Structure of WM bundles constituting the working memory system in early multiple sclerosis: a quantitative DTI tractography study

Working memory impairment is frequently observed in patients with early multiple sclerosis (MS). MRI and functional MRI studies have shown that working memory impairment is mostly due to diffuse white matter (WM) damage affecting the connectivity between distant cortical areas. However, working memory deficits in early MS patients can be either completely or partly masked by compensatory functional plasticity. It seems likely that concomitantly with the WM bundle injury resulting from pathological processes, the functional plasticity present in early MS patients may be accompanied by reactive structural WM plasticity. This structural plasticity may effectively compensate for connectivity disturbances and/or contribute to functional brain reorganization. The diffusion characteristics of WM bundles involved in working memory were assessed here by performing quantitative diffusion tensor imaging (DTI) tractography on 24 patients with early relapsing-remitting MS and 15 healthy control subjects. The DTI tractography findings showed that WM connections constituting the executive system of working memory were structurally impaired (the fractional anisotropy was lower than normal and the mean diffusivity, higher than normal). A significantly larger number of connections between the left and right thalami was concurrently observed in the MS patients than in the control subjects, which suggests that the WM is endowed with reactive structural plasticity.     

Modelling neural correlates of working memory: a coordinate-based meta-analysis

Working memory subsumes the capability to memorize, retrieve and utilize information for a limited period of time which is essential to many human behaviours. Moreover, impairments of working memory functions may be found in nearly all neurological and psychiatric diseases. To examine what brain regions are commonly and differently active during various working memory tasks, we performed a coordinate-based meta-analysis over 189 fMRI experiments on healthy subjects. The main effect yielded a widespread bilateral fronto-parietal network. Further meta-analyses revealed that several regions were sensitive to specific task components, e.g. Broca's region was selectively active during verbal tasks or ventral and dorsal premotor cortex were preferentially involved in memory for object identity and location, respectively. Moreover, the lateral prefrontal cortex showed a division in a rostral and a caudal part based on differential involvement in task set and load effects. Nevertheless, a consistent but more restricted "core" network emerged from conjunctions across analyses of specific task designs and contrasts. This "core" network appears to comprise the quintessence of regions, which are necessary during working memory tasks. It may be argued that the core regions form a distributed executive network with potentially generalized functions for focussing on competing representations in the brain. The present study demonstrates that meta-analyses are a powerful tool to integrate the data of functional imaging studies on a (broader) psychological construct, probing the consistency across various paradigms as well as the differential effects of different experimental implementations.     

Neural correlates of working memory in Temporal Lobe Epilepsy--an fMRI study

It has traditionally been held that the hippocampus is not part of the neural substrate of working memory (WM), and that WM is preserved in Temporal Lobe Epilepsy (TLE). Recent imaging and neuropsychological data suggest this view may need revision. The aim of this study was to investigate the neural correlates of WM in TLE using functional MRI (fMRI). We used a visuo-spatial 'n-back' paradigm to compare WM network activity in 38 unilateral hippocampal sclerosis (HS) patients (19 left) and 15 healthy controls. WM performance was impaired in both left and right HS groups compared to controls. The TLE groups showed reduced right superior parietal lobe activity during single- and multiple-item WM. No significant hippocampal activation was found during the active task in any group, but the hippocampi progressively deactivated as the task demand increased. This effect was bilateral for controls, whereas the TLE patients showed progressive unilateral deactivation only contralateral to the side of the hippocampal sclerosis and seizure focus. Progressive deactivation of the posterior medial temporal lobe was associated with better performance in all groups. Our results suggest that WM is impaired in unilateral HS and the underlying neural correlates of WM are disrupted. Our findings suggest that hippocampal activity is progressively suppressed as the WM load increases, with maintenance of good performance. Implications for understanding the role of the hippocampus in WM are discussed.     

Similarities and differences in the neural correlates of episodic memory retrieval and working memory

Functional neuroimaging studies have shown that different cognitive functions activate overlapping brain regions. An activation overlap may occur because a region is involved in operations tapped by different cognitive functions or because the activated area comprises subregions differentially involved in each of the functions. To investigate these issues, we directly compared brain activity during episodic retrieval (ER) and working memory (WM) using event-related functional MRI (fMRI). ER was investigated with a word recognition test, and WM was investigated with a word delayed-response test. Two-phase trials distinguished between retrieval mode and cue-specific aspects of ER, as well as between encoding/maintenance and retrieval aspects of WM. The results revealed a common fronto-parieto-cerebellar network for ER and WM, as well as subregions differentially involved in each function. Specifically, there were two main findings. First, the results differentiated common and specific subregions within the prefrontal cortex: (i) left dorsolateral areas were recruited by both functions, possibly reflecting monitoring operations; (ii) bilateral anterior and ventrolateral areas were more activated during ER than during WM, possibly reflecting retrieval mode and cue-specific ER operations, respectively; and (iii) left posterior/ventral (Broca's area) and bilateral posterior/dorsal areas were more activated during WM than during ER, possibly reflecting phonological and generic WM operations, respectively. Second, hippocampal and parahippocampal regions were activated not only for ER but also for WM. This result suggests that indexing operations mediated by the medial temporal lobes apply to both long-term and short-term memory traces. Overall, our results show that direct cross-function comparisons are critical to understand the role of different brain regions in various cognitive functions.     

Remembering forward: neural correlates of memory and prediction in human motor adaptation

We used functional MR imaging (FMRI), a robotic manipulandum and systems identification techniques to examine neural correlates of predictive compensation for spring-like loads during goal-directed wrist movements in neurologically-intact humans. Although load changed unpredictably from one trial to the next, subjects nevertheless used sensorimotor memories from recent movements to predict and compensate upcoming loads. Prediction enabled subjects to adapt performance so that the task was accomplished with minimum effort. Population analyses of functional images revealed a distributed, bilateral network of cortical and subcortical activity supporting predictive load compensation during visual target capture. Cortical regions - including prefrontal, parietal and hippocampal cortices - exhibited trial-by-trial fluctuations in BOLD signal consistent with the storage and recall of sensorimotor memories or “states” important for spatial working memory. Bilateral activations in associative regions of the striatum demonstrated temporal correlation with the magnitude of kinematic performance error (a signal that could drive reward-optimizing reinforcement learning and the prospective scaling of previously learned motor programs). BOLD signal correlations with load prediction were observed in the cerebellar cortex and red nuclei (consistent with the idea that these structures generate adaptive fusimotor signals facilitating cancelation of expected proprioceptive feedback, as required for conditional feedback adjustments to ongoing motor commands and feedback error learning). Analysis of single subject images revealed that predictive activity was at least as likely to be observed in more than one of these neural systems as in just one. We conclude therefore that motor adaptation is mediated by predictive compensations supported by multiple, distributed, cortical and subcortical structures.     

Distinct neural correlates of associative working memory and long-term memory encoding in the medial temporal lobe

Increasing evidence suggests a role for the hippocampus not only in long-term memory (LTM) but also in relational working memory (WM) processes, challenging the view of the hippocampus as being solely involved in episodic LTM. However, hippocampal involvement reported in some neuroimaging studies using "classical" WM tasks may at least partly reflect incidental LTM encoding. To disentangle WM processing and LTM formation we administered a delayed-match-to-sample associative WM task in an event-related fMRI study design. Each trial of the WM task consisted of four pairs of faces and houses, which had to be maintained during a delay of 10s. This was followed by a probe phase consisting of three consecutively presented pairs; for each pair participants were to indicate whether it matched one of the pairs of the encoding phase. After scanning, an unexpected recognition-memory (LTM) task was administered. Brain activity during encoding was analyzed based on WM and LTM performance. Hence, encoding-related activity predicting WM success in the absence of successful LTM formation could be isolated. Furthermore, regions critical for successful LTM formation for pairs previously correctly processed in WM were analyzed. Results showed that the left parahippocampal gyrus including the fusiform gyrus predicted subsequent accuracy on WM decisions. The right anterior hippocampus and left inferior frontal gyrus, in contrast, predicted successful LTM for pairs that were previously correctly classified in the WM task. Our results suggest that brain regions associated with higher-level visuo-perceptual processing are involved in successful associative WM encoding, whereas the anterior hippocampus and left inferior frontal gyrus are involved in successful LTM formation during incidental encoding.     

Assessment of the early organization and maturation of infants' cerebral white matter fiber bundles: a feasibility study using quantitative diffusion tensor imaging and tractography

The human infant is particularly immature at birth and brain maturation, with the myelination of white matter fibers, is protracted until adulthood. Diffusion tensor imaging offers the possibility to describe non invasively the fascicles spatial organization at an early stage and to follow the cerebral maturation with quantitative parameters that might be correlated with behavioral development. Here, we assessed the feasibility to study the organization and maturation of major white matter bundles in eighteen 1- to 4-month-old healthy infants, using a specific acquisition protocol customized to the immature brain (with 15 orientations of the diffusion gradients and a 700 s mm(-2)b factor). We were able to track most of the main fascicles described at later ages despite the low anisotropy of the infant white matter, using the FACT algorithm. This mapping allows us to propose a new method of quantification based on reconstructed tracts, split between specific regions, which should be more sensitive to specific changes in a bundle than the conventional approach, based on regions-of-interest. We observed variations in fractional anisotropy and mean diffusivity over the considered developmental period in most bundles (corpus callosum, cerebellar peduncles, cortico-spinal tract, spino-thalamic tract, capsules, radiations, longitudinal and uncinate fascicles, cingulum). The results are in good agreement with the known stages of white matter maturation and myelination, and the proposed approach might provide important insights on brain development.     

Failing to deactivate: the association between brain activity during a working memory task and creativity

Working memory (WM) is an essential component for human higher order cognitive activities. Creativity has been essential to the development of human civilization. Previous studies from different fields have suggested creativity and capacity of WM have opposing characteristics possibly in terms of diffuse attention. However, despite a number of functional imaging studies on creativity, how creativity relates to brain activity during WM has never been investigated. In this functional magnetic resonance imaging (fMRI) study, we investigated this issue using an n-back WM paradigm and a psychometric measure of creativity (a divergent thinking test). A multiple regression analysis revealed that individual creativity was significantly and positively correlated with brain activity in the precuneus during the 2-back task (WM task), but not during the non-WM 0-back task. As the precuneus shows deactivation during cognitive tasks, our findings show that reduced task induced deactivation (TID) in the precuneus is associated with higher creativity measured by divergent thinking. The precuneus is included in the default mode network, which is deactivated during cognitive tasks. The magnitude of TID in the default mode network is considered to reflect the reallocation of cognitive resources from networks irrelevant to the performance of the task. Thus, our findings may indicate that individual creativity, as measured by the divergent thinking test, is related to the inefficient reallocation of attention, congruent with the idea that diffuse attention is associated with individual creativity.     

Neural correlates of relational and item-specific encoding during working and long-term memory in schizophrenia

Successful long-term memory (LTM) depends upon effective control of information in working memory (WM), and there is evidence that both WM and LTM are impaired by schizophrenia. This study tests the hypothesis that LTM deficits in schizophrenia may result from impaired control of relational processing in WM due to dorsolateral prefrontal cortex (DLPFC) dysfunction. fMRI was performed on 19 healthy controls and 20 patients with schizophrenia during WM tasks emphasizing relational (reorder trials) versus item-specific (rehearse trials) processing. WM activity was also examined with respect to LTM recognition on a task administered outside the scanner. Receiver operator characteristic analysis assessed familiarity and recollection components of LTM. Patients showed a disproportionate familiarity deficit for reorder versus rehearse trials against a background of generalized LTM impairments. Relational processing during WM led to DLPFC activation in both groups. However, this activation was less focal in patients than in controls, and patients with more severe negative symptoms showed less of a DLPFC increase. fMRI analysis of subsequent recognition performance revealed a group by condition interaction. High LTM for reorder versus rehearse trials was associated with bilateral DLPFC activation in controls, but not in patients who activated the left middle temporal and inferior occipital gyrus. Results indicate that although patients can activate the DLPFC on a structured relational WM task, this activation is less focal and does not translate to high retrieval success, suggesting a disruption in the interaction between WM and LTM processes in schizophrenia.     

Problem solving and diabetes self-management: investigation in a large, multiracial sample

OBJECTIVE: Problem solving is a core aspect of effective diabetes and chronic illness self-management, yet there are relatively few objective evaluations of problem-solving skills, especially in large, multiracial samples. RESEARCH DESIGN AND METHODS: A multiracial sample of 506 adults who have type 2 diabetes were assessed on a variety of patient characteristics, self-management behaviors, and biological and psychosocial measures. They also completed the Diabetes Problem-Solving Interview (DPSI). RESULTS: DPSI scores revealed significant variability across patients in problem-solving skill and were related to a number of comorbid conditions and complications but not to several other demographic factors, including race/ethnicity. Problem solving was also related to self-management behaviors (eating and exercise patterns), biological variables (A1C and lipids), and psychosocial measures (Diabetes Distress Scale) in multivariable analyses controlling for a variety of potential confounding factors. CONCLUSIONS: Diabetes problem solving, as measured by the DPSI, is an important patient skill related to several key diabetes management variables that appears applicable across racial and ethnic groups. Future research is needed to identify the generality versus specificity of diabetes problem solving and practical interventions to enhance problem-solving skills.     

Changes in brain network activity during working memory tasks: a magnetoencephalography study

In this study, we elucidate the changes in neural oscillatory processes that are induced by simple working memory tasks. A group of eight subjects took part in modified versions of the N-back and Sternberg working memory paradigms. Magnetoencephalography (MEG) data were recorded, and subsequently processed using beamformer based source imaging methodology. Our study shows statistically significant increases in θ oscillations during both N-back and Sternberg tasks. These oscillations were shown to originate in the medial frontal cortex, and further to scale with memory load. We have also shown that increases in θ oscillations are accompanied by decreases in β and γ band oscillations at the same spatial coordinate. These decreases were most prominent in the 20-40 Hz frequency range, although spectral analysis showed that γ band power decrease extends up to at least 80 Hz. β/γ Power decrease also scales with memory load. Whilst θ increases were predominately observed in the medial frontal cortex, β/γ decreases were associated with other brain areas, including nodes of the default mode network (for the N-back task) and areas associated with language processing (for the Sternberg task). These observations are in agreement with intracranial EEG and fMRI studies. Finally, we have shown an intimate relationship between changes in β/γ band oscillatory power at spatially separate network nodes, implying that activity in these nodes is not reflective of uni-modal task driven changes in spatially separate brain regions, but rather represents correlated network activity. The utility of MEG as a non-invasive means to measure neural oscillatory modulation has been demonstrated and future studies employing this technology have the potential to gain a better understanding of neural oscillatory processes, their relationship to functional and effective connectivity, and their correspondence to BOLD fMRI.     

Neurocognitive correlates of incidental verbal memory encoding: a magnetoencephalographic (MEG) study

In our current study, we applied whole head magnetoencephalography (MEG) in a subsequent memory paradigm. Magnetic fields were recorded while 20 healthy subjects (10 females, 10 males) incidentally encoded words during semantic and structural verbal processing tasks. Physiological data were then sorted according to the performance in subsequent memory tests and according to levels of processing, respectively, and analyzed for gender effects. Behavioral results show a clear advantage of semantic processing over structural processing with respect to retrieval success for both females and males. Despite alikeness of behavioral data, MEG results show considerable differences between males and females concerning both subsequent memory effects and levels of processing effects. For male subjects, we identified more distinct magnetic fields in anterior regions for subsequently remembered than for subsequently forgotten words (latency range from 300-650 ms after word onset) and for semantic processing than for structural processing, respectively. For female subjects, corresponding magnetic field differences pointed to posterior regions (subsequent memory effects from 450 ms to 750 ms after word onset). No qualitative differences were observed between subsequent memory effects during semantic processing compared to subsequent memory effects during structural processing. We try to reconcile results from male data with previous findings concerning subsequent memory effects by proposing the concept of width of processing, which holds that incidental memory formation is mediated by frontal activity on a physiological level and brought forward on a cognitive level by enhanced associating imposed by the task demands of semantic processing. Female data cannot be fully incorporated in this framework, but all the more prompt further gender-specific analyses of subsequent memory effects.     

Individual differences in rCBF correlates of syntactic processing in sentence comprehension: effects of working memory and speed of processing

Positron emission tomography (PET) was used to determine the effect of working memory and speed of sentence processing on regional cerebral blood flow (rCBF) during syntactic processing in sentence comprehension. PET activity associated with making plausibility judgments about syntactically more complex subject-object (SO) sentences (e.g., The juice that the child spilled stained the rug) was compared to that associated with making judgments about synonymous syntactically simpler object-subject (OS) sentences (e.g., The child spilled the juice that stained the rug). Two groups of nine subjects differing in working memory and matched for speed of sentence processing both showed increases in rCBF in lateral posteroinferior frontal lobe bilaterally. The subjects were reclassified to form two groups of eight subjects who were matched for working memory but who differed in speed of sentence processing. Fast-performing subjects activated lateral posteroinferior frontal lobe bilaterally and slow-performing subjects showed activation of left superior temporal lobe. The results indicate that rCBF responses to syntactic comprehension tasks vary as a function of speed of sentence processing but not as a function of working memory.     

基于fMRI功能连接度分析正常人相关脑区在运动过程中的参与程度

目的 在运动及静息两种状态下,观察初级运动区(M1)与其他运动相关区域之间功能连接程度,分析特定功能区在运动执行过程中的作用.方法 选取6名正常人作为研究对象,进行血氧水平依赖功能磁共振成像(BOLD-fMRI)检查.功能成像分为静息功能、右手运动功能、左手运动功能三部分.运动功能采用Block设计,采取手指顺序对指任务.扫描结果 采用统计参数图 (SPM2)进行数据分析和脑功能区定位.功能连接度采用时间相关算法,选取运动任务时对应的最强激活点(均为一侧M1区)作为种子点,分别在静息功能数据和运动功能数据中将该种子区与相应全脑做相关分析,计算不同脑区与种子区之间的相关性,以Z值反映其功能连接程度,并观察同一脑区在运动及静息两种状态下与种子点之间Z值的变化.结果 在静息状态下,与种子点相关联的区域为双侧躯体感觉运动区(SMC)、辅助运动区(SMA)及同侧顶上小叶(SPL);在运动状态下,与种子点相关联的区域为双侧SMC、SMA、同侧SPL及小脑前叶(ALC);在运动状态下双侧SMC及SMA之间功能联系的Z值较静息状态下普遍增大.结论 静息状态下双侧SMC、SMA及同侧SPL之间存在比较稳定的功能联系;运动状态下双侧SMC及SMA之间功能联系增强.运动肢体同侧ALC参与运动任务的执行,但不参与静息状态下运动区之间的功能连接.     

Cortico-striatal connectivity and cognition in normal aging: a combined DTI and resting state fMRI study

Resting state fMRI studies have found that cognitive decline in aging is associated with alterations in functional connectivity of distributed neural systems in the brain. While functional connections have been shown to rely on the underlying structural connectivity, direct structural connections have been studied in only a few distributed cortical systems so far. It is well known that subcortical nuclei have structural connections to the entire cortex. We hypothesized that structural subcortico-cortical connections may provide integral routes for communication between cortical resting state networks, and that changes in the integrity of these connections have a role in cognitive aging. We combined anatomical MRI, diffusion tensor MRI, and resting state fMRI in 100 healthy elderly to identify fiber bundles connecting cortical resting state networks to subcortical nuclei. In identified tracts, white matter fiber bundle integrity measures were compared to composite cognitive measures on executive function, processing speed, and memory performance. The integrity (FA values) in selected fiber bundles correlated strongly with cognitive measures on executive function and processing speed. Correlation was most pronounced between executive function and fiber bundles connecting the putamen to the dorsal attention network (r=0.73, p<0.001). Our findings show that unique cortico-subcortical fiber bundles can be identified for a range of cortical resting state networks, and indicate that these connections play an important role in cortical resting state network communication and cognition.     

Problem solving in nursing practice: application, process, skill acquisition and measurement

This paper analyses the role of problem solving in nursing practice including the process, acquisition and measurement of problem-solving skills It is argued that while problem-solving ability is acknowledged as critical if today's nurse practitioner is to maintain effective clinical practice, to date it retains a marginal place in nurse education curricula Further, it has attracted limited empirical study Such an omission, it is argued, requires urgent redress if the nursing profession is to meet effectively the challenges of the next decade and beyond     

Cerebrovascular hemodynamic correlates of aging in the Lou/c rat: a model of healthy aging

The LOU/c rat is an inbred strain considered a model of healthy aging. It exhibits a longer free disease lifespan and a low adiposity throughout life. While this animal model has been shown to maintain eating behavior and neuroendocrine, metabolic and cognitive functions with age, no study has yet investigated vascular correlates in this model of healthy aging. In the present work, multispectral optical imaging was used to investigate the hemodynamic response in the somatosensory cortex of LOU/c rats following forepaw stimulation in three age groups, 4, 24 and 40months. Results indicate reduced hemodynamic responses in the contralateral somatosensory cortex between young (4months) and older groups following stimulation. This decrease was associated with an increase in the spatial extent of activation. The ipsilateral response did not change with aging leading to decreased laterality. Estimations of the relative change in the local cerebral metabolic rate of oxygen during stimulation based on multimodal data showed no significant change with age. The exponent describing the relation between blood volume and blood flow changes, Grubb's parameter, did display a significant change with age which may suggest vessel compliance modifications. This work finds its relevance in recent findings underlying the importance of vascular changes with aging and its impact on neurodegenerative disease.     

Involvement of the cerebellar cortex and nuclei in verbal and visuospatial working memory: a 7 T fMRI study

The first aim of the present study was to extend previous findings of similar cerebellar cortical areas being involved in verbal and spatial n-back working memory to the level of the cerebellar nuclei. The second aim was to investigate whether different areas of the cerebellar cortex and nuclei contribute to different working memory tasks (n-back vs. Sternberg tasks). Young and healthy subjects participated in two functional magnetic resonance imaging (fMRI) studies using a 7 T MR scanner with its increased signal-to-noise ratio. One group of subjects (n=21) performed an abstract and a verbal version of an n-back task contrasting a 2-back and 0-back condition. Another group of subjects (n=23) performed an abstract and a verbal version of a Sternberg task contrasting a high load and a low load condition. A block design was used. For image processing of the dentate nuclei, a recently developed region of interest (ROI) driven normalization method of the dentate nuclei was applied (Diedrichsen et al., 2011). Whereas activated areas of the cerebellar cortex and dentate nuclei were not significantly different comparing the abstract and verbal versions of the n-back task, activation in the abstract and verbal Sternberg tasks was significantly different. In both n-back tasks activation was most prominent at the border of lobules VI and Crus I, within lobule VII, and within the more caudal parts of the dentate nucleus bilaterally. In Sternberg tasks the most prominent activations were found in lobule VI extending into Crus I on the right. In the verbal Sternberg task activation was significantly larger within right lobule VI compared to the abstract Sternberg task and compared to the verbal n-back task. Activations of rostral parts of the dentate were most prominent in the verbal Sternberg task, whereas activation of caudal parts predominated in the abstract Sternberg task. On the one hand, the lack of difference between abstract and verbal n-back tasks and the lack of significant lateralization suggest a more general contribution of the cerebellum to working memory regardless of the modality. On the other hand, the focus of activation in right lobule VI in the verbal Sternberg task suggests specific cerebellar contributions to verbal working memory. The verbal Sternberg task emphasizes maintenance of stimuli via phonological rehearsal, whereas central executive demands prevail in n-back tasks. Based on the model of working memory by Baddeley and Hitch (1974), the present results show that different regions of the cerebellum support functions of the central executive system and one of the subsidiary systems, the phonological loop.     

Load- and practice-dependent increases in cerebro-cerebellar activation in verbal working memory: an fMRI study

Load-dependent and practice-related changes in neocortical and cerebellar structures involved in verbal working memory (VWM) were investigated using functional MRI (fMRI) and a two alternative forced choice Sternberg paradigm. Using working memory loads ranging from 2 to 6 letters, regions exhibiting linear and quadratic trends in load-dependent activations were identified. Behaviorally, reaction time measurements revealed significant linear increases with increasing memory load, and significant decreases with increased task practice. Brain activations indicated a preponderance of linear load-dependent responses in both superior (lobule VI/Crus I) and inferior (lobule VIIB/VIIIA) cerebellar hemispheres, as well as in areas of neocortex including left precentral (BA 6), inferior frontal (BA 47), parahippocampal (BA 35), inferior parietal (BA 40), cingulate (BA 32), and right inferior and middle frontal (BA 46/47) regions. Fewer voxels exhibited quadratic without linear trends with the most prominent of these activations located in left inferior parietal (BA 40), precuneus, and parahippocampal regions. Analysis of load x session interactions revealed that right inferior cerebellar and left inferior parietal activations increased with practice, as did the correlations between activation in each region with reaction time, suggesting that changes in this cerebro-cerebellar network underlie practice-related increases in efficiency of VWM performance. These results replicate and extend our previous findings of fMRI activation in the cerebellum during VWM, and demonstrate predominately linear increases in cerebro-cerebellar activation with increasing memory load as well as changes in network function with increased task proficiency.     

Altered effective connectivity during working memory performance in schizophrenia: a study with fMRI and structural equation modeling

The present study aimed to explore altered effective connectivity in schizophrenic patients while performing a 2-back working memory task. Twelve right-handed, schizophrenic patients treated with typical or atypical antipsychotics and 6 healthy control subjects were studied with fMRI while performing a "2-back" working memory task. Effective connectivity within a cortical-subcortical-cerebellar network for mnemonic information processing was assessed and compared between both groups. The path model included cortico-cortical connections comprising the parietal association cortex, ventrolateral prefrontal cortex (VLPFC), and the dorsolateral prefrontal cortex (DLPFC) as well as a cortico-cerebellar feedback loop comprising prefrontal cortex, contralateral cerebellum, and thalamus. Group differences were analyzed with a stacked models approach. Relative to normal controls, both patient groups revealed a pattern of reduced connectivity within the prefrontal-cerebellar and the cerebellar-thalamic limbs but enhanced connectivity in the thalamo-cortical limb of the cortical-cerebellar circuit. Moreover, a direct comparison of both treatment groups revealed enhanced connectivity in the interhemispheric connections between the cortical association areas in patients treated with atypical antipsychotics. However, right prefrontal and left parieto-frontal path coefficients were lower in the patient group receiving atypical antispychotic drugs. The findings suggest that the relationship between pathology in cortical-subcortical cerebellar networks and associated functional connectivity is complex and may include aspects of increased and decreased levels of connectivity consistent with the notion of "cognitive dysmetria" in schizophrenia. The observed pronounced connectivity within thalamo-cortical projections could be attributed to a compensatory increase of thalamic input in the presence of disrupted effective connectivity within the preceding limb of the cortical-cerebellar circuitry. The study demonstrated the feasibility of structural equation modeling for the investigation of group and treatment-related differences in effective connectivity and provides a promising approach to further disentangle the relationship between altered functional capacity and associated fMRI signal changes.