Patients with schizophrenia show deficits of working memory maintenance components in circuit-specific tasks

David Zilles 0 Eva Gruber 0 Peter Falkai 0 Oliver Gruber 0 0 D. Zilles (&) E. Gruber P. Falkai O. Gruber Department of Psychiatry and Psychotherapy, Georg August University , Von-Siebold-Str. 5, 37075 Goettingen, Germany Working memory (WM) deficits are a neuropsychological core finding in patients with schizophrenia and also supposed to be a potential endophenotype of schizophrenia. Yet, there is a large heterogeneity between different WM tasks which is partly due to the lack of process specificity of the tasks applied. Therefore, we investigated WM functioning in patients with schizophrenia using process- and circuit-specific tasks. Thirty-one patients with schizophrenia and 47 controls were tested with respect to different aspects of verbal and visuospatial working memory using modified Sternberg paradigms in a computer-based behavioural experiment. Total group analysis revealed significant impairment of patients with schizophrenia in each of the tested WM components. Furthermore, we were able to identify subgroups of patients showing different patterns of selective deficits. Patients with schizophrenia exhibit specific and, in part, selective WM deficits with indirect but conclusive evidence of dysfunctions of the underlying neural networks. These deficits are present in tasks requiring only maintenance of verbal or visuospatial information. In contrast to a seemingly global working memory deficit, individual analysis revealed differential patterns of working memory impairments in patients with schizophrenia. - Schizophrenia is a severe mental disorder that usually occurs in early adulthood with a lifetime prevalence of about 1%. It is characterized by positive (delusions and hallucinations) as well as negative (blunted affect, psychomotor retardation, apathy) symptoms. Another frequent finding is a broad range of cognitive impairments [21], including lack of concentration and attention, problems in memory and learning and executive functions. Especially working memory function, which comprises the maintenance and manipulation of information over a short period of time, has been proven to be a core deficit of the disorder [30]. Since working memory is considered as a basic mental function underlying many other higher cognitive functions such as reasoning, learning and comprehension, it is of particular interest for psychiatric research, especially with respect to schizophrenic psychoses. In contrast to the broad and heterogeneous spectrum of illness phase-dependent symptoms, the neuropsychological impairments seem to remain stable over the course of the disorder [20]. Thus, working memory is suggested to be a promising endophenotype for schizophrenia [11] and as such could represent a link between the clinical symptoms of the disease and genetic or other aetiological factors. Cognitive endophenotypes are thought to be influenced more directly by the genetic basis of the disorder and to be under the influence of a smaller number of genes. Indeed, there is a growing evidence for associations between specific genetic polymorphisms and cognitive dysfunction in schizophrenia [32]. Furthermore, specific single nucleotide polymorphisms are correlated with cerebral activation during working memory task performance [28]. Thus, an exact characterization of specific working memory processes and their disturbances in schizophrenia could prove helpful in the search for schizophrenia risk genes. Beyond that there is certain evidence that the investigation of endophenotypes could help to improve differential diagnosis between psychiatric disorders. For example, prior studies were able to show differential working memory impairments in patients with schizophrenia and schizoaffective disorder [14] and a differential influence of familial loading on working memory performance in these two diagnostic groups [34]. Human working memory has been hypothesized to be no unitary system but to consist of different specialized subsystems: the phonological loop for the maintenance of verbal information, the visuospatial sketchpad for the maintenance of spatial information, a central executive serving as a supervisory control system and the so-called episodic buffer as an interface between working memory subsystems and long-term memory [4]. Previous functional MRI studies have indeed identified several dissociable neural networks underlying specific verbal and visuospatial working memory functions in healthy individuals [12, 13, 1618]. In one study [18], for instance, the performance of a verbal working memory task requiring an articulatory rehearsal mechanism elicited activation in a left-lateralised network including premotor and parietal brain regions, whereas performance of specific visuospatial working memory tasks activated a bilateral brain system including the cortices along posterior parts of the superior frontal sulci and along the intraparietal sulci. Based upon these former studies investigating healthy individuals, a further large series of subsequent fMRI studies in clinical samples [19, 2224] as well as complementary lesion studies [15], clear brainbehaviour relationships could be established between specific brain circuits and subcomponents of working memory in humans. A recent meta-analysis confirmed pronounced working memory deficits in patients with schizophrenia across all working memory domains and different working memory measures [10] and thus again provided support for the presence of broad working memory deficits in schizophrenia. However, there is still the problem of a poor comparability of the different working memory tasks as the different test paradigms markedly differ with respect to their complexity (maintenance, manipulation or the additional requirement of executive functions) leading to a lack of process specificity. For the further investigation of working memory and its subprocesses, it is thus reasonable to use well-characterized, process-specific neuropsychological tasks that are validated with respect to their neural basis. In the present study, we used such process-specific tasks probing working memory functioning with respect to maintenance of verbal and visuospatial information, respectively. The experimental design that was here applied to a sample of patients with schizophrenia was the same as in our former fMRI studies in which we were able to characterize the neural networks underlying specific working memory components in healthy subjects [18]. On the basis of the established brainbehaviour relationships as outlined above [12, 13, 1619, 2224], we were able to indirectly attribute specific working memory deficits of patients with schizophrenia on the behavioural level to dysfunctions of these underlying neural networks. Beyond the problems with task specificity, there is a debate on a possible differential working memory impairment in patients with schizophrenia. E.g. several studies have stated a greater impairment in tasks requiring hig (...truncated)