Peter J. McKenna

Functional Connectivity and Brain Networks in Schizophrenia

Schizophrenia has often been conceived as a disorder of connectivity between components of large-scale brain networks. We tested this hypothesis by measuring aspects of both functional connectivity and functional network topology derived from resting-state fMRI time series acquired at 72 cerebral regions over 17 min from 15 healthy volunteers (14 male, 1 female) and 12 people diagnosed with schizophrenia (10 male, 2 female). We investigated between-group differences in strength and diversity of functional connectivity in the 0.06–0.125 Hz frequency interval, and some topological properties of undirected graphs constructed from thresholded interregional correlation matrices. In people with schizophrenia, strength of functional connectivity was significantly decreased, whereas diversity of functional connections was increased. Topologically, functional brain networks had reduced clustering and small-worldness, reduced probability of high-degree hubs, and increased robustness in the schizophrenic group. Reduced degree and clustering were locally significant in medial parietal, premotor and cingulate, and right orbitofrontal cortical nodes of functional networks in schizophrenia. Functional connectivity and topological metrics were correlated with each other and with behavioral performance on a verbal fluency task. We conclude that people with schizophrenia tend to have a less strongly integrated, more diverse profile of brain functional connectivity, associated with a less hub-dominated configuration of complex brain functional networks. Alongside these behaviorally disadvantageous differences, however, brain networks in the schizophrenic group also showed a greater robustness to random attack, pointing to a possible benefit of the schizophrenia connectome, if less extremely expressed.

Memory impairment in schizophrenia : its extent, affiliations and neuropsychological character

In a sample of 60 schizophrenic patients encompassing all grades of severity and chronicity memory impairment was found to be prevalent, often substantial, and disproportionate to the overall level of intellectual impairment. The deficits were not easily attributable to poor cooperation, attention or motivation; nor were they related to neuroleptic or anticholinergic medication. Memory impairment was significantly associated with severity and chronicity of illness and also with negative symptoms and formal thought disorder. There was evidence from the sample as a whole, and from a more detailed examination of five patients with relatively isolated deficits, that schizophrenic memory impairment conformed to the pattern seen in the classical amnesic syndrome. Additionally, there was preliminary evidence for a marked deficit in semantic memory.

Amnesic syndrome in schizophrenia.

Memory impairment is not usually considered to form part of the clinical picture of schizophrenia, except perhaps in severely deteriorated patients. In a survey of 60 patients encompassing all grades of severity and chronicity poor memory performance was found to be common, sometimes substantial, and disproportionately pronounced compared to the degree of general intellectual impairment. Although associated with severity and chronicity of illness, impaired memory was by no means confined to old, institutionalized, or markedly deteriorated patients. The pattern of deficit appeared to resemble that of the classic amnesic syndrome rather than that seen in Alzheimer-type dementia.

Abnormal Cingulate Modulation of Fronto-Temporal Connectivity in Schizophrenia☆

Functional neuroimaging provides a novel means of exploring neurophysiological function in schizophrenia. However, most of the studies that have been carried out report their findings in terms of regionally localized abnormalities. In this paper we propose an alternative method of data analysis that emphasizes global integration rather than isolated regional changes in response to psychological tasks. In doing so, we suggest that brain abnormalities in schizophrenia are best characterized as a disturbance in the integration of activity across a number of brain regions. Using a hypothesis-led analysis, we show that the condition is associated with a disruption of the normal anterior cingulate modulation of prefronto-temporal integration. This analytical technique, we suggest, provides a conceptually powerful approach to the imaging of abnormal brain function in psychopathological conditions.

Memory in schizophrenia: What is impaired and what is preserved?

This study assesses the pattern of long-term memory performance in a sample of 12 schizophrenic patients who were selected on the basis of showing a memory deficit in the absence of gross overall intellectual impairment. When compared with 12 control subjects matched for age, sex and estimated premorbid IQ, presence of an episodic memory deficit was confirmed for both prose recall and forced-choice word and face recognition. Semantic memory was assessed using the sentence verification task developed by Collins and Quillian, an unpaced category judgement task, and the Mill Hill Vocabulary Scale. The schizophrenic patients were slower on sentence verification and they made significantly more errors in all three tasks. Procedural tasks included pursuit rotor performance, speed of repeatedly assembling a jigsaw puzzle and rate of improvement in reading transformed script. Here, while the schizophrenic patients showed poor overall performance on the pursuit rotor and jigsaw learning, their rate of learning on all three procedural tasks was comparable with that of the controls. When examined on two implicit memory tasks involving biasing of spelling of homophones and word stem completion, the patients showed a normal degree of priming in both. Implications for the nature of the memory deficit in schizophrenia are discussed.

Hypofrontality in schizophrenia: a meta-analysis of functional imaging studies.

Objective:  Hypofrontality is not a well‐replicated finding in schizophrenia either at rest or under conditions of task activation.

Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia

Modafinil, a novel cognitive enhancer, selectively improves neuropsychological task performance in healthy volunteers and adult patients with attention deficit hyperactivity disorder (ADHD). It has been argued that persistent cognitive deficits in patients with schizophrenia are responsible for the failure of many patients to rehabilitate socially even when psychotic symptoms are in remission. The present study examined the potential of modafinil as a cognitive enhancer in schizophrenia. Twenty chronic patients with a diagnosis of schizophrenia were entered into a double-blind, randomized, placebo-controlled crossover study using a 200 mg dose of modafinil. Modafinil had some cognitive enhancing properties in schizophrenia similar to those observed in healthy adults and adult patients with ADHD. Improvement was seen on short-term verbal memory span, with trends towards improved visual memory and spatial planning. This was accompanied by slowed response latency on the spatial planning task. No effect on stop-signal performance was seen. Importantly, significant improvement in attentional set shifting was seen, despite no effect of modafinil on this task being seen in healthy volunteers or ADHD patients. Modafinil may have potential as an important therapy for cognitive impairment in patients with schizophrenia, particularly because of its beneficial effects on attentional set shifting.

Cognitive behavioural therapy for major psychiatric disorder: does it really work? A meta-analytical review of well-controlled trials

BACKGROUND Although cognitive behavioural therapy (CBT) is claimed to be effective in schizophrenia, major depression and bipolar disorder, there have been negative findings in well-conducted studies and meta-analyses have not fully considered the potential influence of blindness or the use of control interventions. METHOD We pooled data from published trials of CBT in schizophrenia, major depression and bipolar disorder that used controls for non-specific effects of intervention. Trials of effectiveness against relapse were also pooled, including those that compared CBT to treatment as usual (TAU). Blinding was examined as a moderating factor. RESULTS CBT was not effective in reducing symptoms in schizophrenia or in preventing relapse. CBT was effective in reducing symptoms in major depression, although the effect size was small, and in reducing relapse. CBT was ineffective in reducing relapse in bipolar disorder. CONCLUSIONS CBT is no better than non-specific control interventions in the treatment of schizophrenia and does not reduce relapse rates. It is effective in major depression but the size of the effect is small in treatment studies. On present evidence CBT is not an effective treatment strategy for prevention of relapse in bipolar disorder.

Systemic sulpiride in young adult volunteers simulates the profile of cognitive deficits in Parkinson’s disease

Abstract  Rationale: The mesotelencephalic dopamine system has been implicated in cognitive processes dependent on an intact prefrontal cortex. Most previous research in humans has focused on dopaminergic agonists and their effects on tasks of working memory. Objectives: The present study was designed to investigate the cognitive and subjective effects of two doses (200 mg and 400 mg) of the dopaminergic D2 receptor antagonist, sulpiride on a broad range of well-validated neuropsychological tasks in a group of 34 young healthy male volunteers. Methods: Cognitive tasks were administered to subjects after ingestion of either drug or placebo within a double-blind, placebo-controlled, cross-over design. The cognitive tests included tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and were designed to assess visuospatial recognition memory, planning ability, working memory, strategy learning, sustained attention and attentional set-shifting. In addition, the National Adult Reading Test (NART) was used to assess verbal IQ, and visual analogue scales to assess subjective effects of the drug. Results: Subjects on sulpiride were impaired on the tasks of spatial recognition, spatial working memory (sequence generation), planning (one-touch Tower of London) and attentional set-shifting. Only the spatial working memory task demonstrated a dose dependent effect. The impairments were not due to generalised sedative or motoric influences of sulpiride. Conclusions: All of the tasks impaired following sulpiride are known to be sensitive to frontal lobe damage and the precise pattern of deficits seen is consistent with the anatomical distribution of central dopamine receptors. The results are discussed with particular reference to their close simulation of the impairments seen in idiopathic Parkinson’s disease.

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.