in adults, even when diagnosed in childhood. Neurodevelopmental disorders share similarities with and frequently interact in a complex way with neurodegenerative disorders. Considering these aspects during memory clinic assessments can provide a new perspective on lifelong neurocognitive trajectories. Assessing both neurodevelopmental and neurodegenerative dimensions is challenging but should improve diagnostic accuracy. It is therefore necessary to understand the lifelong specific neurocognitive trajectory of each patient in order to develop personalized and focused cognitive medicine and care.

(±)-BIGI-3h: Pentatarget-Directed Ligand combining Cholinesterase, Monoamine Oxidase, and Glycogen Synthase Kinase 3ß Inhibition with Calcium Channel Antagonism and Antiaggregating Properties for Alzheimer's Disease.

Multitarget-directed ligands (MTDLs) are considered a promising therapeutic strategy to address the multifactorial nature of Alzheimer's disease (AD). Novel MTDLs have been designed as inhibitors of human acetylcholinesterases/butyrylcholinesterases, monoamine oxidase A/B, and glycogen synthase kinase 3ß and as calcium channel antagonists via the Biginelli multicomponent reaction. Among these MTDLs, (±)-BIGI-3h was identified as a promising new hit compound showing in vitro balanced activities toward the aforementioned recognized AD targets. Additional in vitro studies demonstrated antioxidant effects and brain penetration, along with the ability to inhibit the aggregation of both τ protein and ß-amyloid peptide. The in vivo studies have shown that (±)-BIGI-3h (10 mg/kg intraperitoneally) significantly reduces scopolamine-induced cognitive deficits.

Comparison of Noninvasive Imagery Methods to Observe Healthy and Degenerated Olfactory Epithelium in Mice for the Early Diagnosis of Neurodegenerative Diseases.

Olfactory dysfunction could be an early and reliable indicator for the diagnosis of neurodegenerative disorders such as Alzheimer and Parkinson's diseases. In this paper, we compare the potential of different noninvasive medical imaging modalities (optical coherence tomography, confocal microscopy, and fluorescence endomicroscopy) to distinguish how the olfactory epithelium, both at the cellular and the structural levels, is altered. Investigations were carried out on three experimental groups: two pathological groups (mice models with deliberately altered olfactory epithelium and Alzheimer's disease transgenic mice models) were compared with healthy mice models. As histological staining, the three tested noninvasive imaging tools demonstrated the general tubular organization of the olfactory epithelium on healthy mice. Contrary to OCT, confocal microscopy, and endomicroscopy allowed visualizing the inner structure of olfactory epithelium as well as its morphological or functional changes on pathological models, alterations classically observed with histological assessment. The results could lead to relevant development of imaging tools for noninvasive and early diagnosis of neurodegenerative diseases through the in situ characterization of the olfactory epithelium.

How do adolescents regulate distress according to attachment style? A combined eye-tracking and neurophysiological approach.

According to attachment theory, attachment representations influence emotion regulation (ER) across the lifespan. However, research into attachment-related ER in adolescence is still scarce. The aim of this study was to assess attachment-related ER using a multimodal approach, relying on behavioral and neurophysiological parameters. Attachment styles in eighty-one adolescents were assessed with the Attachment Style Interview (ASI). A distress-then-comfort paradigm based on visual stimuli (the Besancon Affective Picture Set-Adolescents) was employed to "activate" then "deactivate" the attachment system. Gaze and neurophysiological parameters of ER strategies were assessed using eye-tracking synchronized with a physiological device. During the first phase "distress exposure", attachment style was associated with the early stage of distress processing indexed by first fixation duration. Withdrawn adolescents fixated distress pictures less than other groups. Fearful adolescents showed a longer first fixation duration than withdrawn adolescents. During the following phase, "comfort-seeking", all groups initially fixed joy-complicity and comfort pictures earlier than neutral pictures, except for withdrawn adolescents, who fixated comfort pictures later than neutral pictures. Additionally, withdrawn adolescents explored comfort pictures less than enmeshed adolescents. Enmeshed adolescents explored neutral pictures less than comfort and joy-complicity pictures. Concerning neurophysiological parameters, first fixation duration correlated positively with Skin Conductance Response (SCR) rise time in fearful adolescents, while glance count correlated negatively with SCR latency in withdrawn adolescents. This study provides an innovative and objective evaluation of behavioral and neurophysiological parameters for attachment-related ER in adolescents, with a temporal resolution. These parameters constitute potential biomarkers that could contribute to our understanding of ER differences in insecure adolescents. This study was registered with the clinical trials database ClinicalTrials.gov on August 01, 2016, under the number NCT02851810.

The Besançon affective picture set-adult (BAPS-Adult): Development and validation.

We developed and validated a new picture database of attachment-related photographs, the BAPS-Adult. Participants (N = 315) rated 256 pictures, according to dimension (valence, arousal, and dominance) using Self-Assessment Manikins (SAM), emotional category (positive, negative, mixed, and neutral) using labels, and discrete emotion (comfort, joy, complicity, distress, horror, and hate) using linear scales. Pictures were then classified into four types, depending on content (distress, comfort, complicity-joy, and neutral). Dimensional ratings of valence, arousal, and dominance, as well as discrete emotion ratings, differed significantly from each other between picture types. The BAPS-Adult is a new, highly discriminated database, allowing researchers to select from a variety of pre-rated, attachment-related pictures.

Evidence for a neural signature of musical preference during silence.

One of the most basic and person-specific affective responses to music is liking. The present investigation sought to determine whether liking was preserved during spontaneous auditory imagery. To this purpose, we inserted two-second silent intervals into liked and disliked songs, a method known to automatically recreate a mental image of these songs. Neural correlates of musical preference were measured by high-density electroencephalography in twenty subjects who had to listen to a set of five pre-selected unknown songs the same number of times for two weeks. Time frequency analysis of the two most liked and the two most disliked songs confirmed the presence of neural responses related to liking. At the beginning of silent intervals (400-900 ms and 1000-1300 ms), significant differences in theta activity were originating from the inferior frontal and superior temporal gyrus. These two brain structures are known to work together to process various aspects of music and are also activated when measuring liking while listening to music. At the end of silent intervals (1400-1900 ms), significant alpha activity differences originating from the insula were observed, whose exact role remains to be explored. Although exposure was controlled for liked and disliked songs, liked songs were rated as more familiar, underlying the strong relationship that exists between liking, exposure, and familiarity.

Saccadic Eye Movements and Attentional Control in Alzheimer's Disease.

OBJECTIVE: Several studies have demonstrated saccadic eye movement (SEM) abnormalities in Alzheimer's disease (AD) when patients performed prosaccade (PS) and antisaccade (AS) tasks. Some studies have also showed that SEM abnormalities were correlated with dementia rating tests such as the Mini Mental State Evaluation (MMSE). Therefore, it has been suggested that SEMs could provide useful information for diagnosis. However, little is known about predictive saccades (PreS)-saccades triggered before or very quickly after stimuli appearance-and their relationships with cognition in AD. Here, we aimed to examine the relationships between our usual dementia screening tests and SEM parameters in PS, AS, and also PreS task. METHOD: We compared SEMs in 20 patients suffering from AD and in 35 healthy older adults (OA) in PS, AS, and PreS task. All participants also completed a neuropsychological evaluation. RESULTS: We showed that AD patients had higher latency and latency variability regardless the tasks, and also higher AS cost, in comparison with OA. Moreover, AD patients made more uncorrected AS and took more time-to-correct incorrect AS. In PreS task, AD patients showed higher gain and gain variability than OA when they made anticipated saccades. Close relationships were found between the majority of SEM variables in PS, AS, and PreS tasks and dementia screening tests, especially the MMSE and episodic memory measures. CONCLUSION: Our findings, in agreement with previous studies, demonstrated that AD affects several SEM parameters. SEM abnormalities may reflect selective and executive-attention impairments in AD.

The antidepressant-like effect of tDCS in mice: A behavioral and neurobiological characterization.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-invasive method increasingly popular for the treatment of several brain disorders, such as major depression. Despite great enthusiasm and promising results, some studies report discrepant findings and no consensus exists for the clinical use of tDCS. OBJECTIVE: The present study aims to (i) determine the most effective stimulation parameters to optimize antidepressant-like effect of tDCS in the forced-swim test in mice and (ii) identify brain regions recruited by tDCS and possibly involved in its behavioral effect using Fos immunohistochemistry. RESULTS: We reported that tDCS induced long-lasting antidepressant-like effect, which varied as a function of stimulation settings including number, duration, intensity and polarity of stimulation. Interestingly, the present study also demonstrated that tDCS reduced depressive-like behaviors induced by chronic corticosterone exposure. Furthermore, behavioral outcomes induced by a single stimulation were associated with neuronal activation in the prefrontal cortex, dorsal hippocampus, ventral tegmental area and nucleus accumbens, whereas no overexpression of c-fos was associated with 10 stimulations. CONCLUSION: The strongest behavioral response was observed with an anodal stimulation of 200 µA during 20min. The repetition of this stimulation was necessary to induce long-lasting behavioral effects that are probably associated with plastic changes in the neuronal response.

Effects of Intranasal Oxytocin on Emotion Regulation in Insecure Adolescents: Study Protocol for a Double-Blind, Randomized Controlled Trial.

BACKGROUND: Emotional dysregulation and impaired attachment are potential contributors to the development of psychopathology in adolescence. This raises the question of whether oxytocin (OT), the paradigmatic "attachment hormone," may be beneficial in such contexts. Recent evidence suggests that intranasal administration of OT increases affiliative behavior, including trust and empathy. OT may also facilitate social reciprocity by attenuating the stress response to interpersonal conflict. To date, few studies have investigated the effects of intranasal oxytocin (IN-OT) on neurophysiological emotion regulation strategies in healthy adolescents, particularly during parent-adolescent interaction. To understand these mechanisms, our study will examine the effects of IN-OT on emotion regulation in adolescents during parent-adolescent stressful interactions, and on each adolescent's visual and neurophysiological strategies when visualizing attachment-related pictures. We hypothesize that IN-OT will influence psychophysiological outcomes under conditions of stress. We predict that IN-OT will momentarily increase feelings of safety and attenuate stress and hostile behavior during conflict situations. OT may also enhance attachment security by increasing comfort and proximity-seeking, and reducing neurophysiological hyperactivation. OBJECTIVE: The objective of this study is to evaluate the effects of IN-OT on insecure adolescents by studying their behavior and discourse during a disagreement with one of their parents. Their neurophysiological responses to pictures eliciting attachment-related emotions and their visual exploration strategies will also be investigated. METHODS: In this randomized, double-blind, placebo-controlled parallel-group design, 60 healthy male adolescents classified as insecurely attached will receive 24 international units (IU) of IN-OT versus placebo (PB), 45 minutes before the experimental tasks. Each adolescent will then be invited to engage in an experimental conflict discussion with one of his parents. The conflict session will be videotaped and coded for verbal and non-verbal interaction behavior, using the Goal-Corrected Partnership in Adolescence Coding System (GPACS). Each adolescent will then be asked to visualize attachment-related pictures on a screen. Eye-tracking (ET) and neurophysiological responses, including electrodermal activity (EDA) and heart rate (HR), will be recorded simultaneously and continuously during attachment-related picture viewing (Besançon Affective Picture Set-Adolescents, BAPS-Ado). RESULTS: Enrollment for the study was completed in May 2016. Data analysis commenced in July 2016. Study results will be submitted for publication in the winter of 2017. CONCLUSIONS: OT is a complex molecule with many facets that are not yet fully understood. This experimental protocol will increase scientific and clinical knowledge of emotion regulation skills in insecure adolescents by assessing the impact of IN-OT on parent-adolescent interaction and on the visual processing of attachment-related emotions. Positive results could lead to therapeutic uses of IN-OT to treat emotion dysregulation in adolescence.

Left Prefrontal Repetitive Transcranial Magnetic Stimulation in a Logopenic Variant of Primary Progressive Aphasia: A Case Report.

BACKGROUND/AIMS: High frequency repetitive transcranial magnetic stimulation (hf-rTMS) improves language skills in Alzheimer's disease (AD). We report the use of hf-rTMS in a patient with logopenic primary progressive aphasia (LPPA) due to AD. METHOD: hf-rTMS was applied to the left dorsolateral prefrontal cortex of a LPPA patient. Cerebral perfusion, neuropsychological and linguistic performances were evaluated before and 1 month after hf-rTMS. RESULTS: The tolerance was good. Improvements on linguistic (fluency, naming, lesser paraphasia) and cognitive skills (Mini Mental State Examination, verbal memory free recall, speed processing) and cerebral perfusion were observed. CONCLUSION: hf-rTMS can be used in LPPA patients. A procognitive effect persisting several weeks after stimulation in LPPA patients was suggested and should therefore be evaluated in a clinical trial as an adjunctive therapeutic tool.

Don't forget the lyrics! Spatiotemporal dynamics of neural mechanisms spontaneously evoked by gaps of silence in familiar and newly learned songs.

The vast majority of people experience musical imagery, the sensation of reliving a song in absence of any external stimulation. Internal perception of a song can be deliberate and effortful, but also may occur involuntarily and spontaneously. Moreover, musical imagery is also involuntarily used for automatically completing missing parts of music or lyrics from a familiar song. The aim of our study was to explore the onset of musical imagery dynamics that leads to the automatic completion of missing lyrics. High-density electroencephalography was used to record the cerebral activity of twenty healthy volunteers while they were passively listening to unfamiliar songs, very familiar songs, and songs previously listened to for two weeks. Silent gaps inserted into these songs elicited a series of neural activations encompassing perceptual, attentional and cognitive mechanisms (range 100-500ms). Familiarity and learning effects emerged as early as 100ms and lasted 400ms after silence occurred. Although participants reported more easily mentally imagining lyrics in familiar rather than passively learnt songs, the onset of neural mechanisms and the power spectrum underlying musical imagery were similar for both types of songs. This study offers new insights into the musical imagery dynamics evoked by gaps of silence and on the role of familiarity and learning processes in the generation of these dynamics. The automatic and effortless method presented here is a potentially useful tool to understand failure in the familiarity and learning processes of pathological populations.

The Besançon Affective Picture Set-Adolescents (the BAPS-Ado): Development and validation.

Emotional pictures are commonly used as visual stimuli in a number of research fields. Choosing relevant visual stimuli to induce emotion is fundamental in attachment and affective research. Attachment theory provides a theoretical basis for the understanding of emotional and relational problems, and is especially related to two specific emotions: distress and comfort. The lack of normalized visual stimuli soliciting these attachment-related emotions has led us to create and validate a new photographic database: the Besançon Affective Picture Set-Adolescents. This novel stimulus set is composed of 93 photographs, divided into four categories: distress, comfort, joy-complicity and neutral. A group of 140 adolescents rated the pictures with the Self-Assessment Manikin system, yielding three dimensions: valence, emotional arousal, and dominance. The pictures were also assessed, using a continuous scale, for different emotions (distress, hate, horror, comfort, complicity and joy). The ANOVAs for arousal and the Kruskal-Wallis tests for valence and dominance showed strong effects for category. However, for comfort and complicity, the dimensions of valence and dominance were not significantly different, while results for arousal showed no significant difference between complicity and distress. Our study provides a tool that allows researchers to select visual stimuli to investigate attachment-related emotion processing in adolescence.

Neural Correlates of Successful and Unsuccessful Strategical Mechanisms Involved in Uncertain Decision-Making.

The ability to develop successful long-term strategies in uncertain situations relies on complex neural mechanisms. Although lesion studies have shown some of the mechanisms involved, it is still unknown why some healthy subjects are able to make the right decision whereas others are not. The aim of our study was to investigate neurophysiological differences underlying this ability to develop a successful strategy in a group of healthy subjects playing a monetary card game called the Iowa Gambling Task (IGT). In this task, subjects have to win and earn money by choosing between four decks of cards, two were advantageous in the long term and two disadvantageous. Twenty healthy right-handed subjects performed the IGT while their cerebral activity was recorded by electroencephalography. Based on their behavioral performances, two groups of subjects could clearly be distinguished: one who selected the good decks and thus succeeded in developing a Favorable strategy (9 subjects) and one who remained Undecided (11 subjects). No neural difference was found between each group before the selection of a deck, but in both groups a greater negativity was found emerging from the right superior frontal gyrus 600 ms before a disadvantageous selection. During the processing of the feedback, an attenuation of the P200 and P300 waveforms was found for the Undecided group, and a P300 originating from the medial frontal gyrus was found in response to a loss only in the Favorable group. Our results suggest that undecided subjects are hyposensitive to the valence of the cards during gambling, which affects the feedback processing.

Visual scanning behavior during processing of emotional faces in older adults with major depression.

OBJECTIVES: Although several reported studies have suggested that younger adults with depression display depression-related biases during the processing of emotional faces, there remains a lack of data concerning these biases in older adults. The aim of our study was to assess scanning behavior during the processing of emotional faces in depressed older adults. METHOD: Older adults with and without depression viewed happy, neutral or sad portraits during an eye movement recording. RESULTS: Depressed older adults spent less time with fewer fixations on emotional features than healthy older adults, but only for sad and neutral portraits, with no significant difference for happy portraits. CONCLUSION: These results suggest disengagement from sad and neutral faces in depressed older adults, which is not consistent with standard theoretical proposals on congruence biases in depression. Also, aging and associated emotional regulation change may explain the expression of depression-related biases. Our preliminary results suggest that information processing in depression consists of a more complex phenomenon than merely a general searching for mood-congruent stimuli or general disengagement from all kinds of stimuli. These findings underline that care must be used when evaluating potential variables, such as aging, which interact with depression and selectively influence the choice of relevant stimulus dimensions.

Motor imagery in unipolar major depression.

BACKGROUND: Motor imagery is a potential tool to investigate action representation, as it can provide insights into the processes of action planning and preparation. Recent studies suggest that depressed patients present specific impairment in mental rotation. The present study was designed to investigate the influence of unipolar depression on motor imagery ability. METHODS: Fourteen right-handed patients meeting DSM-IV criteria for unipolar depression were compared to 14 matched healthy controls. Imagery ability was accessed by the timing correspondence between executed and imagined movements during a pointing task, involving strong spatiotemporal constraints (speed/accuracy trade-off paradigm). RESULTS: Compared to controls, depressed patients showed marked motor slowing on both actual and imagined movements. Furthermore, we observed greater temporal discrepancies between actual and mental movements in depressed patients than in healthy controls. Lastly, depressed patients modulated, to some extent, mental movement durations according to the difficulty of the task, but this modulation was not as strong as that of healthy subjects. CONCLUSION: These results suggest that unipolar depression significantly affects the higher stages of action planning and point out a selective decline of motor prediction.

Transcranial direct current stimulation for memory enhancement: from clinical research to animal models.

There is a growing demand for new brain-enhancing technologies to improve mental performance, both for patients with cognitive disorders and for healthy individuals. Transcranial direct current stimulation (tDCS) is a non-invasive, painless, and easy to use neuromodulatory technique that can improve performance on a variety of cognitive tasks in humans despite its exact mode of action remains unclear. We have conducted a mini-review of the literature to first briefly summarize the growing amount of data from clinical trials assessing the efficacy of tDCS, focusing exclusively on learning and memory performances in healthy human subjects and in patients with depression, schizophrenia, and other neurological disorders. We then discuss these findings in the context of the strikingly few studies resulting from animal research. Finally, we highlight future directions and limitations in this field and emphasize the need to develop translational studies to better understand how tDCS improves memory, a necessary condition before it can be used as a therapeutic tool.

Saccadic eye movements in depressed elderly patients.

The primary aim of this study was to characterize oculomotor performances in elderly depressed patients. The second aim was to investigate whether cognitive inhibition measured by the antisaccade task was associated with a psychomotor retardation or rather with a more specific cognitive-motor inhibition deficit. Twenty patients with a major depressive disorder and forty-seven healthy subjects performed two eye movement tasks. Saccadic reaction time and error rates were analyzed in the prosaccade task to obtain basic parameters of eye movements. Saccade latency, error rates and correction rates were evaluated in the antisaccade task to investigate inhibition capacities. Performances were impaired in patients, who exhibited a higher reaction time and error rates compared to controls. The higher time cost of inhibition suggested that the reaction time was not related to global psychomotor retardation alone. The higher time cost of inhibition could be explained by a specific alteration of inhibition processes evaluated by the antisaccade task. These changes were associated with the severity of depression. These findings provide a new perspective on cognitive inhibition in elderly depressed patients and could have important clinical implications for our understanding of critical behaviors involving deficits in inhibitory processes in the elderly.

Metacognitive training for schizophrenia: a multicentre randomised controlled trial.

A psychotherapeutic approach for schizophrenia is now recommended as an adjuvant for psychopharmacology, since antipsychotic medications only have a partial impact especially as regards positive symptoms and insight. In addition, cognitive distortions and the lack of metacognitive skills might increase positive symptoms leading to poor social functioning. This underlines the need for specific approaches which target cognitive processes relevant for insight, and abilities in metacognition. Metacognitive training (MCT) is a structured group intervention, which enhances a patient's reflection on cognitive biases and improves problem-solving. The aim of our study was to assess MCTs' short term impact on insight, symptoms and quality of life. Fifty patients with schizophrenia or schizoaffective disorders and persistent positive symptoms (delusions or hallucinations) were enrolled in the study. After baseline assessment participants were randomised either to supportive therapy or MCT. Both groups used the same design (1h-session twice a week during 8weeks) although the basic knowledge given to participants was different between interventions. Participants were assessed at eight weeks based on the Scale to Assess Unawareness of Mental Disorder, Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scales, the Calgary Depression Scale for Schizophrenia and the Quality of Life Scale. Between-group differences were significant in favour of MCT on the PANSS positive scale. Between-group differences in post- and pre-test values showed a trend in favour of MCT for insight on hallucinations. Results of our study indicate that the MCT has an effect on reducing positive symptomatology, and a trend impact on insight and social functioning.