The neural substrates of musical memory revealed by fMRI and two semantic tasks.

Recognizing a musical excerpt without necessarily retrieving its title typically reflects the existence of a memory system dedicated to the retrieval of musical knowledge. The functional distinction between musical and verbal semantic memory has seldom been investigated. In this fMRI study, we directly compared the musical and verbal memory of 20 nonmusicians, using a congruence task involving automatic semantic retrieval and a familiarity task requiring more thorough semantic retrieval. In the former, participants had to access their semantic store to retrieve musical or verbal representations of melodies or expressions they heard, in order to decide whether these were then given the right ending or not. In the latter, they had to judge the level of familiarity of musical excerpts and expressions. Both tasks revealed activation of the left inferior frontal and posterior middle temporal cortices, suggesting that executive and selection processes are common to both verbal and musical retrievals. Distinct patterns of activation were observed within the left temporal cortex, with musical material mainly activating the superior temporal gyrus and verbal material the middle and inferior gyri. This cortical organization of musical and verbal semantic representations could explain clinical dissociations featuring selective disturbances for musical or verbal material.

Musical and verbal semantic memory: two distinct neural networks?

Semantic memory has been investigated in numerous neuroimaging and clinical studies, most of which have used verbal or visual, but only very seldom, musical material. Clinical studies have suggested that there is a relative neural independence between verbal and musical semantic memory. In the present study, "musical semantic memory" is defined as memory for "well-known" melodies without any knowledge of the spatial or temporal circumstances of learning, while "verbal semantic memory" corresponds to general knowledge about concepts, again without any knowledge of the spatial or temporal circumstances of learning. Our aim was to compare the neural substrates of musical and verbal semantic memory by administering the same type of task in each modality. We used high-resolution PET H(2)O(15) to observe 11 young subjects performing two main tasks: (1) a musical semantic memory task, where the subjects heard the first part of familiar melodies and had to decide whether the second part they heard matched the first, and (2) a verbal semantic memory task with the same design, but where the material consisted of well-known expressions or proverbs. The musical semantic memory condition activated the superior temporal area and inferior and middle frontal areas in the left hemisphere and the inferior frontal area in the right hemisphere. The verbal semantic memory condition activated the middle temporal region in the left hemisphere and the cerebellum in the right hemisphere. We found that the verbal and musical semantic processes activated a common network extending throughout the left temporal neocortex. In addition, there was a material-dependent topographical preference within this network, with predominantly anterior activation during musical tasks and predominantly posterior activation during semantic verbal tasks.

Direct voxel-based comparison between grey matter hypometabolism and atrophy in Alzheimer's disease.

Although the patterns of structural and metabolic brain alterations in Alzheimer's disease are being refined and discrepancies between them are being underlined, the exact relationships between atrophy and hypometabolism are still unclear. In this study, we aimed to provide a direct comparison between grey matter atrophy and hypometabolism in a sample of patients with clinically probable Alzheimer's disease, using a voxel-based method specially designed to statistically compare the two imaging modalities. Eighteen patients with probable Alzheimer's disease of mild severity and 15 healthy aged controls underwent both high-resolution T1 MRI and resting-state (18)FDG-PET. The MRI data sets were handled using optimized VBM. The PET data were coregistered to their corresponding MRI, corrected voxel-wise for partial volume averaging and spatially normalized using the same parameters as those of their corresponding MRI volume. A differential smoothing was applied on the MRI and PET data sets to equalize their effective smoothness and resolution. For each patient, Z-score maps of atrophy and hypometabolism were created by comparing to the controls data set, respectively averaged to provide the profile of hypometabolism and atrophy, and entered in a voxel-by-voxel SPM analysis to assess the statistical differences between hypometabolism and atrophy. The observed patterns of hypometabolism and atrophy were consistent with previous studies. However, the direct comparison revealed marked regional variability in the relationship between hypometabolism and atrophy. Thus, the hypometabolism significantly exceeded atrophy in most altered structures, particularly in the posterior cingulate-precuneus, orbitofrontal, inferior temporo-parietal, parahippocampal, angular and fusiform areas. In contrast, a few hypometabolic structures among which the hippocampus exhibited similar degrees of atrophy and hypometabolism, a profile that significantly differed from the posterior cingulate. Excessive hypometabolism relative to atrophy suggests the intervention of additional hypometabolism-inducing factors, such as disconnection and amyloid deposition, resulting in genuine functional perturbation ahead of actual atrophy and perhaps of pathology as well. Conversely, in the hippocampus, where disconnection processes are also likely to occur, relative synaptic compensatory mechanisms may be taking place, maintaining neuronal activity in the face of structural alterations.

Three-dimensional surface mapping of hippocampal atrophy progression from MCI to AD and over normal aging as assessed using voxel-based morphometry.

The hippocampus is the brain structure of highest and earliest structural alteration in Alzheimer's disease (AD). New developments in neuroimaging methods recently made it possible to assess the respective involvement of the different hippocampal subfields by mapping atrophy on a 3D hippocampal surface view. In this longitudinal study on patients with mild cognitive impairment (MCI), we used such an approach to map the profile of hippocampal atrophy and its progression over an 18-month follow-up period in rapid converters to AD and "non-converters" compared to age-matched controls. For the sake of comparison, we also assessed the profile of hippocampal atrophy associated with AD and with increasing age in a healthy control population ranging from young adult to elderly. We found major involvement of the lateral part of the superior hippocampus mainly corresponding to the CA1 subfield in MCI and AD while increasing age was mainly associated with subiculum atrophy in the healthy population. Moreover, the CA1 subfield also showed highest atrophy rates during follow-up, in both rapid converters and "non-converters" although increased effects were observed in the former group. This study emphasizes the differences between normal aging and AD processes leading to hippocampal atrophy, pointing to a specific AD-related CA1 involvement while subiculum atrophy would represent a normal aging process. Our findings also suggest that the degree of hippocampal atrophy, more than its spatial localization, predicts rapid conversion to AD in patients with MCI.

Mapping the relative contribution of gray matter activity vs. volume in brain PET: a new approach.

Interpretation of brain positron emission tomography (PET) in terms of function vs. structure is ambiguous owing to the partial volume effect (PVE). Therefore, observed differences in tracer distribution could reflect differences in either activity or volume, a problem that applies principally to gray matter (GM) since white matter (WM) virtually always has uniform activity. To assess the contribution of GM volume vs. activity, we implemented a method to directly compare PET images with underlying structure, and applied it to resting-state (18)Fluoro-deoxy-glucose-PET (FDG) of healthy subjects. Methods. Average GM and WM PVE-corrected mean FDG uptake values were applied onto co-registered segmented magnetic resonance imaging data sets to generate a "virtual PET" in which activity is proportional to GM volume and resolution set to that of PET. The raw PET and virtual PET values were then compared across the sample of subjects, first voxel-wise to detect clusters with significant activity-volume mismatch, and second within regions-of-interest (ROI) to quantify mismatches between unsmoothed voxel values. Results. Relative to volume, there was significant hyperactivity of most GM structures of the dorsal brain-except the thalamus-and significant hypoactivity of the temporal lobe, hippocampal region, and cerebellum, consistent across the voxel- and ROI-based analyses. Conclusion. As applied to normals, our method documented the expected contribution of functional activity independently of local differences in GM volume in the normal pattern of FDG uptake, and disclosed marked heterogeneities in functional activity per unit GM volume among structures. This generic method should find applications in pathological states as well as for other PET and SPECT radiotracers.

Mapping the visual recognition memory network with PET in the behaving baboon.

By means of a novel 18F-fluoro-deoxyglucose PET method designed for cognitive activation imaging in the baboon, the large-scale neural network involved in visual recognition memory in the nonhuman primate was mapped for the first time. In this method, the tracer is injected in the awake, unanesthetized, and unrestrained baboon performing the memory task, and brain imaging is performed later under light anesthesia. Brain maps obtained during a computerized trialunique delayed matching-to-sample task (lists of meaningless geometrical patterns and delay > 9 seconds) were statistically compared pixel-by-pixel to maps obtained during a specially designed visuomotor control task. When displayed onto the baboon's own anatomic magnetic resonance images, foci of significant activation were distributed along the ventral occipitotemporal pathway, the inferomedial temporal lobe (especially the perirhinal cortex and posterior hippocampal region), and the orbitofrontal cortex, consistent with lesion, single-unit, and autoradiographic studies in monkeys, as well as with activation studies in healthy humans. Additional activated regions included the nucleus basalis of Meynert, the globus pallidus and the putamen. The results also document an unexpected left-sided advantage, suggesting hemispheric functional specialization for recognition of figural material in nonhuman primates.

Estimation of neocortical serotonin-2 receptor binding potential by single-dose fluorine-18-setoperone kinetic PET data analysis.

UNLABELLED: Because it satisfies most of the characteristics required to quantify in vivo neocortical serotonin-2 (5HT2) receptors, 18F-setoperone was selected for use in PET estimation of the neocortical 5HT2 binding parameters in baboons according to a single-dose paradigm. METHODS: The neocortical binding potential (i.e., Bmax/KD or the k3/k4 ratio) was assessed by three different methods, with the cerebellum taken as the reference structure in all instances. Method 1 was based on a Logan-Patlak graphical analysis of both cerebellar and neocortical data, which allows estimation of the neocortical k3'/k4 ratio; it required a separate estimation of k5 and k6 from classical nonlinear least-squares (NLSQ) three-compartment modeling of cerebellar data. Method 2 was an original combination of a four-compartment Logan-Patlak procedure for neocortical data and an NLSQ three-compartment procedure for cerebellar data, allowing the neocortical k3/k4 ratio to be obtained directly. In Method 3, an NLSQ three-compartment procedure was applied to cerebellar data and an NLSQ four-compartment procedure to neocortical data, allowing separate determinations of k3 and k4 for the neocortex and, in turn, the k3/k4 ratio. RESULTS: In all three methods, the arterial plasma input function was corrected for the presence of 18F-metabolites, and the vascular fraction was either fitted or fixed. Statistical analysis showed no significant difference among the k3/k4 values obtained from the three methods. Method 3 was the least stable because of an occasional poor NLSQ four-compartment fit on neocortical data. Method 2 provided the least cumbersome estimate of the k3/k4 ratio and was found easy and accurate for generating parametric maps of the 5HT2 binding potential. CONCLUSION: This method might be useful in clinical investigations to provide quantitative assessment of receptor binding potential. In semiquantitative investigations, the neocortical-to-cerebellum pseudoequilibrium ratio may be adequate, as suggested by the significant correlations with measured k3/k4 ratios found here.

Parametric PET imaging of 5HT2A receptor distribution with 18F-setoperone in the normal human neocortex.

UNLABELLED: Because of 5HT2A receptor's (5HT2AR) putative role in several neuropsychiatric diseases, studying it in vivo is an important goal. 18F-setoperone is a well-validated and widely used PET radioligand for the study of neocortical 5HT2AR. We have previously developed and validated in baboons a method to generate parametric maps of the binding potential (i.e., the k3-to-k4 ratio) on a pixel-by-pixel basis, based on a single-dose tracer amount dynamic 18F-setoperone PET paradigm, and with the receptor-poor cerebellum as reference structure. However, previous semiquantitative PET human studies suggested that nonspecific (NS) binding in the neocortex might not be identical to that in the cerebellum. METHODS: As a first step in the development of k3:k4 parametric mapping in humans, we therefore estimated directly the NS binding of 18F-setoperone in the neocortex of four young healthy volunteers who were studied with PET both before and after 2 wk of daily therapeutic oral doses of sertindole, an atypical neuroleptic possessing strong 5HT2AR antagonistic activity. RESULTS: Visual analysis of the dynamic PET data obtained over 120 min confirmed that virtually full receptor saturation had indeed been achieved; however, the late neocortical time-activity curves (TACs) progressively fell to lower uptake values than corresponding cerebellar TACs and could not be fitted according to a four-compartment (four-Cpt) nonlinear model, indicating lack of specific binding. The cerebellum TACs for both the control and the challenge conditions, as well as the challenge neocortical TACs, were fitted according to three-Cpt modeling, providing the k/k6 ratio and in turn the f2 fraction for both structures. Despite the small sample of only four subjects, the f2 fraction for the neocortex was significantly larger (i.e., NS binding was smaller) than that estimated for the cerebellum. This allowed us to determine the k3-to-k4 ratio for the control neocortex using the challenge neocortex as reference structure, that is, without using the cerebellum at all. This "assumption-free" approach was also successfully used to generate k3:k4 maps for these four subjects, which showed highest values for the temporal cortex. CONCLUSION: This study shows that, for every new PET or SPECT radioligand and when estimation of specific binding is based on a reference structure, it is important to determine the uniformity of nonspecific binding before proceeding with human investigations.

Transient global amnesia: concomitant episodic memory and positron emission tomography assessment in two additional patients.

Transient global amnesia (TGA) is characterized by a profound but transient deficit of episodic memory. The study of cerebral blood flow and oxygen metabolism with positron emission tomography (PET) provides relevant pathophysiologic data, but only three patients have been reported so far and in only one was concomitant neuropsychological testing performed. We report here the concomitant neuropsychological and PET assessment of two additional patients. Episodic disturbance was characterized by a storage disturbance for one case and an incapacity to learn episodic associations in the other, illustrating cognitive heterogeneity despite similar neurological presentation. PET findings disclosed mild but significant changes in the amygdala (right or left) and left posterior hippocampus, which could account for both the storage disturbance and the inability to associate episodic components. The PET findings also argued in favor of a vascular disturbance accompanying TGA.

Neural correlates underlying musical semantic memory.

Numerous functional imaging studies have examined the neural basis of semantic memory mainly using verbal and visuospatial materials. Musical material also allows an original way to explore semantic memory processes. We used PET imaging to determine the neural substrates that underlie musical semantic memory using different tasks and stimuli. The results of three PET studies revealed a greater involvement of the anterior part of the temporal lobe. Concerning clinical observations and our neuroimaging data, the musical lexicon (and most widely musical semantic memory) appears to be sustained by a temporo-prefrontal cerebral network involving right and left cerebral regions.

Using voxel-based morphometry to map the structural changes associated with rapid conversion in MCI: a longitudinal MRI study.

Capturing the dynamics of gray matter (GM) atrophy in relation to the conversion from mild cognitive impairment (MCI) to clinically probable Alzheimer's disease (AD) would be of considerable interest. In this prospective study we have used a novel longitudinal voxel-based method to map the progression of GM loss in MCI patients over time and compared converters to non-converters. Eighteen amnestic MCI patients were followed-up for a predefined fixed period of 18 months and conversion was judged according to NINCDS-ADRDA criteria for probable AD. Each patient underwent a high-resolution T1-weighted volume MRI scan both at entry in the study and 18 months later. We used an optimal VBM protocol to compare baseline imaging data of converters to those of non-converters. Moreover, to map GM loss from baseline to follow-up assessment, we used a modified voxel-based morphometry (VBM) procedure specially designed for longitudinal studies. At the end of the follow-up period, seven patients had converted to probable AD. Areas of lower baseline GM value in converters mainly included the hippocampus, parahippocampal cortex, and lingual and fusiform gyri. Regions of significant GM loss over the 18-month follow-up period common to both converters and non-converters included the temporal neocortex, parahippocampal cortex, orbitofrontal and inferior parietal areas, and the left thalamus. However, there was significantly greater GM loss in converters relative to non-converters in the hippocampal area, inferior and middle temporal gyrus, posterior cingulate, and precuneus. This accelerated atrophy may result from both neurofibrillary tangles accumulation and parallel pathological processes such as functional alteration in the posterior cingulate. The ability to longitudinally assess GM changes in MCI offers new perspectives to better understand the pathological processes underlying AD and to monitor the effects of treatment on brain structure.

Visual priming within and across symbolic format using a tachistoscopic picture identification task: a PET study.

The present work was aimed at characterizing picture priming effects from two complementary behavioral and functional neuroimaging (positron emission tomography, PET) studies. In two experiments, we used the same line drawings of common living/nonliving objects in a tachistoscopic identification task to contrast two forms of priming. In the within-format priming condition (picture-picture), subjects were instructed to perform a perceptual encoding task in the study phase, whereas in the cross-format priming condition (word-picture), they were instructed to perform a semantic encoding task. In Experiment 1, we showed significant priming effects in both priming conditions. However, the magnitude of priming effects in the same-format/perceptual encoding condition was higher than that in the different-format/semantic encoding condition, while the recognition performance did not differ between the two conditions. This finding supports the existence of two forms of priming that may be subserved by different systems. Consistent with these behavioral findings, the PET data for Experiment 2 revealed distinct priming-related patterns of regional cerebral blood flow (rCBF) decreases for the two priming conditions when primed items were compared to unprimed items. The same-format priming condition involved reductions in cerebral activity particularly in the right extrastriate cortex and left cerebellum, while the different-format priming condition was associated with rCBF decreases in the left inferior temporo-occipital cortex, left frontal regions, and the right cerebellum. These results suggest that the extrastriate cortex may subserve general aspects of perceptual priming, independent of the kind of stimuli, and that the right part of this cortex could underlie the same-format-specific system for pictures. These data also support the idea that the cross-format/semantic encoding priming for pictures represents a form of lexico-semantic priming subserved by a semantic neural network extending from left temporo-occipital cortex to left frontal regions. These results reinforce the distinction between perceptual and conceptual priming for pictures, indicating that different cerebral processes and systems are implicated in these two forms of picture priming.

Relations between hypometabolism in the posterior association neocortex and hippocampal atrophy in Alzheimer's disease: a PET/MRI correlative study.

OBJECTIVES: Hippocampal atrophy and hypometabolism in the posterior association neocortex are two well known features of Alzheimer's disease. A correlation between these two features was reported twice previously, suggesting intriguing relations. This question has been reassessed, this time controlling for severity of dementia as well as assessing each side of the brain separately and using a voxel based image analysis in addition to the previously employed regions of interest (ROIs). PATIENTS AND METHODS: Eleven patients were studied with probable Alzheimer's disease and mild to moderate dementia in whom both volume MRI and PET assessed cerebral glucose consumption (CMRGlc) were available. Hypothesis driven correlations between hippocampal width (an index of atrophy) and CMRGlc were performed for two posterior association regions, the superior temporal and the inferior parietal (angular gyrus) cortices, using ROIs set separately for each hemisphere. To confirm significant correlations from the ROIs approach, if any, and to assess their specificity for the posterior association neocortex, CMRGlc image voxel based analysis of correlations with hippocampal width was then carried out. RESULTS: There was a significant correlation, in the positive-neurobiologically expected-direction, between right hippocampal width and right angular gyrus metabolism (p< 0.01, Spearman), which remained significant with Kendall partial correlation controlling for dementia severity (estimated by mini mental state scores). Statistical non-parametric mapping (SnPM) confirmed this correlation (p< 0.025), and showed a single additional correlation in the right middle temporal gyrus (p< 0.005), which is also part of the posterior association cortex. CONCLUSION: The findings with both ROIs and voxel based mapping replicate earlier reports of a relation between hippocampal atrophy and ipsilateral association cortex hypometabolism in Alzheimer's disease, and for the first time document that this relation is both region specific and independent of the dementing process itself. Why the correlation was significant only for the right hemisphere is unclear but may be related to the limited sample. Hippocampal-neocortical disconnection due to early and severe medial temporal lobe pathology may at least partly explain the posterior association cortex hypometabolism found in Alzheimer's disease.

Excitotoxic lesions of the rhinal cortex in the baboon differentially affect visual recognition memory, habit memory and spatial executive functions.

To specify the functional role of the rhinal cortex, baboons with bilateral excitotoxic lesions of the rhinal cortex (RH group) were tested on a series of computerized memory and learning tasks. Preoperatively, they were trained to and then tested on a delayed nonmatching-to-sample (DNMS) task with trial-unique stimuli. Postoperatively, this visual recognition memory task was given twice. As compared to a sham-operated group, the RH group showed good retention of rule learning and were unimpaired on the Delay memory subtest. Performance on the List Length memory subtest was, however, severely impaired at both postoperative evaluations, with a significant negative correlation between cognitive performance and neuronal loss in rhinal areas. Visual habit memory and spatial working memory were assessed postoperatively only, using a concurrent discrimination learning task and both a delayed-response task (with a two- and four-location choice) and a delayed alternation task, respectively. The RH group was unimpaired on the first two tasks and was even faster than the controls in learning the delayed-response task with four locations. Finally, most RH baboons failed to learn the delayed alternation task within the limits of testing. These results indicate that neuronal loss in the rhinal cortex is sufficient to impair visual recognition memory, and extend the implication of this area to spatial executive functions. Furthermore, the observation of impaired recognition memory and executive processes with preserved procedural memory and retrograde memory suggests that damage to the rhinal cortex probably participates in the cognitive deficits typical of the early stages of Alzheimer's disease.

Effects of healthy aging on the regional cerebral metabolic rate of glucose assessed with statistical parametric mapping.

The aging process is thought to result in changes in synaptic activity reflecting both functional and structural cell derangement. However, previous PET reports on age-related changes in resting brain glucose utilization (CMRglc) have been discrepant, presumably because of methodological as well as subject screening differences. In contrast to other studies, which used a region of interest approach, the objective of the present work was to determine, by means of the SPM software, the changes in regional CMRglc as a function of age in 24 optimally healthy, unmedicated volunteers of ages from 20 to 67 years. Global CMRglc showed a significant decline with age (approximately 6% per decade, P < 0.05), which concerned all the voxels studied save for most of the occipital cortex and part of the cerebellum. The most significant effects (P < 0.001) concerned the association neocortex in perisylvian temporoparietal and anterior temporal areas, the insula, the inferior and posterior-lateral frontal regions, the anterior cingulate cortex, the head of caudate nucleus, and the anterior thalamus, in a bilateral and essentially symmetrical fashion. The high posterior parietal cortex was not sampled in this study. This distribution of changes in CMRglc with age may differ from that seen in Alzheimer' disease, where the earliest metabolic reduction has been shown to affect the posterior cingulate cortex.

In vivo mapping of gray matter loss with voxel-based morphometry in mild Alzheimer's disease.

Up till now, the study of regional gray matter atrophy in Alzheimer's disease (AD) has been assessed with regions of interest, but this method is time-consuming, observer dependent, and poorly reproducible (especially in terms of cortical regions boundaries) and in addition is not suited to provide a comprehensive assessment of the brain. In this study, we have mapped gray matter density by means of voxel-based morphometry on T1-weighted MRI volume sets in 19 patients with mild AD and 16 healthy subjects of similar age and gender ratio and report highly significant clusters of gray matter loss with almost symmetrical distribution, affecting mainly and in decreasing order of significance the medial temporal structures, the posterior cingulate gyrus and adjacent precuneus, and the temporoparietal association and perisylvian neocortex, with only little atrophy in the frontal lobe. The findings are discussed in light of previous studies of gray matter atrophy in AD based either on postmortem or neuroimaging data and in relation to PET studies of resting glucose consumption. The limitations of the method are also discussed in some detail, especially with respect to the segmentation and spatial normalization procedures as they apply to pathological brains. Some potential applications of voxel-based morphometry in the study of AD are also mentioned.

Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.

An anatomical parcellation of the spatially normalized single-subject high-resolution T1 volume provided by the Montreal Neurological Institute (MNI) (D. L. Collins et al., 1998, Trans. Med. Imag. 17, 463-468) was performed. The MNI single-subject main sulci were first delineated and further used as landmarks for the 3D definition of 45 anatomical volumes of interest (AVOI) in each hemisphere. This procedure was performed using a dedicated software which allowed a 3D following of the sulci course on the edited brain. Regions of interest were then drawn manually with the same software every 2 mm on the axial slices of the high-resolution MNI single subject. The 90 AVOI were reconstructed and assigned a label. Using this parcellation method, three procedures to perform the automated anatomical labeling of functional studies are proposed: (1) labeling of an extremum defined by a set of coordinates, (2) percentage of voxels belonging to each of the AVOI intersected by a sphere centered by a set of coordinates, and (3) percentage of voxels belonging to each of the AVOI intersected by an activated cluster. An interface with the Statistical Parametric Mapping package (SPM, J. Ashburner and K. J. Friston, 1999, Hum. Brain Mapp. 7, 254-266) is provided as a freeware to researchers of the neuroimaging community. We believe that this tool is an improvement for the macroscopical labeling of activated area compared to labeling assessed using the Talairach atlas brain in which deformations are well known. However, this tool does not alleviate the need for more sophisticated labeling strategies based on anatomical or cytoarchitectonic probabilistic maps.

Cognitive processes involved in delayed non-matching-to-sample performance in Parkinson's disease.

Visual recognition memory was assessed in terms of delay duration, memory load and amount of interference(s) in non-demented patients with Parkinson's disease (PD) using an automated delayed non-matching-to-sample (DNMS) task with trial-unique stimuli. Special attention was focused on the different cognitive functions engaged by these patients in solving this recognition memory task. Thirteen patients with PD, carefully selected according to their stable regimen and anticholinergic medication, were compared to 12 controls matched by age and educational level. Besides the DNMS task, a neuropsychological battery that included tasks carefully selected according to processes potentially required to perform the DNMS task (e.g. attention, executive functions, visual discrimination and motor speed) was administered to the subjects. As compared with controls, patients with PD showed a deficit on most DNMS subscores, except those requiring the least cognitive load. The correlative analysis between the DNMS and other neuropsychological tasks suggests involvement of long-term memory mainly in the DNMS performance for the control group, contrasting with a major involvement of executive functions for the patients with PD. These data indicate that visual recognition memory impairment in non-demented patients with PD is largely due to an executive dysfunction, notably in working memory. Several hypotheses are proposed concerning the neuronal substrates underlying the impairment on the visual DNMS task in PD.

The neural substrates of memory systems impairment in Alzheimer's disease. A PET study of resting brain glucose utilization.

The aim of this study was to determine the neuronal basis for memory impairment in Alzheimer's disease by taking advantage of the clinical and metabolic heterogeneity of this pathology. To this end, 19 patients satisfying the NINCDSADRDA criteria for probably Alzheimer's disease of mild-to-moderate severity underwent a detailed examination of the five memory systems according to Tulving's model, together with a PET measurement of resting regional cerebral glucose utilization (CMRGlc). Compared with controls, the patients as a group showed the expected memory and metabolic profiles of impairment. Correlations (corrected for the effects of ageing) were calculated between memory scores and CMRGlc (normalized by the vermis CMRGlc) using two methods: (i) the classic regions-of-interest method, based on a priori hypotheses and individual coregistered structural MRI; and (ii) the statistical parametric mapping method which allows a systematic voxel-by-voxel analysis, in a more descriptive and exploratory way. Significant correlations were above chance levels and largely consistent between the two methods. They were almost exclusively positive (i.e. in the neurobiologically expected direction) and their distribution showed striking differences according to each memory system. Thus, verbal episodic memory impairment was related to changes in a large neuronal network including not only the limbic structures (mesial temporal cortex, thalamus and cingulate gyrus, with left side predominance) but also the parietotemporal and frontal association cortices of the right hemisphere, possibly on a compensatory basis. Regardless of modality, short-term memory tests were mainly correlated with bilateral activity in posterior association cortex, and also with activity in left prefrontal cortex for the visuospatial span, possibly indicating essentially uniform strategies for the performance of the different tasks. As predicted, semantic memory scores correlated with activity in temporoparietal and frontal association cortices of the left hemisphere, and also with activity in left cingulate cortex. Thus, for episodic, short-term and semantic memory, many findings fit classical neuropsychology, while most of the less expected ones were consistent with recent results from functional neuro-imaging in healthy subjects, notably with the hemispheric encoding/ retrieval asymmetry (HERA) model; only few findings suggested possible reorganization processes and/or recourse to unexpected cognitive strategy. Finally, only negative correlations were found for perceptual priming and procedural memory; although they could arise by chance, some of these unexpected findings give rise to interesting hypotheses about the cognitive relationships between the most and least affected memory systems. This study documents the validity and usefulness of our approach in unravelling the neural substrates of cognitive impairment in brain pathology without focal tissue loss such as that seen in neurodegenerative diseases.