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Background: Working memory (WM) has been a matter of intensive basic and clinical research for some decades now. The investigation of WM function and dysfunction may facilitate the understanding of both physiological and pathological processes in the human brain. Though WM paradigms are widely used in neuroscientific and psychiatric research, conclusive knowledge about potential moderating variables such as gender is still missing. Methods: We used functional magnetic resonance imaging to investigate the effects of gender on verbal and visuospatial WM maintenance tasks in a large and homogeneous sample of young healthy subjects. Results: We found significant gender effects on both the behavioral and neurofunctional level. Females exhibited disadvantages with a small effect size in both WM domains accompanied by stronger activations in a set of brain regions (including bilateral substantia nigra/ven-tral tegmental area and right Broca's area) independent of WM modality. As load and task difficulty effects have been shown for some of these regions, the stronger activations may reflect a slightly lower capacity of both WM domains in females. Males showed stronger bilateral intraparietal activations next to the precuneus which were specific for the visuospatial WM task. Activity in this specific region may be associated with visuospatial short-term memory capacity. Conclusion: These findings provide evidence for a slightly lower capacity in both WM modalities in females. [ABSTRACT FROM AUTHOR]

Patients suffering from bipolar affective disorder show deficits in working memory functions. In a previous functional magnetic resonance imaging study, we observed an abnormal hyperactivity of the amygdala in bipolar patients during articulatory rehearsal in verbal working memory. In the present study, we investigated the dynamic neurofunctional interactions between the right amygdala and the brain systems that underlie verbal working memory in both bipolar patients and healthy controls. In total, 18 euthymic bipolar patients and 18 healthy controls performed a modified version of the Sternberg item-recognition (working memory) task. We used the psychophysiological interaction approach in order to assess functional connectivity between the right amygdala and the brain regions involved in verbal working memory. In healthy subjects, we found significant negative functional interactions between the right amygdala and multiple cortical brain areas involved in verbal working memory. In comparison with the healthy control subjects, bipolar patients exhibited significantly reduced functional interactions of the right amygdala particularly with the right-hemispheric, i.e., ipsilateral, cortical regions supporting verbal working memory. Together with our previous finding of amygdala hyperactivity in bipolar patients during verbal rehearsal, the present results suggest that a disturbed right-hemispheric 'cognitive-emotional' interaction between the amygdala and cortical brain regions underlying working memory may be responsible for amygdala hyperactivation and affects verbal working memory (deficits) in bipolar patients. [ABSTRACT FROM AUTHOR]

Objectives. Impairments in memory and executive function are key components of schizophrenia. These disturbances have been linked to several subcortical and cortical networks. For example, anatomical and functional changes in the hippocampus have been linked to deficits in these cognitive domains. However, the association between hippocampal morphometry, neurochemistry and function is controversial. Therefore, we aimed to investigate the relationship between hippocampal anomalies and their functional relevance. Methods. Fifty-seven first-episode schizophrenia patients (FE-SZ) and 61 healthy control subjects (HC) participated in this study. Hippocampal volumes were investigated using structural magnetic resonance imaging (sMRI) and hippocampal neurochemistry was determined using proton magnetic resonance spectroscopy (1H MRS). Verbal memory was used as a hippocampus-dependent cognitive task whereas working memory and cognitive flexibility assessed frontal lobe function. Results. FE-SZ presented smaller volumes of the left hippocampus, with a significant correlation between left hippocampal volume and verbal memory performance (immediate recall). There was also an inverse correlation between neurochemical ratios (NAA/Cho and Cho/Cr) and verbal memory (delayed recognition). Tests of cognitive flexibility and working memory were not correlated with MRI and 1H MRS values. Compared to HC, FE-SZ demonstrated reduced performance in all of the assessed neurocognitive domains. Conclusions. These results point to a relationship between verbal memory and hippocampal integrity in schizophrenia patients which might be independent from deficits in other memory domains. Disturbed verbal memory functions in FE-SZ might be linked specifically to hippocampal function. [ABSTRACT FROM AUTHOR]

Many studies have demonstrated attenuated verbal working memory (WM) under articulatory suppression. However, performance is not completely abolished, suggesting a less efficient, non-articulatory mechanism for the maintenance of verbal information. The neural causes for the reduced efficiency of such a putative complementary maintenance system have not yet been addressed. The present study was conducted to fill this gap. Subjects performed a Sternberg task (a) under articulatory maintenance at low, high, and supracapacity set sizes and (b) under non-articulatory maintenance at low and high set sizes. With functional magnetic resonance imaging, set-size related increases in activity were compared between subvocal articulatory rehearsal and non-articulatory maintenance. First, the results replicate previous findings showing different networks underlying these two maintenance strategies. Second, activation of all key nodes of the articulatory maintenance network increased with the amount of memorized information, showing no plateau at high set sizes. In contrast, for non-articulatory maintenance, there was evidence for a plateau at high set sizes in all relevant areas of the network. Third, for articulatory maintenance, the non-articulatory maintenance network was additionally recruited at supracapacity set sizes, presumably to assist processing in this highly demanding condition. This is the first demonstration of differential neural bottlenecks for articulatory and non-articulatory maintenance. This study adds to our understanding of the performance differences between these two strategies supporting verbal WM. [ABSTRACT FROM AUTHOR]

Via influencing brain plasticity, aerobic exercise could contribute to the treatment of schizophrenia patients. As previously shown, physical exercise increases hippocampus volume and improves short-term memory. We now investigated gray matter density and brain surface expansion in this sample using MRI-based cortical pattern matching methods. Comparing schizophrenia patients to healthy controls before and after 3 months of aerobic exercise training (cycling) plus patients playing table football yielded gray matter density increases in the right frontal and occipital cortex merely in healthy controls. However, respective exercise effects might be attenuated in chronic schizophrenia, which should be verified in a larger sample. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Recent functional neuroimaging studies have provided evidence that human verbal working memory is represented by two complementary neural systems, a left lateralized premotor-parietal network implementing articulatory rehearsal and a presumably phylogenetically older bilateral anterior-prefrontal/inferior-parietal network subserving non-articulatory maintenance of phonological information. In order to corroborate these findings from functional neuroimaging, we performed a targeted behavioural study in patients with very selective and circumscribed brain lesions to key regions suggested to support these different subcomponents of human verbal working memory. Methods: Within a sample of over 500 neurological patients assessed with high-resolution structural magnetic resonance imaging, we identified 2 patients with corresponding brain lesions, one with an isolated lesion to Broca's area and the other with a selective lesion bilaterally to the anterior middle frontal gyrus. These 2 patients as well as groups of age-matched healthy controls performed two circuit-specific verbal working memory tasks. In this way, we systematically assessed the hypothesized selective behavioural effects of these brain lesions on the different subcomponents of verbal working memory in terms of a double dissociation. Results: Confirming prior findings, the lesion to Broca's area led to reduced performance under articulatory rehearsal, whereas the non-articulatory maintenance of phonological information was unimpaired. Conversely, the bifrontopolar brain lesion was associated with impaired non-articulatory phonological working memory, whereas performance under articulatory rehearsal was unaffected. Conclusion: The present experimental neuropsychological study in patients with specific and circumscribed brain lesions confirms the hypothesized double dissociation of two complementary brain systems underlying verbal working memory in humans. In particular, the results demonstrate the functional relevance of the anterior prefrontal cortex for non-articulatory maintenance of phonological information and, in this way, provide further support for the evolutionary-based functional-neuroanatomical model of human working memory. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Objective: Brain mechanisms underlying performance of working memory (WM) vary according to domain specific requirements of the WM task. In Parkinson’s Disease (PD) domain specific WM tasks can be differentially affected. Method: We investigated the pattern of brain activation during performance of domain specific working memory tasks in nine patients with early PD before (OFF-state) and after challenge with 200mg of levodopa (ON-state) by functional Magnetic Resonance Imaging (fMRI) using two variants of a phonological and one visual delayed matched to sample task paradigm. Eleven healthy volunteers were studied with the same protocol once. Results: Behavioural data showed no significant difference of accuracy in performance of the WM tasks between PD and healthy controls. During performance of the verbal WM task fMRI revealed reduced activity within the left middle frontal gyrus, right cerebellum and left posterior inferior temporal gyrus in patients with PD. These abnormalities could be reversed by levodopa. In contrast, reduced activity within the right prefrontal cortex, that was found during visuospatial WM performance remained unchanged after levodopa administration. Conclusions: Our findings demonstrate altered brain activity in PD during verbal and visuospatial WM tasks and show different responses of these disturbed WM networks to levodopa. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Previous studies using advanced imaging techniques have suggested subtle structural and functional changes in patients with juvenile myoclonic epilepsy (JME), mainly associated with the frontal lobes. In addition, it has been reported that these patients show neuropsychological deficits, often summarized as frontal lobe dysfunction. The aim of this study was a comprehensive analysis of neuropsychological parameters, and functional and structural magnetic resonance imaging (MRI) in an independent cohort of patients with JME. We studied 19 JME patients and 20 age-, sex-, and education-matched controls using a battery of standardized neuropsychological tests, optimized voxel-based morphometry (VBM), and two domain-specific working-memory paradigms combined with functional MRI (fMRI). Our investigations did not reveal statistically significant differences between the groups of JME patients and normal controls in either the VBM or the fMRI study of working memory. The neuropsychological examination showed a slightly worse performance for the JME patients across most tests used, reaching statistical significance for semantic and verbal fluency. In our cohort of JME patients, we could not reproduce the findings of frontal gray matter changes from previous studies, and we could not detect an fMRI correlate of previously reported differences in working memory in JME. The neuropsychological deficits may be attributed partially to antiepileptic medication. We conclude that structural and functional frontal lobe deficits in JME patients have to be interpreted with care. One reason for a variation between different cohorts may be the genetic heterogeneity of the disease. [ABSTRACT FROM AUTHOR]

Working memory disturbances are a frequently replicated finding in schizophrenia and less consistent also in schizoaffective disorder. Working memory dysfunctions have been shown to be heritable and have been proposed to represent a promising endophenotype of schizophrenic psychoses. In the present study, we investigated the effects of familial loading on performance rates in circuit-specific verbal and visuospatial working memory tasks in matched samples of schizophrenic patients (from multiply affected or uniaffected families), schizoaffective patients (from multiply affected or uniaffected families), and healthy subjects. We found a significant interaction effect between familial loading and diagnosis in terms of a diagnosis-specific detrimental effect of familial loading on the performance of schizophrenic (but not schizoaffective) patients in the articulatory rehearsal task. This finding of a circuit-specific verbal working memory deficit in schizophrenic patients with additional familial loading is consistent with prior studies, which provided evidence for the existence of specific subgroups of schizophrenic patients with selective working memory impairments and for diagnosis-specific dysfunctions of the articulatory rehearsal mechanism in schizophrenic, but not in schizoaffective patients. Together, these findings suggest that the genetic risk for (a subtype of) schizophrenia may be associated with dysfunctions of the brain system, which underlies the articulatory rehearsal mechanism, the probably phylogenetically youngest part of human working memory. [ABSTRACT FROM AUTHOR]

Objective: Behavioural studies have implicated working memory (WM) deficits in obsessive-compulsive disorder (OCD). However, findings are inconsistent, which could be explained by compensation strategies used by a subgroup of OCD patients. To test this hypothesis, we examined patients without a behavioural deficit in WM during performance of different WM tasks using functional magnetic resonance imaging (fMRI). Methods: We scaned 11 patients and 11 matched control subjects while they performed 3 verbal and spatial item-recognition tasks. Results: Patients and healthy subjects engaged the same set of brain regions. However, in direct comparison, the patients exhibited significantly greater task-related activation in several frontal and parietal brain areas known to underlie WM. Conclusion: Patients without manifest WM deficits exhibit increased activation in frontal and parietal brain areas relative to healthy subjects during WM task performance. These hyperactivations may permit them to compensate for reduced efficiency of their WM systems and may thus serve as markers of latent WM dysfunctions. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

In the present event-related functional magnetic resonance imaging study, the neural implementation of human working memory was reinvestigated using a factorial design with verbal and visuospatial item-recognition tasks each performed under single-task conditions, under articulatory suppression, and under visuospatial suppression. This approach allowed to differentiate between brain systems subserving domain-specific working memory processes and possible neural correlates of more “central” executive or storage functions. The results of this study indicate (1) a domain-specific functional-neuroanatomical organization of verbal and visuospatial working memory, (2) a dual architecture of verbal working memory in contrast to a unitary macroscopic architecture of visuospatial working memory, (3) possible neural correlates for a domain-unspecific “episodic buffer” in contrast to a failure to find brain areas attributable to a “central executive,” and (4) competition for neuronal processing resources as the causal principle for the occurrence of domain-specific interference in working memory. [Copyright &y& Elsevier]

Abstract: In schizophrenia patients negative symptoms and cognitive impairment often persist despite treatment with second generation antipsychotics leading to reduced quality of life and psychosocial functioning. One core cognitive deficit is impaired working memory (WM) suggesting malfunctioning of the dorsolateral prefrontal cortex. High frequency repetitive transcranial magnetic stimulation (rTMS) has been used to transiently facilitate or consolidate neuronal processes. Pilot studies using rTMS have demonstrated improvement of psychopathology in other psychiatric disorders, but a systematic investigation of working memory effects outlasting the stimulation procedure has not been performed so far. The aim of our study was to explore the effect of a 3-week high frequency active or sham 10Hz rTMS on cognition, specifically on working memory, in schizophrenia patients (n =25) in addition to antipsychotic therapy and in healthy controls (n =22). We used functional magnetic resonance imaging (fMRI) to compare activation patterns during verbal WM (letter 2-back task) before and after 3-weeks treatment with rTMS. Additionally, other cognitive tasks were conducted. 10Hz rTMS was applied over the left posterior middle frontal gyrus (EEG electrode location F3) with an intensity of 110% of the individual resting motor threshold (RMT) over a total of 15 sessions. Participants recruited the common fronto- parietal and subcortical WM network. Multiple regression analyses revealed no significant activation differences over time in any contrast or sample. According to the ANOVAs for repeated measures performance remained without alterations in all groups. This is the first fMRI study that has systematically investigated this topic within a randomized, placebo-controlled, double-blind design, contrasting the effects in schizophrenia patients and healthy controls. [Copyright &y& Elsevier]

Abstract: Introduction: Disturbed interregional functional connectivity has been hypothesized to be a promising marker of schizophrenia. The relationship between working memory (WM) impairment, disturbed functional connectivity, and the characteristic symptoms of schizophrenia, however, remains elusive. Methods: We used functional MRI (fMRI) to investigate in patients with schizophrenia and matched controls the patterns of functional connectivity during the performance of different tasks selectively engaging subcomponent processes of working memory. Results: Compared with controls, patients showed reduced connectivity of the prefrontal cortex with the intraparietal cortex and the hippocampus and abnormal negative interactions between the ventrolateral and dorsolateral prefrontal cortex during the non-articulatory maintenance of phonological information. During the maintenance of visuospatial information, patients presented reduced connectivity between regions in the superior parietal and occipital cortex, as well as enhanced positive connectivity of the frontal eye field with visual processing areas. Discussion: Our findings suggest complex dysregulations within the networks supporting working memory functions in schizophrenia, which manifest as decreased positive and abnormal negative interactions. Correlations between the connection strength and WM performance suggest that these dysregulations may be neurofunctional correlates of the WM deficits seen in schizophrenia. Altered prefronto-hippocampal and parieto-occipital connectivity was further found to be associated with higher positive symptoms, providing a possible explanation for the development of delusions and disorganization symptoms. Conclusion: The present findings can help to better understand the relationship between altered patterns of synchronized brain activity and the cognitive and clinical symptoms of schizophrenia. [Copyright &y& Elsevier]

The most anterior portion of prefrontal cortex (aPFC), more specifically Brodman Area 10 (BA10), has been implicated in ‘branching operations’, or the ability to perform tasks related to one goal, while keeping in working memory information related to a secondary goal. Such findings have been based on fMRI recordings under complex behavioral paradigms that compare ‘branching’ tasks with tasks where one goal is pursued at a time, but are limited by their complete reliance on verbal working memory and by small sample sizes. Here, we test the specificity of BA 10 to branching in similar behavioral paradigms but with a larger sample and in two different conditions involving verbal and visual working memory respectively. We find that BA 10 and other frontal and parietal brain areas are activated in all tasks, with an extent and level of significance increasing with the complexity of the task. We conclude that the activation of BA 10 is not specific to branching as previously hypothesized, but is related to the level of complexity of working memory performance. For further insight into the specific role of anterior portions of the frontal cortex we highlight the importance of simple control tasks with gradual and incremental increase in complexity. [ABSTRACT FROM AUTHOR]