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Schizophrenia is a mental disorder associated with profoundly disruptive positive and negative symptomology that result in difficulties building close relationships with others, performing daily tasks and sustaining independent living, resulting in poor social, vocational and occupational attainment (functional outcome). Mismatch Negativity (MMN) is a change in the sensory event-related potential that occurs in response to deviation from an established pattern of stimulation. Patients with schizophrenia show a reduction in MMN that is positively associated with impaired cognition and poor functional outcome. This has led to interest in MMN as a potential clinical and pre-clinical biomarker of fundamental neural processes responsible for reduced functional outcome. To date, relatively few studies have sought to assess MMN in non-human primates or rodents. The validity of these studies will be reviewed using criteria used to identify true deviance detection based MMN responses in human subjects. Although MMN has been difficult to establish in pre-clinical models the weight of evidence suggests that non-human animals show true deviance based MMN., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Schizophrenia patients exhibit abnormalities in several different auditory event-related potential (ERP) measures. It is unclear how these abnormalities relate to each other, since multiple measures are rarely acquired from the same sample. This study addressed two related questions: 1) Are specific auditory ERP measures differentially impaired in schizophrenia? 2) Do abnormalities co-aggregate within the same patients? Nine auditory ERP measures were acquired in a single testing session from 23 schizophrenia patients and 22 healthy subjects. Hierarchical oblique factor analysis revealed that these measures aggregated into four factors, with each loading primarily on a single factor. Patient deficits were observed for two independent factors: N100/mismatch negativity (MMN) and P3a/P3b. N100/MMN abnormalities were associated with symptoms of alogia and formal thought disorder. P3a/P3b abnormalities were associated with avolition, attentional disturbances and delusions. We conclude that deficits in different ERP measures of early sensory processing at the level of the auditory cortex co-occur in patients. These likely represent a single differential deficit indexing the physiological abnormality underlying impaired language and verbal processing. This is relatively independent of a higher cortical deficit that mediates cognitive stimulus evaluation and underlies deficits in motivation, attention and reality testing. Such multidimensional profiling of ERP abnormalities may help to clarify the clinical and genetic heterogeneity of schizophrenia.

Verbal fluency deficits in schizophrenia are difficult to interpret because the tasks are multi-factorial and groups differ in total words generated. We manipulated retrieval and switching demands by requiring alternation between over-learned sequences in which retrieval is relatively automatic (OS) and semantic categories requiring increased retrieval effort (SC). Controlled processing was also manipulated by including switching and non-switching conditions, and formal thought disorder (FTD) was assessed with the communication disorders index (CDI). The OS/SC semantic fluency paradigm was administered during fMRI to 13 patients with schizophrenia and 14 matched controls. Images were acquired on a 3 Tesla Siemens scanner using compressed image acquisition to allow for cued overt word production. Subjects alternated between OS, SC, OS-switch, SC-switch, and baseline blocks. Images were pre-processed in SPM-2, and a two-stage random effects analysis tested within and between group contrasts. There were no group performance differences. fMRI analysis did not reveal any group differences during the OS non-switching condition. Both groups produced expected activation in bilateral prefrontal and inferior parietal regions. However, during the SC condition patients had greater activation than controls in left prefrontal, right anterior cingulate, right superior temporal, bilateral thalamus, and left parietal regions. There was also evidence of patient over-activation in prefrontal, superior temporal, superior parietal, and visual association areas when a switching component was added. FTD was negatively correlated with BOLD response in the right anterior cingulate, cuneus and superior frontal gyrus during increased retrieval demand, and positively correlated with fMRI activation in the left lingual gyrus, right fusiform gyrus and left superior parietal lobule during increased switching demand. These results indicate that patients are able to successfully perform effortful semantic fluency tasks during non-speeded conditions. When retrieval is relatively automatic there does not appear to be an effect of schizophrenia on fMRI response. However, when retrieval and controlled processing demands increase, patients have greater activation than controls despite unimpaired task performance. This inefficient BOLD response may explain why patients are slower and less accurate on standard self-paced fluency tasks.

Objective: Schizophrenia patients have problems directing attention. Sustained attention requires ensuring that brain resources are focused on a selected target (top-down task) while ignoring irrelevant distractors (bottom-up interference). Whether patients have too little ability to focus or too much interference from distraction has not been clarified. The oddball paradigm embeds infrequent targets and distractors into the stimulus train, and schizophrenia deficits have been linked to diminished responses to both. Cerebral activity underlying abnormal attention can be examined with event-related functional magnetic resonance imaging., Method: A visual oddball task was presented to 22 patients with schizophrenia and 28 comparison subjects. Statistical probability maps reflecting blood-oxygenation-level-dependent changes were generated for infrequent targets and novel distractors relative to frequent standard stimuli. Activation was related to performance and symptoms., Results: Activation specific to targets and distractors was associated with faster performance. For targets, patients had diminished activation in superior temporal and frontal gyri, cingulate, thalamus, and basal ganglia. They had increased activation in right insula, mid-frontal gyrus, posterior cingulate, and left inferior parietal lobule. For distractors, patients showed less activation in occipital regions and left inferior parietal lobule but increased activation in parietal-occipital, right mid-frontal, and left inferior frontal gyri. Abnormal activation correlated with positive and negative symptoms., Conclusions: Abnormal activation in schizophrenia in response to attentional demands reflects both insufficient recruitment of brain systems required for target detection and overcommitment of resources for processing irrelevant distractors. Schizophrenia patients appear to have an inability both to focus on targets and ignore distraction.

Previous studies report birhinal impairments in odor identification in patients with schizophrenia and their family members. The authors employed unirhinal odor identification and detection threshold sensitivity tests in schizophrenia patients, healthy first-degree family members, and healthy comparison subjects. Patients and family members showed deficits in odor identification performance in both nostrils. Odor detection thresholds differed only between patients and healthy comparison subjects. Comparable odor identification deficits in both patients and healthy family members suggest that odor identification measures may serve as a sensitive endophenotypic vulnerability marker and that unirhinal olfactory measures are as precise, if not more so, than birhinal performance measures.

Objective: This study assessed the relationship between symptoms and cognitive measures at intake and functional outcome 2-8 years later (average 3 years) in first-episode and previously treated schizophrenia patients., Method: A composite cognitive score was assessed at intake to determine the influence of cognition on later functional outcome. At intake and follow-up, positive and negative symptoms were assessed with the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms, and affective symptoms were assessed with the Hamilton Depression Rating Scale. Level of function in seven domains (social function, occupational function, independent living, symptom severity, fullness of life, extent of psychiatric hospitalization, and overall level of function) at intake and follow-up was assessed with the Strauss-Carpenter Level of Function scale. The contributions of sex, education, and duration of illness to functional outcome were also examined., Results: The results indicated that symptoms at intake had distinct patterns of prognostic significance for functional outcome in previously treated patients, compared with first-episode patients. In addition, male and female patients differed in the degree to which initial symptoms were correlated with later function., Conclusions: Initial level of function, symptoms, sex, education, and duration of illness are all important predictors for functional outcome in patients with schizophrenia.

Objective: Patients with schizophrenia improve episodic memory accuracy when given organizational strategies through levels-of-processing paradigms. This study tested if improvement is accompanied by normalized frontotemporal function., Method: Event-related blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) was used to measure activation during shallow (perceptual) and deep (semantic) word encoding and recognition in 14 patients with schizophrenia and 14 healthy comparison subjects., Results: Despite slower and less accurate overall word classification, the patients showed normal levels-of-processing effects, with faster and more accurate recognition of deeply processed words. These effects were accompanied by left ventrolateral prefrontal activation during encoding in both groups, although the thalamus, hippocampus, and lingual gyrus were overactivated in the patients. During word recognition, the patients showed overactivation in the left frontal pole and had a less robust right prefrontal response., Conclusions: Evidence of normal levels-of-processing effects and left prefrontal activation suggests that patients with schizophrenia can form and maintain semantic representations when they are provided with organizational cues and can improve their word encoding and retrieval. Areas of overactivation suggest residual inefficiencies. Nevertheless, the effect of teaching organizational strategies on episodic memory and brain function is a worthwhile topic for future interventional studies.

First-episode schizophrenia (FE-SZP) presents a diagnostic challenge because of symptomatic overlap between the various causes of psychosis. An early and accurate diagnosis is important for the implementation of appropriate treatment, for determining prognosis and for identifying research participants. In an effort to facilitate early diagnosis, we followed a group of first-episode psychosis patients with a presumptive diagnosis of schizophrenia who were subsequently diagnosed at 6-month follow-up with either schizophrenia (n=104) or other psychiatric diagnoses (n=19). The two groups-first-episode schizophrenia and first-episode non-schizophrenia-were compared on measures of demographics, symptoms, quality of life, premorbid adjustment and lateral dominance. Odds ratios were calculated for each variable and all significant variables were entered into a multivariate prediction model. The model showed that higher levels of anhedonia and hallucinations increased the odds of a final diagnosis of schizophrenia. This predictive model was validated in a smaller group of patients.

Background: Individuals with schizophrenia have difficulty organizing words semantically to facilitate encoding. This is commonly attributed to organizational rather than semantic processing limitations. By requiring participants to classify and encode words on either a shallow (e.g., uppercase/lowercase) or deep level (e.g., concrete/abstract), the levels-of-processing paradigm eliminates the need to generate organizational strategies., Methods: This paradigm was administered to 30 patients with schizophrenia and 30 healthy comparison subjects to test whether providing a strategy would improve patient performance., Results: Word classification during shallow and deep encoding was slower and less accurate in patients. Patients also responded slowly during recognition testing and maintained a more conservative response bias following deep encoding; however, both groups showed a robust levels-of-processing effect on recognition accuracy, with unimpaired patient performance following both shallow and deep encoding., Conclusions: This normal levels-of-processing effect in the patient sample suggests that semantic processing is sufficiently intact for patients to benefit from organizational cues. Memory remediation efforts may therefore be most successful if they focus on teaching patients to form organizational strategies during initial encoding.

Diffuse cognitive impairment characterizes patients with schizophrenia throughout the course of illness. The deficits persist despite clinical improvement associated with neuroleptic intervention and are related to outcome. It is unclear whether treatment with atypical agents is associated with improved cognition that relates to symptoms and outcome. Using a set of computerized neurocognitive measures, we evaluated whether the effects of olanzapine are greater than practice effects for specific neurocognitive domains that could provide targets for large-scale randomized studies. We enrolled 19 patients with schizophrenia before initiation of treatment with olanzapine and 16 of them were examined at 6 weeks and 6 months of follow-up. They were compared to 34 healthy participants who enrolled, 24 of whom were evaluated longitudinally. Improvement exceeding practice effects was observed in patients for abstraction and spatial memory and the latter correlated with clinical improvement in negative symptoms. These results suggest that some effects of olanzapine may impact both symptoms and cognitive performance.

Objective: The authors used color photographs of emotional and neutral expressions to investigate recognition patterns of five universal emotions in schizophrenia., Method: Twenty-eight stable outpatients with schizophrenia (19 men and nine women) and 61 healthy subjects (29 men and 32 women) completed an emotion discrimination test that presented mild and extreme intensities of happy, sad, angry, fearful, disgusted, and neutral faces, balanced for gender and ethnicity. Analyses evaluated accuracy of identifying emotions as a function of intensity, diagnosis, and gender of poser and rater., Results: Patients performed worse than comparison subjects on recognition of all emotions and neutral faces combined, including mild and extreme expressions. For specific emotions, patients performed worse on recognition of fearful, disgusted, and neutral expressions. For all emotions except disgust, recognition of extreme intensity was better than recognition of mild intensity. However, patients showed less benefit from increased intensity for all emotions combined, and the difference was most pronounced for fear. Thus, patients were more impaired than healthy comparison subjects in identifying high-intensity expressions, even though this was an easier task than identifying low-intensity expressions. In the comparison of patterns of errors, patients and healthy subjects differed only in misattributions of neutral expressions; patients overattributed disgusted expressions and underattributed happy expressions., Conclusions: Patients with schizophrenia were impaired in overall emotion recognition, particularly fear and disgust, and did not benefit from increased emotional intensity. Error patterns indicate that patients misidentified neutral cues as negatively valenced.

The goal of the study was to develop and apply a predictive model approach to reduce the number of items collected for scales that yield a total summary score. A parsimonious subset of items from the 21-item Quality of Life Scale (QLS) that can accurately predict the total scale score was sought and evaluated in 198 patients with schizophrenia, using a statistical modeling approach. Two additional data sets were used for model validation: the subset of 101 patients used in the model construction who had the QLS administered approximately 1 year later and a new sample of 37 patients. Using only seven QLS items as predictors, the correlation was 0.9831 between the predicted and true QLS totals. Applying the model based for these seven QLS items, the correlations from the first and second validation data sets were 0.9791 and 0.9637, respectively. The study demonstrates that a small subset of items of the QLS predicts the entire 21-item scale with high accuracy. Two validation samples have confirmed the finding. This reduces the effort associated with scale administration and is likely to increase the assessment of an important functional domain. Such models can guide efforts for item reduction in other rating instruments.

Cognitive dysfunction in schizophrenia is well established with neuropsychological batteries, which have assessed multiple domains indicating diffuse deficits especially in processing related to frontotemporal systems. Two studies are reported examining the feasibility of the computerized neurocognitive scan to assess differential deficits in schizophrenia. In Study 1, we tested 53 patients and 71 controls with the traditional and computerized assessments counterbalanced in order. Both showed comparable generalized impairment in schizophrenia with differential deficits in executive functions and memory. The profile was replicated in Study 2 in a new sample of 68 patients and 37 controls, receiving only the computerized scan. The combined sample showed robust correlations between performance on both speed and accuracy measures of the neurocognitive scan and clinical variables, including premorbid adjustment, onset age, illness duration, quality of life, and severity of negative symptoms. These correlations were higher and more prevalent in women than men, who showed correlations predominantly for speed rather than accuracy. Neuroleptic exposure was associated with poorer performance only for speed of memory processing, and in men, this association was seen only for typical neuroleptics. We conclude that the computerized neurocognitive scan can be applied reliably in people with schizophrenia, yielding data that support its construct and criterion validity.