Activation of working memory in patients at the earliest stage of multiple sclerosis—An fMRI study

Objective

Previous fMRI studies on activation of working memory in multiple sclerosis (MS) patients presented heterogeneous results. Patients were reported to have altered brain activation patterns either in typical working memory circuits or in other brain regions even if they did not have any cognitive impairment according to the test batteries. We hypothesized that brain activation patterns in patients at a very early stage of the disease at very low EDSS-Score would not differ from healthy subjects.

Methods

We examined 13 patients at an early stage of MS matched with 13 healthy controls with a detailed psychometric test battery and an fMRI working memory paradigm.

Results

Patients and healthy controls did not differ in psychometric test batteries. In both groups those cortex areas typically involved in working memory processes like dorso-lateral prefrontal (DLPFC), ventro-lateral-prefrontal (VLPFC), fronto-medial and parietal cortex areas (Brodmann 6, 7, 8, 9, 10, 32, 40, 45, 46, 47) were equally activated.

Conclusion

In contrast to former studies we found no differences in activation patterns in the fMRI scanning measuring working memory tasks between psychometrically tested homogenous groups of patients in early stages of MS and control subjects.     

Hippocampal activation in patients with mild cognitive impairment is necessary for successful memory encoding

Background

Episodic memory enables us to consciously recollect personally experienced past events. Memory performance is reduced in patients with mild cognitive impairment (MCI), an at‐risk condition for Alzheimer''s disease (AD).

Patients and methods

We used functional MRI (fMRI) to compare brain activity during memory encoding in 29 healthy elderly subjects (mean age 67.7 (SD 5.4) years) and 21 patients with MCI (mean age 69.7 (SD 7.0) years). Subjects remembered a list of words while fMRI data were acquired. Later, they had to recognise these words among a list of distractor words. The use of an event related paradigm made it possible to selectively analyse successfully encoded items in each individual. We compared activation for successfully encoded words between healthy elderly subjects and patients with MCI.

Results

The main intergroup difference was found in the left hippocampus and surrounding medial temporal lobe (MTL) regions for the patients with MCI compared with healthy subjects during successful encoding.

Conclusion

These results suggest that in patients with MCI, an increase in MTL activation is necessary for successful memory encoding. Hippocampal activation may help to link newly learned information to items already stored in memory. Increased activation in MTL regions in MCI may reflect a compensatory response to the beginning of AD pathology.Episodic memory, which enables humans to consciously recollect personally experienced past events, is based on at least two fundamental mnemonic operations: memory formation and retrieval. Event related functional MRI (fMRI) provides a unique opportunity to study the neural correlates of these processes and their subcomponents, such as successful and failed encoding.¹Studies in young healthy subjects have shown that successful declarative memory formation, measured as the difference in brain activity during encoding between subsequently remembered and forgotten items, is accompanied by increases in activity in medial temporal and inferior prefrontal areas.^{2,3,4,5,6,7,8,9,10} Structures within the medial temporal lobe (MTL) region, especially hippocampal formation,^7,11 are believed to be essential in establishing new memories.Patients with mild cognitive impairment (MCI)¹² are characterised by significant memory impairment, which is not severe enough to interfere with usual activities of daily living.¹³ The majority of patients with MCI go on to develop Alzheimer''s disease (AD).Patients with AD, in comparison with older controls, show consistently decreased MTL activation during encoding of new materials.^14,15,16,17 Fewer fMRI studies have investigated MTL encoding activation in patients with MCI,^15,16,18 showing inconsistent results. A recent fMRI study showed decreased MTL activation during a memory encoding task.¹⁵ However, another study¹⁶ found that only a subgroup of subjects with “isolated memory decline” demonstrated decreased hippocampal activation during encoding, whereas still another study¹⁹ reported increased MTL activation in cognitively intact individuals genetically at risk for AD. The variability in these fMRI results may be because the groups differed in the degree of impairment and underlying neural pathology.The degree of activation detected by fMRI within MTL regions during encoding strongly correlates with subjects'' subsequent ability to remember the items encoded.^2,8 Decreased MTL activation in patients with MCI and AD has been associated with relatively poor performance on post scan memory testing.^14,15,17 In contrast, subjects who were genetically at risk for AD, but could successfully perform the fMRI encoding task, showed increased MTL activation. It has been hypothesised that increased MTL activation during successful encoding may represent a compensatory response that allows for relatively normal memory function in the face of developing pathological change¹⁹ There is first evidence that elderly subjects with MCI and with a relatively preserved performance in the fMRI memory task show such a compensatory increased hippocampal response in comparison with healthy subjects, while patients with AD who exhibited poorer performance in the task had lower hippocampal activation.²⁰To further examine this question, it is not sufficient to compare general encoding related activation between patients with MCI and healthy subjects as this comparison would be confounded by task performance. Therefore, we used an event related fMRI paradigm, where subjects are instructed to remember visually presented words. According to task performance in subsequent recognition memory tests, all learned items can then be separated into those that are later remembered (subsequent hits) and those that are later forgotten (subsequent misses), individually for each subject. By comparing brain activation between healthy subjects and patients with MCI only for subsequent hits, brain regions can be identified that differ between groups during successful encoding into episodic memory. It has been shown previously that the degree of neural activity increases with the demands of the cognitive task and that the magnitude and spatial extent of brain activation increases with cognitive effort.^21,22,23 We hypothesise that successful memory encoding, which should be more demanding for patients with MCI than for healthy elderly subjects, would result in increased MTL activation in patients with MCI.     

Semantic strategy training increases memory performance and brain activity in patients with prefrontal cortex lesions

Objective

Memory deficit is a frequent cognitive disorder following acquired prefrontal cortex lesions. In the present study, we investigated the brain correlates of a short semantic strategy training and memory performance of patients with distinct prefrontal cortex lesions using fMRI and cognitive tests.

Methods

Twenty-one adult patients with post-acute prefrontal cortex (PFC) lesions, twelve with left dorsolateral PFC (LPFC) and nine with bilateral orbitofrontal cortex (BOFC) were assessed before and after a short cognitive semantic training using a verbal memory encoding paradigm during scanning and neuropsychological tests outside the scanner.

Results

After the semantic strategy training both groups of patients showed significant behavioral improvement in verbal memory recall and use of semantic strategies. In the LPFC group, greater activity in left inferior and medial frontal gyrus, precentral gyrus and insula was found after training. For the BOFC group, a greater activation was found in the left parietal cortex, right cingulated and precuneus after training.

Conclusion

The activation of these specific areas in the memory and executive networks following cognitive training was associated to compensatory brain mechanisms and application of the semantic strategy.     

fMRI memory assessment in healthy subjects: a new approach to view lateralization data at an individual level

We present a comprehensive and clinically applicable fMRI test—including both a verbal and a visuospatial task—for assessment of hemispheric specific memory in the medial temporal lobe (MTL). fMRI data was collected from 15 healthy right-handed volunteers. Whole-brain activation was analyzed as well as activation in two regions of interest: the MTL and the anterior speech area. Laterality indices (LI) and LI-curves were calculated using the LI toolbox of Wilke and Lidzba, 2007. The fMRI paradigms successfully visualized memory-related activity in the MTL, the verbal memory measure also provided information of language lateralization. Eleven subjects showed left lateralized verbal encoding in the MTL, visuospatial memory activation was divided equally between left and right, and 14/15 subjects had left lateralized language. Lateralization data at the group level were consistent with previous studies, but a variety of activation effects were found at the individual level indicating differences in strategy during verbal and visuospatial processing. Further studies using the presented method are needed to determine its clinical usefulness.     

Memory lateralization in medial temporal lobe epilepsy assessed by functional MRI

PURPOSE: To determine the utility of functional magnetic resonance imaging (fMRI) in preoperative lateralization of memory function in patients with medial temporal lobe epilepsy (MTLE). METHODS: Nine patients with MTLE underwent standard preoperative assessment including video-EEG and intracarotid amytal testing (IAT). fMRI was performed while subjects encoded four types of stimuli (patterns, faces, scenes, and words). Activation maps were created for each subject representing areas more active for novel than for repeated stimuli. Regions of interest were drawn around the MTL in individual subjects, suprathreshold voxels were counted, and an asymmetry index was calculated. RESULTS: In eight of nine subjects, lateralization of memory encoding by fMRI was concordant with that obtained from the IAT. Group-level analysis demonstrated greater activation in the MTL contralateral to the seizure focus such that in the left MTLE group, verbal encoding engaged the right MTL, whereas in the right MTLE group, nonverbal encoding engaged the left MTL. CONCLUSIONS: fMRI is a valid tool for assessing of memory lateralization in patients with MTLE and may therefore allow noninvasive preoperative evaluation of memory lateralization. FMRI revealed that memory encoding may be reorganized to the contralateral MTL in patients with MTLE.     

Effects of emotionally valenced working memory taxation on negative memories

Background and objectives

Memories enter a labile state during recollection. Thus, memory changes that occur during recollection can affect future instances of its activation. Having subjects perform a secondary task that taxes working memory while they recall a negative emotional memory often reduces its vividness and emotional intensity during subsequent recollections. However, researchers have not manipulated the emotional valence of the secondary task itself.

Methods

Subjects viewed a video depicting the aftermath of three fatal road traffic accidents, establishing the same negative emotional memory for all subjects. We then tested their memory for the video after randomly assigning them to no secondary task or a delayed match-to-sample secondary task involving photographs of positive, negative, or neutral emotional valence.

Results

The positive secondary task reduced memory for details about the video, whereas negative and neutral tasks did not.

Limitations

We did not assess the vividness and emotionality of the subjects' memory of the video.

Conclusions

Having subjects recall a stressful experience while performing a positively valent secondary task can decrement details of the memory and perhaps its emotionality.     

Modelling hemodynamic response function in epilepsy

Objective

Electroencephalography and functional magnetic resonance imaging (fMRI) can be combined to noninvasively map abnormal brain activation elicited by epileptic processes. A major aim was to investigate the impact of a subject-specific hemodynamic response function (HRF) to describe the differences across patients versus the use of a standard model.

Methods

We developed and applied on simulated and real data a method designed to choose optimum HRF model for identifying fMRI activation maps. In simulation, the ability of five models to reproduce data was assessed: four standard and an individual-based HRF model (ibHRF). In clinical data, drug-resistant epileptic patients underwent fMRI to investigate hemodynamic responses evoked by interictal activity.

Results

When data are simulated with models different from the standard ones, the results obtained with ibHRF are superior to those obtained with the standard HRFs. Results on real data indicate an increase in extent and degree of activation with the ibHRF in comparison of the results obtainable using standard HRFs.

Conclusions

The use of the same HRF in all patients is inappropriate and resolves in biased extension of the activation maps.

Significance

The new method could represent an useful diagnostic tool for other clinical studies that may be biased because of misspecification of HRF.     

Compensatory hyperactivations as markers of latent working memory dysfunctions in patients with obsessive-compulsive disorder: an fMRI study

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.Medical subject headings: obsessive–compulsive disorder, memory, magnetic resonance imaging, cognition     

Estudios normativos españoles en población adulta joven (proyecto NEURONORMA jóvenes): normas para las pruebas Rey-Osterrieth Complex Figure (copia y memoria) y Free and Cued Selective Reminding Test

Introduction

The Rey-Osterrieth Complex Figure (ROCF) and the Free and Cued Selective Reminding Test (FCSRT) are widely used in clinical practice. The ROCF assesses visual perception, constructional praxis, and visuo-spatial memory. The FCSRT assesses verbal learning and memory.

Objective

In this study, as part of the Spanish normative studies project in young adults (NEURONORMA young adults), we present age- and education-adjusted normative data for both tests obtained by using linear regression techniques.

Material and methods

The sample consisted of 179 healthy participants ranging in age from 18 to 49 years. We provide tables for converting raw scores to scaled scores in addition to tables with scores adjusted by socio-demographic factors.

Results

The results showed that education affects scores for some of the memory tests and the figure-copying task. Age was only found to have an effect on the performance of visuo-spatial memory tests, and the effect of sex was negligible.

Conclusions

The normative data obtained will be extremely useful in the clinical neuropsychological evaluation of young Spanish adults.     

Autobiographical memory and its association with neuropsychological function in bipolar disorder

Objective

The aim of this study was to investigate the overgeneralization of autobiographical memory (AM) in bipolar disorder (BD) and assess its association with multiple cognitive domains.

Method

Twenty-eight clinically stable bipolar I patients and an equal number of age- and gender-matched healthy controls (HC) were included. All participants were examined using the autobiographical memory test (AMT) and the neuropsychological battery including the general intelligence, attention, verbal memory, verbal fluency, visual memory, and executive functions domain. Demographic, clinical, and test variables were compared between BD and HC groups. Correlation analyses of AMT scores with cognitive functions were performed within each group, controlling for demographic and clinical variables.

Results

Total and negative scores of AMT were significantly lower in BD patients compared to HC individuals. AMT scores were significantly correlated with WAIS similarities, WCST perseverative errors, and WCST categories completed in BD, whereas AMT scores were correlated with verbal memory and verbal fluency in HC.

Conclusion

Our findings suggest that overgeneral AM is a characteristic of BD and is related to executive function. Future studies should investigate the benefit of additional treatment focusing on overgeneral AM in BD.     

Evidence for specific cognitive deficits in visual information processing in patients with OCD compared to patients with unipolar depression

Objective

Neuropsychological studies comparing cognitive performance in patients suffering from Obsessive-Compulsive Disorder (OCD) or Major Depressive Disorder (MDD) revealed deficits in the domains of verbal fluency and viso-motor speed/set shifting in both groups. Spatial working memory deficits, however, have been identified as specific markers of OCD. As yet, it has not been substantiated whether deficits in visual organization and complex visual memory are also specific to OCD and are not shared by MDD.

Method

Test performance in seven cognitive domains was assessed in 40 OCD patients, 20 MDD patients, and 40 healthy controls. Patient groups were matched according to severity of depressive symptoms.

Results

Deficits shared by both patient groups, as compared to controls, were found in delayed spatial recall and verbal fluency while verbal memory was normal in both patient groups. Only patients with OCD, but not MDD patients were impaired in the domains visual memory, viso-motor speed/set shifting, visual organization, and problem solving. In addition, OCD patients differed significantly from MDD subjects in visual organization and problem solving. Visual organization scores correlated significantly with severity of current compulsions in the OCD group (r = −.324).

Conclusions

OCD patients demonstrate difficulties in visual organization and mental manipulation of complex visual material, which are not accounted for by depressive symptoms and which constitute a specific cognitive deficit of the disorder.     

Encoding and immediate retrieval tasks in patients with epilepsy: A functional MRI study of verbal and visual memory

Purpose

Medial lobe temporal structures and more specifically the hippocampus play a decisive role in episodic memory. Most of the memory functional magnetic resonance imaging (fMRI) studies evaluate the encoding phase; the retrieval phase being performed outside the MRI. We aimed to determine the ability to reveal greater hippocampal fMRI activations during retrieval phase.

Underlying mechanisms of verbal memory deficits in obsessive-compulsive disorder and major depression--the role of cognitive self-consciousness

Background and Objectives

Previous studies have demonstrated that some individuals suffering from obsessive-compulsive disorder (OCD) are impaired in verbal memory performance. This study was designed to investigate the role of cognitive self-consciousness (CSC) as a putative underlying mechanism of these cognitive deficits.

Methods

Verbal memory performance of 36 participants with OCD, 36 individuals with major depression disorder (MDD) and 36 healthy controls was assessed with the California Verbal Learning Test under three different experimental conditions: (1) single-task condition, (2) while simultaneously focusing on their thoughts (CSC condition), (3) while simultaneously focusing on external stimuli (dual-task condition).

Results

Memory performance in the CSC condition and in the dual-task condition was reduced compared to single-task condition but no interaction effect was found.

Limitations

It remains unclear whether CSC and other concepts with an inward self-referential focus of attention (e.g. rumination) differ in the way they influence cognitive performance.

Conclusions

These results confirm the deteriorating influence of heightened CSC on verbal memory encoding but suggest that the effect is not specific to OCD.     

Functional neuroanatomy of response inhibition in bipolar disorders – Combined voxel based and cognitive performance meta-analysis

Objectives

Impaired response inhibition underlies symptoms and altered functioning in patients with bipolar disorders (BD). The interpretation of fMRI studies requires an accurate estimation of neurocognitive performance, for which individual studies are typically underpowered. Thus, we performed the first combined meta-analysis of fMRI activations and neurocognitive performance in studies investigating response inhibition in BD.

Methods

We used signed differential mapping to combine anatomical coordinates of activation and standardized differences between means to evaluate neurocognitive performance in 30 fMRI studies of response inhibition comparing controls (n = 667) and patients with BD (n = 635).

Results

Relative to controls, BD patients underactivated the right inferior frontal gyrus (rIFG) regardless of current mood state and behavioral performance. Unique to euthymia were cortical hyperactivations (left superior temporal, right middle frontal gyri) combined with subcortical hypoactivations (basal ganglia), whereas unique to mania were subcortical hyperactivations (bilateral basal ganglia), combined with cortical hypoactivations (right inferior and medial frontal gyri). The fMRI changes in euthymia were associated with normal cognitive performance, whereas manic patients committed more errors during response inhibition.

Conclusions

The rIFG hypoactivations were congruent with a BD trait, which may underlie the impaired response inhibition in mania. Euthymic BD subjects may compensate for the rIFG hypoactivations by hyperactivations of adjacent cortical areas, yielding comparable performance in inhibitory functions and suggesting possibilities for neuromodulation treatment of these cognitive impairments. The reversal of the activation pattern between mania and euthymia has implications for monitoring of treatment response and identification of imminent relapse.     

Reorganization of anterior and posterior hippocampal networks associated with memory performance in mesial temporal lobe epilepsy

Objective

To investigate the pattern of functional demarcation of hippocampal network and its relationship with memory performance in mesial temporal lobe epilepsy (mTLE) with unilateral hippocampal sclerosis.

Effect of task-irrelevant high-speed verbal stimulation on a visual/verbal word-discrimination task: An event-related potential study

Objectives

We investigated whether incomprehensible high-speed auditory speech stimulation was processed and interacted with visual-word discrimination processing. We hypothesised that an interaction might indicate the capacity of working memory (WM) to perform the temporal processing of auditory verbal information.

Methods

We recorded P300 for a visual-word discrimination Oddball paradigm in 14 healthy subjects. Auditory speech and reversed speech stimulation were presented at various speeds as task-irrelevant stimuli during the P300 tasks.

Results

The P300 latency was prolonged under forward high-speed speech stimuli (×2.5 and ×3.5) compared with the standard speed and white noise, but there was no effect of reversed speech stimuli on the P300 latency during the word-discrimination paradigm.

Conclusions

We considered that high-speed speech stimulation was processed without conscious comprehension and competed with verbal processing during the visual-word-discrimination task, possibly by interfering with the use of WM.

Significance

The present study shows the capacity of the brain to process high-speed verbal stimulation and the interaction with a visual-verbal task.     

Infant febrile seizures: Changes in declarative memory as revealed by event-related potentials

Objective

According to a widespread opinion the vast majority of infant febrile seizures (IFS) are harmless. However, IFS are often associated with hippocampal sclerosis, which should lead to deficient episodic memory with spared context-free semantic memories. Although IFS represent the most common convulsive disorder in children, these consequences are rarely examined.

Methods

We measured the hippocampal volume of 17 IFS children (7–9 years old) and an age-matched control group on the basis of MR images. Furthermore, we examined episodic and semantic memory performance with standardized neuropsychological tests. Two processes underlying recognition memory, namely familiarity and recollection, were assessed by means of event-related potentials (ERP).

Results

The IFS children did not show a decreased hippocampus volume. Intelligence, working memory, semantic and episodic memory were intact. However, ERP indices of recognition memory subprocesses revealed deficits in recollection-based remembering that presumably relies on the integrity of the hippocampus, whereas familiarity-based remembering seemed to be intact.

Conclusions

Although hippocampus volume remains unaffected, IFS seems to induce functional changes in the MTL memory network, characterized by a compensation of recollection by familiarity-based remembering.

Significance

This study significantly adds to the debate on the consequences of IFS by differentiating the impact on memory processing.     

Estudios normativos españoles en población adulta joven (Proyecto NEURONORMA jóvenes): métodos y características de la muestra

Introduction

In clinical neuropsychology, normative data are necessary to relate the performance of a subject to a reference group. These normative data should be collected from a pertinent population taking into account sociodemographic and cultural factors.

Objective

This paper describes the methods and sample characteristics of a series of Spanish normative studies on young adults (NEURONORMA young adults Project). The normative information was based on a series of selected, commonly used, neuropsychological tests covering attention, language, visual-perceptual abilities, constructional tasks, memory, and executive functions.

Material and methods

A sample of 179 cognitively normal subjects from 18 to 49 years was studied. Demographics, socio-cultural, and medical data were collected. The statistical procedure used in the normative studies is described.

Results

Sociodemographic, family background, health habits, medical history and use of drugs are presented.

Conclusions

The use of these norms should improve neuropsychological diagnostic accuracy in young Spanish subjects. These data may also be of considerable use for comparisons with other normative studies.     

Feasibility of cerebral magnetic resonance imaging in patients with externalised spinal cord stimulator

Object

Spinal cord stimulation (SCS) is a well-known treatment option for intractable neuropathic pain after spinal surgery, but its pathophysiological mechanisms are poorly stated. The goal of this study is to analyse the feasibility of using brain MRI, functional MRI (fMRI) and Magnetic Resonance Spectroscopy (MRS) as tools to analyse these mechanisms in patients with externalised neurostimulators during trial period.

Methods

The authors conducted in an in vitro and in vivo study analysing safety issues when performing brain MRI, fMRI and MRS investigations in human subjects with externalised SCS. Temperature measurements in vitro were performed simulating SCS during MRI sequences using head transmit-receive coils in 1.5 and 3 T MRI systems. 40 Patients with externalised SCS were included in the in vivo study. 20 patients underwent brain MRI, fMRI and another 20 patients underwent brain MRI and MRS.

Results

A maximal temperature increase of 0.2 °C was measured and neither electrode displacements nor hardware failures were observed. None of the patients undergoing the MRS sequences at the 1.5 or 3 T MRI scanners described any discomfort or unusual sensations.

Conclusion

We can conclude that brain MRI, fMRI and MRS studies performed in patients with externalised SCS can be safely executed.     

7T fMRI reveals feasibility of covert visual attention-based brain–computer interfacing with signals obtained solely from cortical grey matter accessible by subdural surface electrodes

Objective

There is a growing interest in brain–computer interfaces (BCI) based on invasive technologies. fMRI is exceptionally suited for selecting implant sites since BOLD signals has been shown to correlate well spatially with electric potentials recorded from the brain surface. Previous studies show that it is possible to decode covertly directed visuospatial attention using fMRI. In the present study we increase the relevance of the fMRI analysis for surface-electrodes by only allowing voxels at the surface of the brain.

Methods

We classify visuospatial attention directed to four different directions (left, right, up and down) using a support vector machine while enforcing several spatial restrictions on the voxels available for the classifier. All the spatial restrictions applied are based on how accessible the brain areas are for implanted surface electrodes.

Results

The results show that fMRI signals from only the surface of the brain are sufficient for a good classification. Data also show that the topographical pattern is quite variable across subjects.

Conclusions

A good control of BCI systems based on signals from surface electrodes can be achieved using visuospatial attention. Due to the large spatial variations in brain topography, individual mapping with fMRI to locate the optimal electrode implant sites is essential.

Significance

Visuospatial attention promises to be an effective target for implanted BCI systems.