Eva Gruber

Articulatory rehearsal in verbal working memory: A possible neurocognitive endophenotype that differentiates between schizophrenia and schizoaffective disorder

Recent fMRI studies have identified brain systems underlying different components of working memory in healthy individuals. The aim of this study was to compare the functional integrity of these neural networks in terms of behavioural performance in patients with schizophrenia, schizoaffective disorder and healthy controls. In order to detect specific working memory deficits based on dysfunctions of underlying brain circuits we used the same verbal and visuospatial Sternberg item-recognition tasks as in previous neuroimaging studies. Clinical and performance data from matched groups consisting of 14 subjects each were statistically analyzed. Schizophrenic patients exhibited pronounced impairments of both verbal and visuospatial working memory, whereas verbal working memory performance was preserved in schizoaffective patients. The findings provide first evidence that dysfunction of a brain system subserving articulatory rehearsal could represent a biological marker which differentiates between schizophrenia and schizoaffective disorder.

Genetic polymorphisms of 5-HTT and DAT but not COMT differentially affect verbal and visuospatial working memory functioning.

Working memory deficits are found in different psychiatric populations and are most pronounced in schizophrenia. There is preliminary evidence from pharmacological studies that the verbal and visuospatial subcomponents of working memory are subject to differential neurotransmitter modulation. Here, we investigated the impact of well-known polymorphisms of the dopamine transporter gene (SLC6A3, DAT) and the catechol-O-methyl-transferase gene (COMT) as well as the serotonin transporter gene (SLC6A4, 5-HTT) on these specific working memory subcomponents in a mixed sample of patients and healthy individuals. Twenty healthy subjects and 80 patients diagnosed with schizophrenia, bipolar I disorder, or obsessive-compulsive disorder underwent genotyping for the DAT variable number of tandem repeats (VNTR), the COMT val/met-, and the 5-HTT promoter length polymorphism (5-HTTLPR) and neuropsychological testing using a battery of well-characterized, brain circuit–specific working memory tasks. DAT genotype revealed a significant and selective effect on visuospatial working memory, while there was no effect on verbal working memory functioning. 5-HTT genotype, by contrast, exerted a significant and selective effect on verbal working memory task performance. COMT genotype did not show any influence on either working memory domain. The results of the present study provide evidence for a differential impact of genetic polymorphisms of the dopaminergic and serotonergic systems on verbal and visuospatial working memory functioning. Together with prior evidence suggesting the existence of subgroups of schizophrenia patients exhibiting isolated deficits in only one working memory domain, this finding further supports the idea of endophenotypically and pathophysiologically distinct subgroups of schizophrenia with implications for personalized therapeutic approaches.

Neural correlates of working memory deficits in schizophrenic patients. Ways to establish neurocognitive endophenotypes of psychiatric disorders

ZusammenfassungDieser Beitrag befasst sich mit einigen methodischen Problemen funktionell-bildgebender Studien mit psychiatrischen Patienten, aufgrund derer die Untersuchung der neuronalen Korrelate kognitiver Defizite bei psychiatrischen Erkrankungen einer Kombination funktionell-bildgebender Studien bei gesunden Normalprobanden mit Verhaltensuntersuchungen bei Patienten bedarf. Dieser methodische Ansatz wird am Beispiel von Arbeitsgedächtnisfunktionen erläutert, wobei zunächst neuere Erkenntnisse zur funktionellen Neuroanatomie verschiedener Komponenten des menschlichen Arbeitsgedächtnisses referiert werden. Anschließend werden bei schizophrenen Patienten erhobene Befunde vorgestellt, die auf spezifische Störungen der funktionellen Integrität neuronaler Netzwerke mit Arbeitsgedächtnisfunktionen hinweisen. Die damit verbundene Identifikation von Subgruppen schizophrener Patienten könnte zur Etablierung verhaltensneurophysiologisch definierter Endophänotypen psychiatrischer Störungsbilder führen und die Entwicklung einer neurowissenschaftlich basierten Klassifikation psychiatrischer Erkrankungen fördern.AbstractThis article briefly reviews some methodological limitations of functional neuroimaging studies in psychiatric patients. We argue that the investigation of the neural substrates of cognitive deficits in psychiatric disorders requires a combination of functional neuroimaging studies in healthy subjects with corresponding behavioral experiments in patients. In order to exemplify this methodological approach we review recent findings regarding the functional neuroanatomy of distinct components of human working memory and provide evidence for selective dysfunctions of cortical networks that underlie specific working memory deficits in schizophrenia. This identification of subgroups of schizophrenic patients according to neurocognitive parameters may facilitate the establishment of behavioral and neurophysiological endophenotypes and the development of a neurobiological classification of psychiatric disorders.

A systematic experimental neuropsychological investigation of the functional integrity of working memory circuits in major depression.

Verbal and visuospatial working memory (WM) impairment is a well-documented finding in psychiatric patients suffering from major psychoses such as schizophrenia or bipolar affective disorder. However, in major depression (MDD) the literature on the presence and the extent of WM deficits is inconsistent. The use of a multitude of different WM tasks most of which lack process-specificity may have contributed to these inconsistencies. Eighteen MDD patients and 18 healthy controls matched with regard to age, gender and education were tested using process- and circuit-specific WM tasks for which clear brain-behaviour relationships had been established in prior functional neuroimaging studies. Patients suffering from acute MDD showed a selective impairment in articulatory rehearsal of verbal information in working memory. By contrast, visuospatial WM was unimpaired in this sample. There were no significant correlations between symptom severity and WM performance. These data indicate a dysfunction of a specific verbal WM system in acutely ill patients with MDD. As the observed functional deficit did not correlate with different symptom scores, further, longitudinal studies are required to clarify whether and how this deficit is related to illness acuity and clinical state of MDD patients.

Neuronale Korrelate gestörter Arbeitsgedächtnisfunktionen bei schizophrenen Patienten Ansätze zur Etablierung neurokognitiver Endophänotypen psychiatrischer Erkrankungen

ZusammenfassungDieser Beitrag befasst sich mit einigen methodischen Problemen funktionell-bildgebender Studien mit psychiatrischen Patienten, aufgrund derer die Untersuchung der neuronalen Korrelate kognitiver Defizite bei psychiatrischen Erkrankungen einer Kombination funktionell-bildgebender Studien bei gesunden Normalprobanden mit Verhaltensuntersuchungen bei Patienten bedarf. Dieser methodische Ansatz wird am Beispiel von Arbeitsgedächtnisfunktionen erläutert, wobei zunächst neuere Erkenntnisse zur funktionellen Neuroanatomie verschiedener Komponenten des menschlichen Arbeitsgedächtnisses referiert werden. Anschließend werden bei schizophrenen Patienten erhobene Befunde vorgestellt, die auf spezifische Störungen der funktionellen Integrität neuronaler Netzwerke mit Arbeitsgedächtnisfunktionen hinweisen. Die damit verbundene Identifikation von Subgruppen schizophrener Patienten könnte zur Etablierung verhaltensneurophysiologisch definierter Endophänotypen psychiatrischer Störungsbilder führen und die Entwicklung einer neurowissenschaftlich basierten Klassifikation psychiatrischer Erkrankungen fördern.AbstractThis article briefly reviews some methodological limitations of functional neuroimaging studies in psychiatric patients. We argue that the investigation of the neural substrates of cognitive deficits in psychiatric disorders requires a combination of functional neuroimaging studies in healthy subjects with corresponding behavioral experiments in patients. In order to exemplify this methodological approach we review recent findings regarding the functional neuroanatomy of distinct components of human working memory and provide evidence for selective dysfunctions of cortical networks that underlie specific working memory deficits in schizophrenia. This identification of subgroups of schizophrenic patients according to neurocognitive parameters may facilitate the establishment of behavioral and neurophysiological endophenotypes and the development of a neurobiological classification of psychiatric disorders.

Common and disease-specific dysfunctions of brain systems underlying attentional and executive control in schizophrenia and bipolar disorder.

Abstract Schizophrenia and bipolar disorder broadly overlap in multiple areas involving clinical phenomenology, genetics, and neurobiology. Still, the investigation into specific elementary (sub-)processes of executive functioning may help to define clear points of distinction between these categorical diagnoses to validate the nosological dichotomy and, indirectly, to further elucidate their pathophysiological underpinnings. In the present behavioral study, we sought to separate common from diagnosis-specific deficits in a series of specific elementary sub-functions of executive processing in patients with schizophrenia and bipolar disorder. For our purpose, we administered a modern and multi-purpose neuropsychological task paradigm to equal-sized and matched groups of schizophrenia patients, patients with bipolar disorder, and healthy control subjects. First, schizophrenia patients compared to the bipolar group exhibited a more pronounced deficit in general measures of task performance comprising both response speed and accuracy. Additionally, bipolar patients showed increased advance task preparation, i.e., were better able to compensate for response speed deficits when longer preparation intervals were provided. Set-shifting, on the other hand, was impaired to a similar degree in both patient groups. Finally, schizophrenia patients exhibited a specific deficit in conflict processing (inhibitory control) and the shielding of task-relevant processing from distraction (i.e., attentional maintenance). The present investigation suggests that specific neuropsychological measures of elementary executive functions may represent important points of dissociation between schizophrenia and bipolar disorder, which may help to differentiate the pathophysiological underpinnings of these major psychiatric disorders. In this context, the present findings highlight the measures of inhibitory control and attentional maintenance as promising candidates.

Neuronale Korrelate gestörter Arbeitsgedächtnisfunktionen bei schizophrenen Patienten

ZusammenfassungDieser Beitrag befasst sich mit einigen methodischen Problemen funktionell-bildgebender Studien mit psychiatrischen Patienten, aufgrund derer die Untersuchung der neuronalen Korrelate kognitiver Defizite bei psychiatrischen Erkrankungen einer Kombination funktionell-bildgebender Studien bei gesunden Normalprobanden mit Verhaltensuntersuchungen bei Patienten bedarf. Dieser methodische Ansatz wird am Beispiel von Arbeitsgedächtnisfunktionen erläutert, wobei zunächst neuere Erkenntnisse zur funktionellen Neuroanatomie verschiedener Komponenten des menschlichen Arbeitsgedächtnisses referiert werden. Anschließend werden bei schizophrenen Patienten erhobene Befunde vorgestellt, die auf spezifische Störungen der funktionellen Integrität neuronaler Netzwerke mit Arbeitsgedächtnisfunktionen hinweisen. Die damit verbundene Identifikation von Subgruppen schizophrener Patienten könnte zur Etablierung verhaltensneurophysiologisch definierter Endophänotypen psychiatrischer Störungsbilder führen und die Entwicklung einer neurowissenschaftlich basierten Klassifikation psychiatrischer Erkrankungen fördern.AbstractThis article briefly reviews some methodological limitations of functional neuroimaging studies in psychiatric patients. We argue that the investigation of the neural substrates of cognitive deficits in psychiatric disorders requires a combination of functional neuroimaging studies in healthy subjects with corresponding behavioral experiments in patients. In order to exemplify this methodological approach we review recent findings regarding the functional neuroanatomy of distinct components of human working memory and provide evidence for selective dysfunctions of cortical networks that underlie specific working memory deficits in schizophrenia. This identification of subgroups of schizophrenic patients according to neurocognitive parameters may facilitate the establishment of behavioral and neurophysiological endophenotypes and the development of a neurobiological classification of psychiatric disorders.

Differential working memory performance as support for the Kraepelinian dichotomy between schizophrenia and bipolar disorder? An experimental neuropsychological study using circuit-specific working memory tasks

Abstract Objectives. The traditional clinical dichotomy of schizophrenia and bipolar disorder has been challenged by recent findings of an at least in part common genetic basis. The investigation of neurocognitive functions like working memory may thereby contribute to elucidate common versus distinct pathophysiological processes of the major psychoses. To date direct comparisons of working memory functioning in schizophrenia and bipolar disorder have been rare and moreover have revealed inconsistent findings. In this study we aimed to further clarify the diagnostic specificity of working memory deficits in schizophrenia and bipolar disorder. Methods. Fifty patients with schizophrenia, 23 patients with bipolar disorder and 53 healthy controls were tested with regard to specific dysfunctions of verbal and visuospatial working memory components using a set of well-characterized, brain circuit-specific paradigms with established brain-behaviour relationships. Results. Patients with schizophrenia showed marked deficits across different working memory domains while bipolar patients performed intermediate with no significant differences compared to the control group. Working memory performance of patients with schizophrenia and bipolar disorder significantly differed in only one particular task requiring articulatory rehearsal of verbal information. Conclusions. While these results do not provide unequivocal support for the Kraepelinian dichotomy, they are consistent with recent findings suggesting the existence of a specific subgroup of schizophrenia patients phenotypically characterized by selective deficits of the articulatory rehearsal mechanism of verbal working memory.

Neuronale Korrelate gestrter Arbeitsgedchtnisfunktionen bei schizophrenen Patienten@@@Neural correlates of working memory deficits in schizophrenic patients: Anstze zur Etablierung neurokognitiver Endophnotypen psychiatrischer Erkrankungen@@@Ways to establish neurocognitive endophenotypes of psychiatric disorders

ZusammenfassungDieser Beitrag befasst sich mit einigen methodischen Problemen funktionell-bildgebender Studien mit psychiatrischen Patienten, aufgrund derer die Untersuchung der neuronalen Korrelate kognitiver Defizite bei psychiatrischen Erkrankungen einer Kombination funktionell-bildgebender Studien bei gesunden Normalprobanden mit Verhaltensuntersuchungen bei Patienten bedarf. Dieser methodische Ansatz wird am Beispiel von Arbeitsgedächtnisfunktionen erläutert, wobei zunächst neuere Erkenntnisse zur funktionellen Neuroanatomie verschiedener Komponenten des menschlichen Arbeitsgedächtnisses referiert werden. Anschließend werden bei schizophrenen Patienten erhobene Befunde vorgestellt, die auf spezifische Störungen der funktionellen Integrität neuronaler Netzwerke mit Arbeitsgedächtnisfunktionen hinweisen. Die damit verbundene Identifikation von Subgruppen schizophrener Patienten könnte zur Etablierung verhaltensneurophysiologisch definierter Endophänotypen psychiatrischer Störungsbilder führen und die Entwicklung einer neurowissenschaftlich basierten Klassifikation psychiatrischer Erkrankungen fördern.AbstractThis article briefly reviews some methodological limitations of functional neuroimaging studies in psychiatric patients. We argue that the investigation of the neural substrates of cognitive deficits in psychiatric disorders requires a combination of functional neuroimaging studies in healthy subjects with corresponding behavioral experiments in patients. In order to exemplify this methodological approach we review recent findings regarding the functional neuroanatomy of distinct components of human working memory and provide evidence for selective dysfunctions of cortical networks that underlie specific working memory deficits in schizophrenia. This identification of subgroups of schizophrenic patients according to neurocognitive parameters may facilitate the establishment of behavioral and neurophysiological endophenotypes and the development of a neurobiological classification of psychiatric disorders.