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Biomedical subjects

Peter J McKenna

Publications and source records attributed to Peter J McKenna.

17 recordsLinked to original sources
PubMed2006

Formal thought disorder is characterised by impaired lexical access.

Recent studies have proposed that difficulty with accessing the lexical-semantic memory store may underpin some of the specific linguistic problems associated with formal thought disorder (FTD). We examined the consistency of name retrieval as an indicator of the ability to access lexical-semantic knowledge in patients with and without marked FTD to see if problems are specific to the former or common to schizophrenic patients in general. A graded naming test was administered on two separate occasions 8-16 weeks apart to 48 participants in three groups: 16 schizophrenic patients with high ratings of FTD, 16 schizophrenic patients with low ratings of FTD and 16 healthy controls. We compared the groups for naming consistency across time and the relationship between naming consistency and specific symptoms of FTD. Both patient groups had impaired naming and this was significantly greater in high than low FTD patients. The high FTD patients showed a profile that differed from both low FTD patients and healthy controls insofar as their naming was inconsistent across time, characteristic of an access disorder. Specifically, the FTD symptoms of derailment, tangentality and incoherence were related to the ability to access the lexical-semantic store. In conclusion, most patients with schizophrenia show an impaired semantic memory store. Nevertheless, FTD is associated with additional lexical-semantic difficulties that are quantitatively different to those seen in patients without FTD, and which may reflect disorganized semantic access.

Adult↗
PubMed2006

Clozapine alone versus clozapine and risperidone with refractory schizophrenia.

BACKGROUND: The treatment of schizophrenia with multiple antipsychotic drugs is common, but the benefits and risks are not known. METHODS: In a randomized, double-blind study, we evaluated patients with schizophrenia and a poor response to treatment with clozapine. The patients continued to take clozapine and were randomly assigned to receive eight weeks of daily augmentation with 3 mg of risperidone or with placebo. This course of treatment was followed by an optional 18 weeks of augmentation with risperidone. The primary outcome was reduction in the total score for severity of symptoms on the Positive and Negative Syndrome Scale (PANSS). The secondary outcomes included cognitive functioning. RESULTS: A total of 68 patients were randomly assigned to treatment. In the double-blind phase, the mean total score for the severity of symptoms decreased from baseline to eight weeks in both the risperidone and the placebo groups. There was no statistically significant difference in symptomatic benefit between augmentation with risperidone and placebo: 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment (P=0.38). The mean difference in the change in PANSS scores from baseline to eight weeks between those receiving risperidone and those receiving placebo was 0.1 (95 percent confidence interval, -7.3 to 7.0). The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group (P=0.02 for the comparison between the two groups in the change from baseline). The increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group (16.2 vs. 1.8 mg per deciliter [0.90 vs. 0.10 mmol per liter], P=0.04). The incidence and severity of other side effects did not differ between the two groups. CONCLUSIONS: In this short-term study, the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia. (ClinicalTrials.gov number, NCT00272584).

Adult↗
PubMed2006

Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: linking cognition, brain activity, and psychosis.

CONTEXT: Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis. OBJECTIVE: To explore a theoretical model of delusion formation that implicates prediction error-dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine. DESIGN: Within-subject, randomized, placebo-controlled study. SETTING: Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge. PARTICIPANTS: Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean +/- SD age of 29 +/- 7 years and a mean +/- SD predicted full-scale IQ of 113 +/- 4 were recruited from within the local community by advertisement. INTERVENTIONS: Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview. MAIN OUTCOME MEASURES: Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale). RESULTS: Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). High-dose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04). CONCLUSIONS: These findings relate aberrant prediction error-dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning.

Adult↗
PubMed2005

Functional dysconnectivity in schizophrenia associated with attentional modulation of motor function.

It is not known whether there is a core abnormality that occurs in all cases of schizophrenia. The cognitive dysmetria hypothesis proposes that there is such an abnormality which is characterized cognitively by a disruption in control and coordination processes, and functionally by abnormal inter-regional connectivity within the cortico-cerebellar-thalamo-cortical circuit (CCTCC). In the current study, we used functional MRI (fMRI) to investigate these two key aspects of the hypothesis. Since patients with schizophrenia show deficits in attention which have been characterized extensively using the continuous performance task (CPT) and since functional imaging studies have also demonstrated that this task engages the CCTCC, we used this task to investigate whether two patient groups with distinct symptom profiles would show functional dysconnectivity within this network. Three groups of subjects participated in the study: healthy volunteers (n = 12), schizophrenia patients with both negative and positive symptoms (n = 11) and schizophrenia patients with primarily positive symptoms (n = 11). Patient groups were matched for age of illness onset and medication, and to the control group for age, gender and handedness. Subjects were scanned using fMRI whilst they performed a modified version of the CPT, involving both degraded and non-degraded stimuli. Stimulus degradation has been shown to produce decrements in sensitivity, which is thought to reflect increased demands on the limited capacity of visual attention. Between-group comparisons revealed that patients with schizophrenia, irrespective of symptomatology, showed attenuation of the anterior cingulate and cerebellar response to stimulus degradation in comparison with control subjects. We also observed disruptions of inter-regional brain integration in schizophrenia. A task-specific relationship between the medial superior frontal gyrus and both anterior cingulate and the cerebellum was disrupted in both patient groups in comparison with controls. In addition, patients with negative symptoms showed impaired behavioural performance, and abnormal task-related connectivity between anterior cingulate and supplementary motor area. These findings are consistent with theoretical accounts of schizophrenia as a disorder of functional integration, and with the cognitive dysmetria hypothesis, which posits a disconnection within the CCTCC as a fundamental abnormality in schizophrenia, independent of diagnostic subtype. Furthermore, these data show evidence of additional functional deficits in patients with negative symptoms, deficits which may explain the accompanying attentional impairment.

Adult↗
PubMed2005

Executive inhibition and semantic association in schizophrenia.

Research indicates that some patients with schizophrenia display aberrant inhibition of semantic memory, which may underpin formal thought disorder (FTD). We administered a novel Stroop-like paradigm to three groups of participants: 15 schizophrenic patients with formal thought disorder (FTD), 16 with low FTD ratings, and 15 healthy matched controls. They were required to inhibit a prepotent response for a (previously instructed) required response. Four conditions examined the effect of executive demands by manipulating the relatedness between prepotent and required responses (i.e., identical, semantically related, or unrelated). Two further conditions examining executive function working memory demands required the naming of real or abstract pictures that did and did not necessitate inhibition, respectively. Patients with and without FTD experienced increased difficulty when executive function working memory was required. Moreover, those with FTD also showed increased executive inhibition, but the pattern of errors suggested that the result of this was an automatic activation of semantically related representations. The findings support the notion that increased inhibition underpins the disorganised access to semantic memory in patients with FTD.

Association↗
PubMed2005

What happens to semantic memory when formal thought disorder remits? Revisiting a case study.

INTRODUCTION: Laws, Kondel, and McKenna (1999) previously reported a case study analysis of a schizophrenic patient (TC) with severe formal thought disorder (FTD). Examining consistency across item and modality of input, Laws et al. documented an impairment of access to semantic knowledge in TC. METHOD: Following substantial improvement in his FTD, we readministered the same extensive battery of neuropsychological tests tapping semantic memory functioning. RESULTS: Whilst TC's naming remained relatively good, it also became more consistent across both time and modality. Tasks tapping language comprehension and understanding of semantic association revealed some significant improvements. Nevertheless, TC showed a residual propensity to verify false information. CONCLUSION: Improvement in FTD in schizophrenia was accompanied by a better and more stable semantic memory performance in TC. The findings are consistent with, and expand upon the original suggestion that thought disorder reflects disorganised access to semantic memory.

Journal Article↗
PubMed2005

Storage and access procedures in schizophrenia: evidence for a two phase model of lexical impairment.

Evidence has accumulated to show that schizophrenia is characterized by lexical-semantic difficulties; however, questions remain about whether schizophrenics have problems in accessing intact representations or a loss of the representations themselves. Both access and storage types of disorder have been reported and it has been speculated that this may reflect a transition from the former to latter with increasing length of illness. This study investigated whether illness duration, age or estimated premorbid IQ predict the size and accessibility of the lexical store. Fifty-six schizophrenic patients (chosen to represent a wide range of illness duration from 3-40 years) and 24 matched healthy controls were asked to name 120 pictures on two occasions. Estimates of store size and retrieval probability were derived from a two parameter stochastic Markov chain model. This revealed that even early in the course of illness, schizophrenics appear to have suffered a reduction in lexical store size and that those with longer length of illness show deficits in both their store size and their ability to retrieve names from that store.

Adult↗
PubMed2004

A positron emission tomography study of the 5-HT1A receptor in schizophrenia and during clozapine treatment.

Several post-mortem studies have identified increases of 5-HT1A receptor density in frontal cortical areas in schizophrenic patients, and one has found increases in the cerebellar vermis. Clozapine has moderate affinity at the 5-HT1A receptor, and this may be of therapeutic importance. This positron emission tomography (PET) study attempted to replicate the post-mortem findings in vivo and sought an occupancy effect of clozapine at the 5-HT1A receptor. We recruited healthy controls, and patients with schizophrenia who were divided into those receiving clozapine and those receiving neuroleptics lacking 5-HT1A receptor affinity. Each volunteer received a PET scan, using the 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635, and a magnetic resonance imaging scan. The cerebellar vermis was examined by comparing time-activity data between groups. For other brain regions (the raphe and subdivisions of the cerebral cortex), binding potential images were generated to reflect receptor density, then analysed using 'region of interest' and voxel-by-voxel methods. No significant changes of 5-HT1A receptor density were found in schizophrenic patients compared to controls. Two other PET studies, containing drug naïve rather than medicated schizophrenic patients, have also reported no increase in 5-HT1A receptor density in the frontal cortex. The results obtained in vivo bring into question the importance of the receptor in the pathophysiology of the illness. Clozapine did not occupy the 5-HT1A receptor at clinical doses. This is consistent with recent related PET results: 5-HT1A agonists do not appear to measurably block the binding of antagonist radiotracers in man at doses that are pharmacologically active but which are limited by tolerability.

Adult↗
PubMed2003

Assessment of insight in psychosis: a re-standardization of a new scale.

Over the last decade, a number of tools have been developed to evaluate, in a systematic way, patients' insight into their psychotic illness. Such tools, however, capture different clinical phenomena of insight. So far, there is no indication as to which phenomenon of insight might be the most useful or predictive (e.g. clinically or therapeutically) to assess. This article reports the re-standardization of a revised self-administered insight scale in patients with psychosis, first published in 1992. It is meant to capture views held by individuals suffering from psychosis about changes occurring within themselves and in their environment. The scale was administered to 64 patients with a diagnosis of schizophrenia but with a range of symptoms and in different stages of their illnesses. This new version is simpler to use and score than the original instrument and shows good reliability, internal consistency and concurrent validity. This study forms the preliminary basis for future work examining the phenomenon of insight, its relationship to clinical variables and its predictive validity in terms of patients' behaviours and prognoses.

Adult↗
PubMed2003

Expression of Fyn, a non-receptor tyrosine kinase in prefrontal cortex from patients with schizophrenia and its correlation with clinical onset.

Fyn is a member of the non-receptor tyrosine kinase family, which is known to be closely involved in signal transduction in neurons and has an important role in the development and organisation of the central nervous system. In order to explore the possible role of Fyn in schizophrenia, the expression of Fyn messenger RNA (mRNA) and protein were investigated in the postmortem prefrontal cortex of brains from normal and 'schizophrenic' cases. There was an increase in both total area Fyn mRNA signal (17.7%, P<0.05) and cellular mRNA content (15.7%, P<0.05) in the schizophrenic group relative to controls. In parallel the content of Fyn protein detected by immuno-autoradiography was also increased in the schizophrenic cases (21.8% P<0.05). In addition, the cellular Fyn mRNA signal was negatively correlated with the age of onset (r=-0.94, P=0.0026). These results suggest that an increase in Fyn expression may contribute to the pathophysiology of schizophrenia.

Aged↗
PubMed2003

Visual object processing in schizophrenia: evidence for an associative agnosic deficit.

Early studies suggested visual form perception impairment in schizophrenia. To re-examine this claim and characterise the deficit neuropsychologically, 41 schizophrenic patients were administered tests sensitive to different levels of visual object perception and recognition. Intellectually well-preserved patients were examined separately on these and additional tests. Single case analysis was also applied to four patients showing varying degrees of general intellectual impairment. As a group, the patients showed little impairment on tests of early visual object perception, but greater impairment on higher-level visual processing tests, in particular object recognition and naming. This held true for patients with preserved general intellectual function. Single case analysis suggested that patients with schizophrenia have a selective deficit affecting object recognition and identification, with a pattern similar to visual associative agnosia in neurological patients.

Adolescent↗
PubMed2002

Gene expression analysis in schizophrenia: reproducible up-regulation of several members of the apolipoprotein L family located in a high-susceptibility locus for schizophrenia on chromosome 22.

We screened a custom-made candidate gene cDNA array comprising 300 genes. Genes chosen have either been implicated in schizophrenia, make conceptual sense in the light of the current understanding of the disease, or are located on high-susceptibility chromosome locations. The array screen using prefrontal cortex tissue from 10 schizophrenia and 10 control brains revealed robust up-regulation of apolipoprotein L1 (apo L1) by 2.6-fold. The finding was cross-validated in a blinded quantitative PCR study using prefrontal cortex tissue from the Stanley Foundation brain collection, Bethesda, MD. This collection consists of 15 schizophrenia, 15 bipolar disorder, 15 major depression, and 15 control individuals, all 60 brains being well-matched on conventional parameters, with antipsychotic drug exposure in the schizophrenia and bipolar disorder groups. Significant up-regulation of apo L1 gene expression in schizophrenia was confirmed. Using quantitative PCR, expression profiles of other members of the apo L family (apo L2-L6) were investigated, showing that apo L2 and L4 were highly significantly up-regulated in schizophrenia. Results were then confirmed in an independent set of 20 schizophrenia and 20 control brains from Japan and New Zealand. Apo L proteins belong to the group of high density lipoproteins, with all six apo L genes located in close proximity to each other on chromosome 22q12, a confirmed high-susceptibility locus for schizophrenia and close to the region associated with velocardiofacial syndrome that includes symptoms of schizophrenia.

Apolipoprotein L1↗