The Complex Interplay Between Trait Fatigue and Cognition in Multiple Sclerosis.

Cognitive impairments are frequent in patients with Multiple Sclerosis (MS). Yet, the influence of MS-related symptoms on cognitive status is not clear. Studies investigating the impact of trait fatigue along with anxio-depressive symptoms on cognition are seldom, and even less considered fatigue as multidimensional. Moreover, these studies provided conflicting results. Twenty-nine MS patients and 28 healthy controls, matched on age, gender and education underwent a full comprehensive neuropsychological assessment. Anxio-depressive and fatigue symptoms were assessed using the HAD scale and the MFIS, respectively. Six composite scores were derived from the neuropsychological assessment, reflecting the cognitive domains of working memory, verbal and visual learning, executive functions, attention and processing speed. Stepwise regression analyses were conducted in each group to investigate if trait cognitive and physical fatigue, depression and anxiety are relevant predictors of performance in each cognitive domain. In order to control for disease progression, patient's EDSS score was also entered as predictor variable. In the MS group, trait physical fatigue was the only significant predictor of working memory score. Cognitive fatigue was a predictor for executive functioning performance and for processing speed (as well as EDSS score for processing speed). In the healthy controls group, only an association between executive functioning and depression was observed. Fatigue predicted cognition in MS patients only, beyond anxio-depressive symptoms and disease progression. Considering fatigue as a multidimensional symptom is paramount to better understand its association with cognition, as physical and cognitive fatigue are predictors of different cognitive processes.

Incidental Verbal Semantic Processing Recruits the Fronto-temporal Semantic Control Network.

The frontoparietal semantic network, encompassing the inferior frontal gyrus and the posterior middle temporal cortex, is considered to be involved in semantic control processes. The explicit versus implicit nature of these control processes remains however poorly understood. The present study examined this question by assessing regional brain responses to the semantic attributes of an unattended stream of auditory words while participants' top-down attentional control processes were absorbed by a demanding visual search task. Response selectivity to semantic aspects of verbal stimuli was assessed via a functional magnetic resonance imaging response adaptation paradigm. We observed that implicit semantic processing of an unattended verbal stream recruited not only unimodal and amodal cortices in posterior supporting semantic knowledge areas, but also inferior frontal and posterior middle temporal areas considered to be part of the semantic control network. These results indicate that frontotemporal semantic networks support incidental semantic (control) processes.

Brain Metabolic Dysfunction in Capgras Delusion During Alzheimer's Disease: A Positron Emission Tomography Study.

Capgras delusion is characterized by the misidentification of people and by the delusional belief that the misidentified persons have been replaced by impostors, generally perceived as persecutors. Since little is known regarding the neural correlates of Capgras syndrome, the cerebral metabolic pattern of a patient with probable Alzheimer's disease (AD) and Capgras syndrome was compared with those of 24-healthy elderly participants and 26 patients with AD without delusional syndrome. Comparing the healthy group with the AD group, the patient with AD had significant hypometabolism in frontal and posterior midline structures. In the light of current neural models of face perception, our patients with Capgras syndrome may be related to impaired recognition of a familiar face, subserved by the posterior cingulate/precuneus cortex, and impaired reflection about personally relevant knowledge related to a face, subserved by the dorsomedial prefrontal cortex.

[The effect of normal and pathological aging on cognition]. / Les effets du vieillissement normal et pathologique sur la cognition.

Cognitive deficits in the executive and memory domains are observed in normal aging and Alzheimer's disease (AD). These deficits are associated with changes at the brain activity level. However, a series of factors are prone to delay the occurrence of cognitive deficits, such as mental stimulation or physical activity. Similarly, cognitive rehabilitation allows improving the daily life functioning of patients with AD. The identification of factors and techniques that contribute to maintain cognitive efficiency and/or counteract the effects of AD will allow optimizing quality of life of older people.

[Brain imaging of reflection on self]. / Imagerie cérébrale de la réflexion sur soi.

Precise brain regions are activated when a subject gives a judgment on himself. Those are the medial parietal cortex, essentially related to episodic memory processing, and the ventromedial prefrontal cortex, recruited for evaluating the personal valence of an information. These regions are not activated in Alzheimer's disease. The decrease of awareness for own deficits in a patient with Alzheimer's disease would depend on a reduction of episodic memory capacities and a worsening of judgment for self significance.

Metabolic correlates of clinical heterogeneity in questionable Alzheimer's disease.

Thirty-four subjects with questionable Alzheimer's disease (QAD) were included in a 3-year prospective study and underwent neuropsychological testing and measurement of brain metabolism using FDG-PET at entry. Seventeen patients (50%) did not convert to AD during the follow-up period. Compared to elderly controls of similar age, the cerebral activity of non-converters was reduced in the dorsolateral prefrontal cortex. Moreover, the variability of metabolism in the posterior cingulate cortex was related to their visuospatial memory performance, while disparity in parietal activity was related to their verbal memory performance. These results demonstrate the cerebral metabolic heterogeneity of patients with QAD. Initial functional images of converters showed that activity was already impaired in the posterior cingulate, lateral temporal cortex, anterior cingulate and orbitofrontal cortex. This metabolic pattern is consistent with a pre-dementia stage of AD, and highlights the fact that significant frontal metabolic involvement may be associated with impaired activity in posterior associative cortices in very early AD.

A comparison of unawareness in frontotemporal dementia and Alzheimer's disease.

BACKGROUND: Loss of insight is a core diagnostic feature of frontotemporal dementia (FTD) and anosognosia is frequently reported in Alzheimer's disease (AD). AIM: To compare unawareness (anosognosia) for different symptoms, measured with a discrepancy score between patient's and caregiver's assessment, in AD and FTD. METHOD: In a prospective, multi-centre study, 123 patients with probable AD, selected according to the NINCDS-ADRDA procedure, were matched for age, sex, education, disease duration and dementia severity to patients with FTD (n = 41), selected according to international consensus criteria. A research complaint questionnaire was used to obtained patient's and caregiver's assessment concerning neuropsychological and behavioural symptoms. Data were compared in each group and between groups. Unawareness (measured by discrepancy scores) was compared between patients with AD and FTD. RESULTS: The caregivers generally assessed symptoms more severely than did patients, but both patient groups reported changes in affect (depressive mood or irritability) as their caregivers did. Unawareness was greater in patients with FTD than in patients with AD for language and executive difficulties, and for changes in behaviour and daily activities. CONCLUSION: The main finding is that unawareness was observed in both patients with FTD and patients with AD for most clinical domains. However, qualitative and quantitative differences showed that lack of awareness was greater in patients with FTD.

Is Alzheimer's disease a disconnection syndrome? Evidence from a crossmodal audio-visual illusory experiment.

In Alzheimer's disease (AD), loss of connectivity in the patient's brain has been evidenced by a range of electrophysiological and neuroimaging studies. However, few neuropsychological research projects have sought to interpret the cognitive modifications following the appearance of AD in terms of a disconnection syndrome. In this paper, we sought to investigate brain connectivity in AD via the study of a crossmodal effect. More precisely, we examined the integration of auditory and visual speech information (the McGurk effect) in AD patients and matched control subjects. Our results revealed impaired crossmodal integration during speech perception in AD, which was not associated with disturbances in the separate processing of auditory and visual speech stimuli. In conclusion, our data suggest the occurrence of a specific, audio-visual integration deficit in AD, which might be the consequence of a connectivity breakdown and corroborate the observation from other studies of crossmodal deficits between the auditory and visual modalities in this population.

Short-term memory and the left intraparietal sulcus: focus of attention? Further evidence from a face short-term memory paradigm.

This study explored the validity of an attentional account for the involvement of the left intraparietal sulcus (IPS) in visual STM tasks. This account considers that during STM tasks, the IPS acts as an attentional modulator, maintaining activation in long-term memory networks that underlie the initial perception and processing of the specific information to be retained. In a recognition STM paradigm, we presented sequences of unfamiliar faces and instructed the participants to remember different types of information: either the identity of the faces or their order of presentation. We hypothesized that, if the left IPS acts as an attentional modulator, it should be active in both conditions, but connected to different neural networks specialized in serial order or face identity processing. Our results showed that the left IPS was activated during both order and identity encoding conditions, but for different reasons. During order encoding, the left IPS showed functional connectivity with order processing areas in the right IPS, bilateral premotor and cerebellar cortices, reproducing earlier results obtained in a verbal STM experiment. During identity encoding, the left IPS showed preferential functional connectivity with right temporal, inferior parietal and medial frontal areas involved in detailed face processing. These results not only support an attentional account of left IPS involvement in visual STM, but given their similarity with previous results obtained for a verbal STM task, they further highlight the importance of the left IPS as an attentional modulator in a variety of STM tasks.

The left intraparietal sulcus and verbal short-term memory: focus of attention or serial order?

One of the most consistently activated regions during verbal short-term memory (STM) tasks is the left intraparietal sulcus (IPS). However, its precise role remains a matter of debate. While some authors consider the IPS to be a specific store for serial order information, other data suggest that it serves a more general function of attentional focalization. In the current fMRI experiment, we investigated these two hypotheses by presenting different verbal STM conditions that probed recognition for word identity or word order and by assessing functional connectivity of the left IPS with distant brain areas. If the IPS has a role of attentional focalization, then it should be involved in both order and item conditions, but it should be connected to different brain regions, depending on the neural substrates involved in processing the different types of information (order versus phonological/orthographic) to be remembered in the item and order STM conditions. We observed that the left IPS was activated in both order and item STM conditions but for different reasons: during order STM, the left IPS was functionally connected to serial/temporal order processing areas in the right IPS, premotor and cerebellar cortices, while during item STM, the left IPS was connected to phonological and orthographic processing areas in the superior temporal and fusiform gyri. Our data support a position considering that the left IPS acts as an attentional modulator of distant neural networks which themselves are specialized in processing order or language representations. More generally, they strengthen attention-based accounts of verbal STM.

Exploration of the neural substrates of executive functioning by functional neuroimaging.

This review presents neuroimaging studies that have explored the cerebral substrates of executive functioning. These studies have demonstrated that different executive functions not only recruit various frontal areas but also depend upon posterior (mainly parietal) regions. These results are in accordance with the hypothesis that executive functioning relies on a distributed cerebral network that is not restricted to anterior cerebral areas. However, there exists an important heterogeneity in the cerebral areas associated with these different processes, and also between different tasks assessing the same process. Since these discrepant results could be due to the paradigms used (subtraction designs), recent results obtained with conjunction and interaction analyses are presented, which confirm the role of parietal areas in executive functioning and also demonstrate the existence of some specificity in the neural substrates of the executive processes of updating, shifting and inhibition. Finally, functional magnetic resonance imaging studies show that the activity in cerebral areas involved in executive tasks can be transient or sustained. Consequently, to better characterize the functional role of areas associated with executive functioning, it is important to take into account not only the localization of cerebral activity but also the temporal pattern of this activity.

Cerebral metabolic correlates of four dementia scales in Alzheimer's disease.

Different scales can be used to evaluate dementia severity in Alzheimer's disease (AD). They do assess different cognitive or functional abilities, but their global scores are frequently in mutual correlation. Functional imaging provides an objective method for the staging of dementia severity. Positron emission tomography was used to assess the relationship between brain metabolism and four dementia scales that reflect a patient's global cognitive abilities (mini mental state), caregiver's evaluation of cognitive impairment (newly designed scale), daily living functioning (instrumental activities of daily living) and global dementia (clinical dementia rating). We wondered whether different clinical dementia scales would be related to severity of metabolic impairment in the same brain regions, and might reflect impairment of common cognitive processes. 225 patients with probable AD were recruited in a prospective multicentre European study. All clinical scales were related to brain metabolism in associative temporal, parietal or frontal areas. A factorial analysis demonstrated that all scales could be classified in a single factor. That factor was highly correlated to decrease of cerebral activity in bilateral parietal and temporal cortices, precuneus, and left middle frontal gyrus. This finding suggests that global scores for all scales provided similar information on the neural substrate of dementia severity. Capitalizing on the neuroimaging literature, dementia severity reflected by reduced metabolism in posterior and frontal associative areas in AD might be related to a decrease of controlled processes.

Functional imaging of executive functions.

Executive functioning refers to cognitive processes that facilitate our adaptation to new or complex situations when action routines are not efficient. Neuropsychological studies in brain-damaged patients suggested that executive functions were predominantly dependent on prefrontal regions. However, prefrontal lesions frequently occurred in a context of more widespread brain involvement, and a dysexecutive syndrome was described in posterior cortical dementia of the Alzheimer type. Functional imaging can precisely identify brain networks involved in executive functioning. We discuss functional imaging studies that show both frontal and posterior activation during executive tasks and bring information concerning unity and diversity in executive processes.

Alzheimer's disease as a disconnection syndrome?

This paper reviews the growing amount of evidence supporting the hypothesis that Alzheimer's disease includes a disconnection syndrome. This evidence came mainly from neuropathological, electrophysiological, and neuroimaging studies. Moreover, a few recent neuropsychological studies have also explored the effects of a disconnection between cerebral areas on cognitive functioning. Finally, and more generally, the contribution of this interpretation to the understanding of Alzheimer's disease cognitive deficits is considered.

A PET investigation of lexicality and phonotactic frequency in oral language processing.

Lexicality and phonotactic frequency effects are observed in many cognitive studies on language processing, but little is known about their underlying neural substrates, especially with regard to phonotactic frequency effects. Here, we conducted a positron emission tomography (PET) study in which 11 right-handed volunteers had either to repeat or to listen to lists of words, high phonotactic frequency nonwords, and low phonotactic frequency nonwords. The comparison of word versus nonword processing consistently confirmed previous findings of left temporal and prefrontal activations classically ascribed to lexicosemantic processing. Higher activation was found in the right posterior superior temporal gyrus when comparing high phonotactic frequency nonwords to words, but not when comparing low phonotactic frequency nonwords to words. We propose that this region is implicated in the formation of temporary phonological representations for high-probability phonological events, which may support processing of high phonotactic frequency nonwords.

Effects of incidental and intentional feature binding on recognition: a behavioural and PET activation study.

Using Positron Emission Tomography (PET), we investigated cerebral regions associated with the episodic recognition of words alone and words bound to contextual colours. Two modes of colour encoding were tested: incidental and intentional word-to-colour binding. Word-only recognition was associated with brain activation in a lexico-semantic left middle temporal region and in the cerebellum following an incidental colour encoding, and with brain activation in the left posterior middle frontal gyrus, right anterior cingulate and right inferior frontal gyrus following an intentional encoding. Recognition of bound features was associated with activation in left prefrontal and superior parietal regions following an incidental colour encoding, and with preferential right prefrontal cortex activation following an intentional colour encoding. Our results are in line with the hypothesis of a parietal involvement in context processing, and prefrontal areas in monitoring retrieval processes. Our results also support the hypothesis of a 'cortical asymmetry for reflective activity' (CARA).

Contribution of lexico-semantic processes to verbal short-term memory tasks: a PET activation study.

Recent studies have demonstrated the intervention of long-term memory processes in verbal STM tasks and several cognitive models have been proposed to explain these effects. A PET study was performed in order to determine whether supplementary cerebral areas are involved when subjects have to execute short-term memory tasks for items having representations in long-term memory (in comparison to items without such representations: words vs non-words). Results indicate that verbal STM for words specifically involves the left middle temporal gyrus (BA 21) and temporo-parietal junction (BA 39). These areas can be associated with lexical and semantic processes. These results are in agreement with cognitive models that postulate the simultaneous influence of lexical and semantic long-term representations on verbal STM processes and/or a lexico-semantic buffer.

The functional anatomy of inhibition processes investigated with the Hayling task.

The cortical areas involved in inhibition processes were examined with positron emission tomography (PET). The tasks administered to subjects were an adaptation of the Hayling test. In the first condition (response initiation), subjects had to complete sentences with a word clearly suggested by the context, whereas in the second condition (response inhibition), subjects had to produce a word that made no sense in the context of the sentence. Results indicated that the response initiation processes were associated to increases of activity in the left inferior frontal gyrus (BA 45/47), whereas response inhibition processes led to increases in a network of left prefrontal areas, including the middle (BA 9 and BA 10) and inferior (BA 45) frontal areas.

[Working memory: a neuropsychologic and cerebral imagery approach]. / La mémoire de travail: une approche neuropsychologique et par imagerie cérébrale.

The working memory model proposed by Baddeley and Hitch has frequently been used in cognitive psychology and neuropsychological studies. This model consists of several interacting components, responsible for the storage and processing of the information stored in working memory. Many neuropsychological and functional imagery data are consistent with that formulation of working memory. Moreover, many cognitive tasks have been specifically designed to explore particular aspects of working memory functioning. Taken as a whole, these data confirm that the working memory model remains a useful theoretical framework to explore memory functioning both in normal subjects and in pathological conditions.