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To examine whether schizotypal personality is associated with the degree to which concepts activate each other in semantic memory, event-related brain potentials (ERPs) were recorded during a delayed lexical decision task from healthy volunteers rated for schizotypy. Each target word was directly, indirectly, or not at all related to a prime word preceding it at a 300- or 750-ms stimulus-onset asynchrony (SOA). Overall, N400 amplitudes were largest for unrelated targets, smallest for directly related targets, and intermediate for indirectly related targets. Higher total Schizotypal Personality Questionnaire (SPQ) scores correlated with smaller N400 indirect priming effects (i.e., smaller N400 amplitude differences between unrelated and indirectly related targets) at both SOAs. In addition, schizotypal subscale scores were differentially associated with N400 effects. Higher SPQ Cognitive-Perceptual scores correlated with smaller N400 direct priming effects (smaller N400 amplitude differences between unrelated and directly related targets) at both SOAs, and with smaller N400 indirect priming effects at the shorter SOA. These correlations are consistent with the hypothesis that decreased use of meaningful context to activate related concepts in general, and/or to inhibit unrelated concepts, may play some role in the development of unusual beliefs.

The objective of the present study was to compare the pattern of motor activity in unmedicated schizophrenia patients and healthy subjects, and to examine whether the pattern was affected by treatment with typical and atypical antipsychotics. Twenty unmedicated schizophrenic patients wore a wrist actigraph for five days. The actigraph recorded activity levels in one-minute epochs. Patients' pattern of activity was compared with that of healthy subjects. Patients were randomly assigned to treatment with low-dose haloperidol or risperidone. The impact of treatment on the pattern of activity was examined. Compared to controls, untreated patients showed a diminished mean activity count during morning, early and late night periods. Treatment with haloperidol or risperidone at effective doses showed a significant effect on activity level, being more prominent with haloperidol. The results suggest that unmedicated schizophrenic patients exhibit abnormally low levels of motor activity as measured with an...

Disorganized speech, or thought disorder, in schizophrenia may reflect abnormal processing of meaningful concepts. To examine whether schizophrenia involves abnormalities in how a meaningful context influences processing of concepts strongly, weakly, or not related to it, we used the N400, an event-related brain potential (ERP) index of semantic relatedness. ERPs were recorded from schizophrenia patients (n = 18) and normal controls (n = 18) while they viewed category definitions (e.g., a type of fruit), each followed by a target word that was either a high-typicality category exemplar (apple), low-typicality exemplar (cherry), or non-exemplar (clamp). Participants' task was to indicate via button-press whether or not the target belonged to the category. In both patients and controls, N400 amplitude was largest (most negative) for non-exemplars, intermediate for low-typicality exemplars, and smallest (least negative) for high-typicality exemplars. Compared to controls, patients showed a trend toward reduced N400 amplitude differences between non-exemplars and low-typicality exemplars. Most importantly, within patients, reduced N400 amplitude differences between high- and low-typicality exemplars were correlated with psychotic symptoms. This association of an N400 index of semantic processing with psychotic symptoms suggests that psychosis in schizophrenia may be associated with greater similarity in how concepts strongly and weakly meaningfully related to their context are processed.

Disorganized speech in both schizophrenia and schizotypy has been hypothesized to result from abnormalities in how concepts activate one another in semantic memory. To study whether schizotypy is associated with differences in how categories activate their exemplars, we examined the N400 component of the event-related brain potential (ERP) elicited during a category-verification task. ERPs were recorded in young adults from the general population while they viewed category definitions each followed by a target that was either a high-typicality exemplar, low-typicality exemplar, or non-exemplar; participants' task was to indicate whether or not the target belonged to the category. Schizotypy was assessed via the Schizotypal Personality Questionnaire (SPQ). Overall, N400 amplitude was largest for non-exemplars, smallest for high-typicality exemplars, and intermediate for low-typicality exemplars. SPQ score was associated with decreased N400 amplitude to non-exemplars, and increased amplitude to both types of exemplars. SPQ score was negatively correlated with the N400 amplitude difference between non-exemplars and both low- and high-typicality exemplars, but was not correlated with the amplitude difference between low- and high-typicality exemplars. N400 amplitude differences between non-exemplars and both types of exemplars were correlated with the SPQ Interpersonal factor, but not the Disorganized factor. The results are consistent with an association of schizotypy with decreased use of context to activate related items and inhibit unrelated items.

Background: A role of the immune system in the pathogenesis of schizophrenia is supported by convergence of evidence from genetic, epidemiology, and preclinical studies. Previous positron emission tomography (PET) studies using radioligands that target the translocator protein 18kDa (TSPO) in patients with schizophrenia in vivo were limited by radioligand used, resolution of scanners used, and the confounding effect of antipsychotic medications. There is a dearth of evidence on the state of early stages of the illness such as the first-episode psychosis (FEP) and clinical high risk for psychosis (CHR). Methods: Using a second-generation TSPO radioligand, [18F]FEPPA, and a high-resolution research tomograph (HRRT), we examined microglial activation in dorsolateral prefrontal cortex (DLPFC) and hippocampus of CHR and FEP. Dynamic PET data were analyzed using a 2-tissue compartment model with an arterial plasma input function to obtain [18F]FEPPA total volume of distribution (VT), as previously validated. Based on their rs6971 polymorphism, subjects were classified as high-, medium- or low-affinity [18F]FEPPA binders, and all the analyses were controlled for genotype. Results: 24 (mean age = 21.21, SD = 3.35) CHR and 19 patients with untreated FEP (mean age = 27.53, SD = 6.78), and 20 healthy volunteers (mean age =27.75, SD = 8.77) underwent PET and magnetic resonance imaging. No significant differences in [18F]FEPPA VT in DLPFC and hippocampus were found between different diagnostic groups. Explorative association analyses found a trend toward significant association between RBANS total score and [18F]FEPPA VT in hippocampus of FEP (r = .50, P = .04). In CHR, apathy score was associated with [18F]FEPPA VT in DLPFC (r = .604, P = .003) and hippocampus (r = .574, P = .005). Moreover, [18F]FEPPA VT in DLPFC was associated with state anxiety score (r = .56, P = .007). Conclusion: This is the largest study examined microglial activation in the early stages of psychosis using a standard methodology without the confound of antipsychotic medications. Our findings suggest that microglial activation is not present in early stages of psychosis (i.e., CHR and FEP).

The relation of episodic and semantic memory for emotional- (positive, negative) and neutral-valenced autobiographical events to illness insight was examined in individuals with schizophrenia. Reduced recall of episodic details for negative events was significantly associated with impaired awareness of having a past mental disorder and its social consequences. Deficits in episodic memory for negative autobiographical events may underlie impaired insight in schizophrenia.

Impaired illness insight in schizophrenia is associated with non-adherence and worse outcomes. Schizophrenia patients also exhibit error-monitoring deficits, which have been proposed to cause poor insight. To test this hypothesis, we examined whether schizophrenia patients' deficits in neurophysiological error-monitoring indices, the error-related negativity (ERN) and error positivity (Pe) event-related potential (ERP) amplitudes, are associated with impaired insight. ERPs were recorded in 18 schizophrenia patients and 18 normal comparison participants during a Stroop task. Patients' subnormal ERN and Pe amplitudes did not correlate with insight, suggesting that impaired insight in schizophrenia stems from neurocognitive mechanisms other than deficient error monitoring. Canadian Institutes of Health Research (INO-112359)

Schizophrenia is associated with abnormalities in using meaningful stimuli to activate or prime related concepts in semantic long-term memory. A neurophysiological index of this activation is the N400, an event-related brain potential (ERP) waveform elicited by meaningful stimuli, which is normally reduced (made less negative) by relatedness between the eliciting stimulus and preceding ones (N400 semantic priming). Schizophrenia patients exhibit N400 semantic priming deficits, suggesting impairment in using meaningful context to activate related concepts. To address whether this abnormality is a trait-like marker of liability to schizophrenia or, alternatively, a biomarker of the illness itself, we tested for its presence in schizophrenia patients' unaffected biological relatives. We recorded ERPs from 12 unaffected first-degree relatives of schizophrenia patients, 12 schizophrenia patients, and 12 normal control participants (NCPs) who viewed prime words each followed at 300- or 750-ms stimulus-onset asynchrony (SOA) by an unrelated or related target word, or a nonword, in a lexical-decision task. As expected, across SOAs, NCPs exhibited smaller (less negative) N400 amplitudes for related versus unrelated targets. The same pattern held in relatives, whose N400 amplitudes for related and unrelated targets did not differ from NCPs'. In contrast, consistent with previous results, schizophrenia patients exhibited larger N400 amplitudes than NCPs (and relatives) for related targets, such that patients' N400 amplitudes for related and unrelated targets did not differ. N400 amplitudes for unrelated targets did not differ between the three groups. Thus, N400 semantic priming deficits in a visual word-pair paradigm may be an illness biomarker for schizophrenia.

Clinical experience and research findings suggest that schizophrenia is a disorder comprised of multiple genetic and neurophysiological subtypes with differential response to treatment. Electroencephalography (EEG) is a non-invasive, inexpensive and useful tool for investigating the neurobiology of schizophrenia and its subtypes. EEG studies elucidate the neurophysiological mechanisms potentially underlying clinical symptomatology. In this review article recent advances in applying EEG to study pathophysiology, phenomenology, and treatment response in schizophrenia are discussed. Investigative strategies employed include: analyzing quantitative EEG (QEEG) spectral power during the resting state and cognitive tasks; applying machine learning methods to identify QEEG indicators of diagnosis and treatment response; and using the event-related brain potential (ERP) technique to characterize the neurocognitive processes underlying clinical symptoms. Studies attempting to validate potential EEG biomarkers of schizophrenia and its symptoms, which could be useful in assessing familial risk and treatment response, are also reviewed.

Elicited by any meaningful stimulus, the N400 event-related potential (ERP) component is reduced when the stimulus is related to a preceding one. This N400 semantic priming effect has been used to probe abnormal semantic relationship processing in clinical disorders, and suggested as a possible biomarker for treatment studies. Validating N400 semantic priming effects as a clinical biomarker requires characterizing their test-retest reliability.We assessed test-retest reliability of N400 semantic priming in 16 healthy adults who viewed the same related and unrelated prime-target word pairs in two sessions one week apart.As expected, N400 amplitudes were smaller for related versus unrelated targets across sessions. N400 priming effects (amplitude differences between unrelated and related targets) were highly correlated across sessions (r=0.85, P0.0001), but smaller in the second session due to larger N400s to related targets.N400 priming effects have high reliability over a one-week interval. They may decrease with repeat testing, possibly because of motivational changes.Use of N400 priming effects in treatment studies should account for possible magnitude decreases with repeat testing. Further research is needed to delineate N400 priming effects' test-retest reliability and stability in different age and clinical groups, and with different stimulus types.

N400, an event-related brain potential (ERP) waveform elicited by meaningful stimuli, is normally reduced (made less negative) by relatedness between the eliciting stimulus and preceding ones (N400 semantic priming). Schizophrenia patients' N400 semantic priming deficits suggest impairment in using meaningful context to activate related concepts in semantic memory. We aimed to examine the degree to which this impairment can be ameliorated by task instructions that more explicitly require processing of stimulus meaning. We recorded ERPs from 16 schizophrenia patients and 16 controls who viewed prime words each followed at 750-ms stimulus-onset asynchrony by an unrelated or related target word, or a nonword, in a non-semantic task (indicating whether a letter occurred in the target) compared to an explicit semantic task (judging prime-target relatedness). Consistent with previous work, controls exhibited greater N400 semantic priming (larger amplitude reductions for related versus unrelated targets) in the semantic task than in the orthographic task. Schizophrenia patients showed this same pattern, although their N400 semantic priming effects were smaller than controls' across tasks. Nevertheless, patients' priming effects increased as much as did controls' from the orthographic to the semantic task. Thus, connections among related concepts in schizophrenia patients' semantic memory appear grossly intact, such that, given a meaningful stimulus, they can make use of explicit cues to activate related concepts at a neurophysiological level, although their ability to do so remains less than normal. These data provide support for further research on semantic-cueing strategies for cognitive remediation of verbal memory in schizophrenia.

Auditory mismatch negativity (MMN) and P3a index preattentive detection of rare stimuli. Their amplitudes normally decrease with age. Previous studies have reported generally smaller than normal MMN and P3a in schizophrenia patients. We aimed to further characterize the course of these deficits over schizophrenia patients' lifespan.In 253 schizophrenia patients and 147 normal comparison participants (NCPs) encompassing a wide age range (18-65), event-related potentials were recorded while participants watched a silent video and were presented binaurally with 1-kHz tones 500ms apart, including standards (P=.90, 50-ms duration) and deviants (P=0.10, 100-ms).Over the entire age range, MMN and P3a were smaller in schizophrenia patients than NCPs. MMN amplitude declined with age in both groups, though slightly less steeply in schizophrenia patients than NCPs. P3a amplitude declined with age in NCPs but not in schizophrenia patients.In our cohort of schizophrenia patients, MMN and P3a deficits were already present at the youngest ages. MMN declined further with age, whereas P3a amplitude remained stable.This knowledge about how MMN and P3a amplitudes vary with age in schizophrenia patients compared to NCPs can help improve the utility of these indices as clinical endophenotypes or biomarkers.

Following a meaningful prime stimulus, schizophrenia patients have been hypothesized to exhibit impaired neurophysiological activation of related concepts in general, and/or supranormal activation of weakly related concepts in particular, within semantic memory. The former abnormality may occur at longer intervals, and the latter at shorter intervals, after the prime. The authors tested these hypotheses using the N400 event-related brain potential as a probe of activation of concepts in semantic memory.Event-related potentials were recorded in 16 schizophrenia patients and 16 normal comparison subjects who viewed prime words, each followed by a target that was a directly (strongly) related word, indirectly (weakly) related word, unrelated word, or nonword, in a lexical-decision task. Equal numbers of each target type were presented 300 and 750 msec after the prime.In the comparison subjects, N400 amplitude was largest (most negative) following unrelated targets, intermediate after indirectly related targets, and smallest after directly related targets. In contrast, patients' N400 amplitudes did not differ between these target types, reflecting larger amplitudes following both directly and indirectly related targets in patients than in comparison subjects; these findings held regardless of prime-to-target stimulus-onset asynchrony. Within patients, at the longer asynchrony, larger N400 amplitudes after directly and indirectly related targets correlated with positive psychotic symptoms.The results suggest hypoactivation of strongly and weakly related concepts following a meaningful stimulus, regardless of interval, in schizophrenia. An N400 index of this hypoactivation correlated with severity of delusions, suggesting a role for abnormal semantic processing in their pathogenesis.

A hallmark of schizophrenia is impaired proverb interpretation, which could be due to: (1) aberrant activation of disorganized semantic associations, or (2) working memory (WM) deficits. We assessed 18 schizophrenia patients and 18 normal control participants on proverb interpretation, and evaluated these two hypotheses by examining within patients the correlations of proverb interpretation with disorganized symptoms and auditory WM, respectively. Secondarily, we also explored the relationships between proverb interpretation and a spectrum of cognitive functions including auditory sensory-memory encoding (as indexed by the mismatch negativity (MMN) event-related brain potential (ERP)); executive function; and social0occupational function. As expected, schizophrenia patients produced less accurate and less abstract descriptions of proverbs than did controls. These proverb interpretation difficulties in patients were not significantly correlated with disorganization or other symptom factors, but were significantly correlated (p , .05) with WM impairment, as well as with impairments in sensory-memory encoding, executive function, and social0occupational function. These results offer no support for disorganized associations in abnormal proverb interpretation in schizophrenia, but implicate WM deficits, perhaps as a part of a syndrome related to generalized frontal cortical dysfunction. (JINS, 2007, 13, 653–663.)

While most standard symptom scales regard the 'psychotic' or 'positive' dimension of schizophrenia as a single factor, several lines of evidence suggest that psychosis itself is a multidimensional phenomenon. The foregoing literature suggested at least five distinct dimensions to psychosis; to test this, we developed, validated and applied an instrument to measure these dimensions and then applied it to examine the effect of antipsychotics on the different dimensions of the psychotic experience. The Dimensions of Psychosis Instrument (DIPI) was administered to 91 psychotic patients with schizophrenia spectrum disorders and a confirmatory factor analyses (CFA) was carried out to examine the five dimensions: cognitive preoccupation (CP) with the psychotic experience; emotional involvement (EM); behavioural impact (BI) of the experience; conviction (CO) in it; emotional; and external perspective (EP) about the experience. In a separate cohort of 17 prospectively treated patients, the impact of antipsychotics on these dimensions was assessed. BI showed the greatest improvement (32%) at 2 weeks, while CP and emotional improved somewhat less (22% and 14%, respectively). Improvement in CO was limited (6%) while EP showed no change. These results suggest that over the first few weeks of treatment, antipsychotics rapidly reduce the behavioural impact of the principal psychotic symptom and decrease cognitive and emotional preoccupation with it, without greatly altering the patients' conviction in or perspective about their psychotic experience.

Existing hypotheses about semantic processing in schizophrenia and schizotypy suggest that both conditions are associated with a less than normal difference in the degree to which some concept activates the mental representation of other concepts that are strongly versus weakly related to it in meaning. To seek further evidence for this, we examined response typicality on the Category Fluency Test (CFT) as a function of schizotypy. Individuals from a non-clinical population verbally generated as many exemplars as they could in 1 min for each of four categories (fruits, four-footed animals, articles of clothing, vehicles). Participants subsequently completed the Schizotypal Personality Questionnaire (SPQ). SPQ score was not significantly correlated with the total number of responses generated for any of the categories. Individuals with higher (as opposed to lower) SPQ scores, however, generated more atypical members of the fruit category both in their initial responses and overall (as indexed by the average ratio of each response's ordinal position to its position in population typicality norms). These results support the hypothesis that semantic memory organization in non-clinical individuals with higher schizotypy is functionally altered.

To quantitatively examine the effects of haloperidol and olanzapine on spontaneous motor activity in normal subjects.Randomized, double-blind, placebo-controlled medication study.Normal volunteers (n = 30).Subjects received 1 dose of either haloperidol 2 mg (n = 9), olanzapine 10 mg (n = 10) or placebo (n = 10) and were admitted to hospital for the next 24 hours.Subjects wore an actigraphic monitor, which recorded movement in 15-second epochs. The Simpson-Angus Extrapyramidal Side Effect Scale (SAS) and the Barnes Akathisia Scale (BAS) were administered before and 7 and 24 hours after medication was given.Compared with placebo, total motor activity was decreased by 41% with olanzapine (p = 0.004) and by 12% with haloperidol (NS). There were significantly more epochs with zero movement with olanzapine than with haloperidol or placebo. For non-zero epochs, the mean activity count and the distribution of activity counts did not differ significantly among groups. There were no positive findings on the SAS or the BAS.Olanzapine decreased total motor activity by increasing the amount of time during which subjects were immobile, rather than by affecting the magnitude of movement during periods in which there was activity. This effect occurred at a dose of olanzapine low enough not to cause clinically observed extrapyramidal side effects. Our results suggest that actigraphy is useful as a sensitive, noninvasive tool for measuring the effect of antipsychotics on spontaneous motor activity.

Apathy is considered one of the negative symptoms of schizophrenia, but its natural history and relationship to other clinical characteristics have not been systematically studied. The purpose of this cross-sectional study was to measure the level of apathy in schizophrenia and its relation to other symptoms and functional outcome. Twenty-eight patients with schizophrenia, and receiving antipsychotic treatment, were assessed with the Apathy Evaluation Scale (AES). The mean level of apathy of patients with schizophrenia, as rated by the AES, was significantly higher than that of matched healthy control subjects. In the patients, apathy was not significantly correlated with positive symptoms or depressive symptoms. It was significantly correlated with the item "emotional withdrawal" on the negative subscale of the Positive and Negative Syndrome Scale (PANSS), but was not correlated with the overall negative subscale score. Apathy was more highly associated with functional outcome than were other symptom measures, and it was independently associated with functional outcome above and beyond other negative symptoms. It was not associated with observed interest in playing a video game or performance on a simulated clerical task.

This thesis presents research documenting the effectiveness of computer-assisted cognitive remediation for patients with mood disorders. The first chapter provides an overview of cognitive impairment in patients with bipolar disorder (BD) and major depressive disorder (MDD), and a concise review of cognitive remediation in patients with schizophrenia, where the efficacy of these interventions has been reasonably well studied. The results of an analysis comparing neuropsychological test performance in patients with BD, MDD, and healthy controls is presented in Chapter 2, where we show a similar degree of deficit in both patient groups on processing speed, working memory, and mental flexibility tasks, and a greater degree of deficit in patients with BD on delayed recall and verbal fluency tasks. In Chapter 3 we present the results of our primary analysis examining the effectiveness of CACR for patients with BD and MDD; we show significant improvement on neuropsychological tests of working memory and delayed memory following remediation, and positive associations between improvement in neuropsychological test performance, and improvement in subjectively-rated cognitive and psychosocial functioning. Finally, in Chapter 4 we present functional neuroimaging evidence that shows increased activation following cognitive remediation in frontal control regions supporting working memory and in the right hippocampus supporting recollection memory. Although behavioural performance on the corresponding tasks was stable, the observation of increased activation in frontal and medial temporal brain regions following remediation is in line with our finding of improvement on neuropsychological tests of working memory and delayed recall post-training. Taken together, the results presented in this thesis provide convergent behavioural and neural evidence to demonstrate the efficacy of computer-assisted cognitive remediation for patients with mood disorders. These novel findings contribute to a growing body of literature that shows cognitive remediation to be an effective cognitive management strategy across a range of psychiatric and neurological disorders. Doctor of Philosophy (PhD)