Comparison of BOLD, diffusion-weighted fMRI and ADC-fMRI for stimulation of the primary visual system with a block paradigm.

The blood oxygen level-dependent (BOLD) effect is extensively used for functional MRI (fMRI) but presents some limitations. Diffusion-weighted fMRI (DfMRI) has been proposed as a method more tightly linked to neuronal activity. This work proposes a protocol of DfMRI acquired for several b-values and diffusion directions that is compared to gradient-echo BOLD (GE-BOLD) and to repeated spin-echo BOLD (SE-BOLD, acquisitions performed with b=0s/mm2), which was also used to ensure the reproducibility of the response. A block stimulation paradigm of the primary visual system (V1) was performed in 12 healthy subjects with checkerboard alternations (2Hz frequency). DfMRI was performed at 3T with 5 b-values (b=1500, 1000, 500, 250, 0s/mm2) with TR/TE=1004/93ms, Δ/δ=45.4ms/30ms, and 6 spatial directions for diffusion measures. GE-BOLD was performed with a similar block stimulation design timing. Apparent Diffusion Coefficient (ADC)-fMRI was computed with all b-values used. An identical Z-score level was used for all fMRI modalities for the comparison of volumes of activation. ADC-fMRI and SE-BOLD fMRI activation locations were compared in a voxel-based analysis to a cytoarchitectural probability map of V1. SE-BOLD activation volumes represented only 55% of the GE-BOLD activation volumes (P<0.0001). DfMRI activation volumes averaged for all b-values acquired represented only 12% of GE-BOLD (P<0.0001) and only 22% of SE-BOLD activation volumes (P<0.005). Compared to SE-BOLD-fMRI, ADC-fMRI activations showed fewer pixels outside of V1 and a higher average probability of belonging to V1. DfMRI and ADC-fMRI acquisition at 3T could be easily post-processed with common neuro-imaging software. DfMRI and ADC-fMRI activation volumes were significantly smaller than those obtained with SE-BOLD. ADC-fMRI activations were more precisely localized in V1 than those of SE-BOLD-fMRI. This validated the increased capability of ADC-fMRI compared to BOLD to enhance the precision of localizing an fMRI activation in the cyto-architectural zone V1, thereby justifying the use of ADC-fMRI for neuro-scientific studies.

Lateral masking, levels of processing and stimulus category: a comparative study between normal and dyslexic readers.

The lateral masking effect results in lower performance on letter recognition when items are flanked by other stimuli. Using a new paradigm based on discrimination (feature analysis) and categorization (memory access) tasks, we investigated the influence of level of processing (as addressed, respectively, by these two tasks) and stimulus type (Latin letters, Korean letters and geometrical figures) on lateral masking. In addition, performance of dyslexic and non-dyslexic adult readers was compared. The non-dyslexic participants demonstrated a classical lateral masking effect with lower performance for flanked items than isolated ones. In addition, lateral masking was stronger in the categorization than in the discrimination task and was restricted to familiar items, i.e., Latin letters and geometrical figures. Dyslexic participants showed poorer performance than non-dyslexics on processing isolated items, and the pattern of decrease in performance for lateral masking was similar to non-dyslexics. However, they also showed a stronger decrease in performance in categorization and a stronger decrease related to the lateral masking for this categorization task. Our results in normal readers suggest that lateral masking relies on the interference between the target and the flankers during feature integration that may result in marked impairment of memory access (categorization task). Poorer performance in dyslexic readers may reflect impaired parafoveal/peripheral low-level processing during feature integration that may have worsened during the flanked condition due to a target selection/spatial-attentional disorder. Moreover, dyslexic subjects presented an additional categorization deficit that may relate to a specific left-hemispheric disorder.

Modulation of effective connectivity inside the working memory network in patients at the earliest stage of multiple sclerosis.

fMRI and structural equation modeling (SEM) were used to study effective connectivity inside the working memory network in patients at the earliest stage of multiple sclerosis (MS), while performing paced auditory serial addition test (PASAT), a sensitive task to reveal subtle cognitive impairments related to working memory and information speed processing. The path model used for SEM included bilateral connections between left and right BA 46, left and right BA 40, left and right anterior cingulate cortex (ACC), left BA 44 and left BA 40, right BA 44 and right BA 40, and unidirectional ipsilateral connections from BA 46 to BA 44, from ACC to BA 46, and from ACC to BA 44. Experimental data from the two groups fit accurately the working memory model, in patients [chi20(2) = 13, P = 0.877] as well as in controls [chi20(2) = 13.54, P = 0.853]. The omnibus test indicated a significant difference of model fits in patients and in controls [chi40(2) = 160.07, P < 0.0001]. Connectivity strengths from right BA 46 to left BA 46, from left ACC to left BA 46 were lower in patients than in controls, and higher from right ACC to right BA 46, from left to right and from right to left ACC (stacked model). Effective connectivity inside the working memory network appears altered in patients at the earliest stage of MS. Modulation of effective connectivity is present in patients inside the executive subsystems of working memory, and could be related to adaptive cognitive control processes that may limit the clinical manifestation of MS.

Resistor mesh model of a spherical head: part 1: applications to scalp potential interpolation.

A resistor mesh model (RMM) has been implemented to describe the electrical properties of the head and the configuration of the intracerebral current sources by simulation of forward and inverse problems in electroencephalogram/event related potential (EEG/ERP) studies. For this study, the RMM representing the three basic tissues of the human head (brain, skull and scalp) was superimposed on a spherical volume mimicking the head volume: it included 43 102 resistances and 14 123 nodes. The validation was performed with reference to the analytical model by consideration of a set of four dipoles close to the cortex. Using the RMM and the chosen dipoles, four distinct families of interpolation technique (nearest neighbour, polynomial, splines and lead fields) were tested and compared so that the scalp potentials could be recovered from the electrode potentials. The 3D spline interpolation and the inverse forward technique (IFT) gave the best results. The IFT is very easy to use when the lead-field matrix between scalp electrodes and cortex nodes has been calculated. By simple application of the Moore-Penrose pseudo inverse matrix to the electrode cap potentials, a set of current sources on the cortex is obtained. Then, the forward problem using these cortex sources renders all the scalp potentials.

Resistor mesh model of a spherical head: part 2: a review of applications to cortical mapping.

A resistor mesh model (RMM) has been validated with reference to the analytical model by consideration of a set of four dipoles close to the cortex. The application of the RMM to scalp potential interpolation was detailed in Part 1. Using the RMM and the same four dipoles, the different methods of cortical mapping were compared and have shown the potentiality of this RMM for obtaining current and potential cortical distributions. The lead-field matrices are well-adapted tools, but the use of a square matrix of high dimension does not permit the inverse solution to be improved in the presence of noise, as a regularisation technique is necessary with noisy data. With the RMM, the transfer matrix and the cortical imaging technique proved to be easy to implement. Further development of the RMM will include application to more realistic head models with more accurate conductivities.

Anatomy and time course of discrimination and categorization processes in vision: an fMRI study.

Studies investigating the cerebral areas involved in visual processes generally oppose either different tasks or different stimulus types. This work addresses, by fMRI, the interaction between the type of task (discrimination vs. categorization) and the type of stimulus (Latin letters, well-known geometrical figures, and Korean letters). Behavioral data revealed that the two tasks did not differ in term of percentage of errors or correct responses, but a delay of 185 ms was observed for the categorization task in comparison with the discrimination task. All conditions activated a common neural network that includes both striate and extrastriate areas, especially the fusiform gyri, the precunei, the insulae, and the dorsolateral frontal cortex. In addition, interaction analysis revealed that the right insula was sensitive to both tasks and stimuli, and that stimulus type induced several significant signal variations for the categorization task in right frontal cortex, the right middle occipital gyrus, the right cuneus, and the left and right fusiform gyri, whereas for the discrimination task, significant signal variations were observed in the right occipito-parietal junction only. Finally, analyzing the latency of the BOLD signal also revealed a differential neural dynamics according to tasks but not to stimulus type. These temporal differences suggest a parallel hemisphere processing in the discrimination task vs. a cooperative interhemisphere processing in the categorization task that may reflect the observed differences in reaction time.

Automatic grapheme processing in the left occipitotemporal cortex.

In a previous event-related fMRI study, we showed that the left occipitotemporal cortex was specifically involved in the abstract categorization of visually presented alphabetic symbols. Here, we duplicate the fMRI study by measuring visual event-related potentials to verify whether the left posterior cortex supports the processing of graphemic representations at a perceptual, prelexical level. N170 amplitudes elicited by the categorically ambiguous stimulus 'O' were about twice as small in the left as in the right occipitotemporal region, and comparable to that of other letters on the left, and to that of other geometric figures on the right. The side asymmetry suggests that a graphemic module is unilaterally implemented in the left hemisphere, where it automatically processes heteromorphic representations that do not depend on the physical characteristics of the signal, whereas the difference in amplitude suggests that this left graphemic module is in series with, precedes and does not transmit information to, or inhibits a general shape-analysis module.

Lexical therapy and episodic word learning in dementia of the Alzheimer type.

The effect of a language therapy in a group of eight anomic mild patients (the Lexical Therapy group) was assessed by using a 5-month long Lexical Therapy in comparison with an occupational program used in a matched control group (AD; n = 8). The Lexical Therapy group benefited significantly from a language therapy as shown by the naming improvement postintervention. The improvement reached significance only for items that were included in the language therapy protocol and no significant generalization to untreated items was observed. In mild AD patients with anomia and no severe semantic impairment, a reinforcement of the relationship between the form of the object and the corresponding lexical label in episodic long term memory during language therapy may account for the observed lexical improvement.

Event-related functional magnetic resonance imaging study of the extrastriate cortex response to a categorically ambiguous stimulus primed by letters and familiar geometric figures.

Functional neuroimaging studies have suggested a specific role of the extrastriate cortex in letter string and visual word form processing. However, this region has been shown to be involved in object recognition and its specificity for the processing of linguistic stimuli may be questioned. The authors used an event-related functional magnetic resonance imaging design with category priming to record the response elicited by the passive viewing of single letters, geometric figures, and of the categorically ambiguous stimulus "O" that pertains to both sets of familiar symbols. Bilateral activations in the extrastriate cortex were found, with a left predominance particularly pronounced for the ambiguous stimulus. Individual analysis of spatial extent and signal intensity showed a priming x stimulus x hemisphere interaction. When primed by the congruous categoric set, a bilateral decrease in activation was observed for letters and geometric figures. The ambiguous stimulus behaved as a letter for the left hemisphere, with decreased activation when primed by letters, whereas in the right hemisphere, an adaptation effect occurred when primed by geometric figures. These priming effects suggest that, for the ambiguous stimulus, letter processing was systematically involved in the left extrastriate cortex. The current results support the existence of a neural substrate for the abstract category of letters.

Within-session and between-session reproducibility of cerebral sensorimotor activation: a test--retest effect evidenced with functional magnetic resonance imaging.

The aim of the current study was to assess the reproducibility of functional magnetic resonance imaging (fMRI) brain activation signals in a sensorimotor task in healthy subjects. Because random or systematic changes are likely to happen when movements are repeated over time, the authors searched for time-dependent changes in the fMRI signal intensity and the extent of activation within and between sessions. Reproducibility was studied on a sensorimotor task called "the active task" that includes a motor output and a sensory feedback, and also on a sensory stimulation called "the passive task" that assessed the sensory input alone. The active task consisted of flexion and extension of the right hand. The subjects had performed it several times before fMRI scanning so that it was well learned. The passive task consisted of a calibrated passive flexion and extension of the right wrist. Tasks were 1 Hz-paced. The control state was rest. Subjects naïve to the MRI environment and non--MRI-naïve subjects were studied. Twelve MRI-naïve subjects underwent 3 fMRI sessions separated by 5 hours and 49 days, respectively. During MRI scanning, they performed the active task. Six MRI-naïve subjects underwent 2 fMRI sessions with the passive task 1 month apart. Three non--MRI-naïve subjects performed twice an active 2-Hz self-paced task. The data were analyzed with SPM96 software. For within-session comparison, for active or passive tasks, good reproducibility of fMRI signal activation was found within a session (intra-and interrun reproducibility) whether it was the first, second, or third session. Therefore, no within-session habituation was found with a passive or a well-learned active task. For between-session comparison, for MRI-naïve or non--MRI-naïve subjects, and with the active or the passive task, activation was increased in the contralateral premotor cortex and in ispsilateral anterior cerebellar cortex but was decreased in the primary sensorimotor cortex, parietal cortex, and posterior supplementary motor area at the second session. The lower cortical signal was characterized by reduced activated areas with no change in maximum peak intensity in most cases. Changes were partially reversed at the third session. Part of the test-retest effect may come from habituation of the MRI experiment context. Less attention and stress at the second and third sessions may be components of the inhibition of cortical activity. Because the changes became reversed, the authors suggest that, beyond the habituation process, a learning process occurred that had nothing to do with procedural learning, because the tasks were well learned or passive. A long-term memory representation of the sensorimotor task, not only with its characteristics (for example, amplitude, frequency) but also with its context (fMRI), can become integrated into the motor system along the sessions. Furthermore, the pattern observed in the fMRI signal changes might evoke a consolidation process.

Neural substrate for the effects of passive training on sensorimotor cortical representation: a study with functional magnetic resonance imaging in healthy subjects.

Repetitive passive movements are part of most rehabilitation procedures, especially in patients with stroke and motor deficit. However, little is known about the consequences of repeated proprioceptive stimulations on the intracerebral sensorimotor network in humans. Twelve healthy subjects were enrolled, and all underwent two functional magnetic resonance imaging (fMRI) sessions separated by a 1-month interval. Passive daily movement training was performed in six subjects during the time between the two fMRI sessions. The other six subjects had no training and were considered as the control group. The task used during fMRI was calibrated repetitive passive flexion-extension of the wrist similar to those performed during training. The control task was rest. The data were analyzed with SPM96 software. Images were realigned, smoothed, and put into Talairach's neuroanatomical space. The time effect from the repetition of the task was assessed in the control group by comparing activation versus rest in the second session with activation versus rest in the first session. This time effect then was used as null hypothesis to assess the training effect alone in our trained group. Passive movements compared with rest showed activation of most of the cortical areas involved in motor control (i.e., contralateral primary sensorimotor cortex, supplementary motor area [SMA], cingulum, Brodmann area 40, ipsilateral cerebellum). Time effect comparison showed a decreased activity of the primary sensorimotor cortex and SMA and an increased activity of ipsilateral cerebellar hemisphere, compatible with a habituation effect. Training brought about an increased activity of contralateral primary sensorimotor cortex and SMA. A redistribution of SMA activity was observed. The authors demonstrated that passive training with repeated proprioceptive stimulation induces a reorganization of sensorimotor representation in healthy subjects. These changes take place in cortical areas involved in motor preparation and motor execution and represent the neural basis of proprioceptive training, which might benefit patients undergoing rehabilitative procedures.

Age-related cognitive decline, mild cognitive impairment or preclinical Alzheimer's disease?

With the promising development of effective treatment, significant improvement in the very early diagnosis of Alzheimer's disease (AD) is required. There is vast agreement that a decline in memory, especially in verbal episodic memory, is the earliest and perhaps the most sensitive sign of incipient AD at the preclinical stage. However, this review offers evidence that impairment in episodic memory can be observed in normal elderly people as well as in aged subjects with mild cognitive impairment (MCI), a large proportion of whom will, however, not convert to dementia. Quantitative measurement of atrophy and brain activation in the hippocampal-parahippocampal formation by using structural and functional magnetic resonance imaging may help to distinguish the MCI decliners from the nondecliners. Cerebrospinal fluid levels of tau protein and Abet1-42 peptide, together with the presence of an apolipoprotein (apo)E epsilon4 allele may also increase our confidence in the early positive diagnosis of AD. This review concludes, however, that while adequate for constituting groups of patients in a research perspective, the extensive diagnostic procedure based on specific cognitive testing, neuroimaging and biological investigations is still out of reach for the practitioner.

Information processing in large-scale cerebral networks: the causal connectivity approach.

Today, cognitive functions are considered to be the offspring of the activity of large-scale networks of functionally interconnected cerebral regions. The interpretation of cerebral activation data provided by functional imaging has therefore recently moved to the search for the effective connectivity of activated regions, which aims at understanding the role of anatomical links in the activation propagation. Our assumption is that only causal connectivity can offer a real understanding of the links between brain and mind. Causal connectivity is based on the anatomical connection pattern, the information processing within cerebral regions and the causal influences that connected regions exert on each other. In our approach, the information processing within a region is implemented by a causal network of functional primitives, which are the interpretation of integrated biological properties. Our choice of a qualitative representation of information reflects the fact that cerebral activation data are only the approximate view, provided by imaging techniques, of the real cerebral activity. This explicit modeling approach allows the formulation and the simulation of functional and physiological assumptions about activation data. Two alternative models explaining results of the striate cortex activation described by Fox and Raichle (Fox PT, Raichle ME (1984) J. Neurophysiol 51:1109-1120; Fox PT, Raichle ME (1985) Ann Neurol 17:303-305) are provided as an example of our approach.

Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks.

Fluoxetine inhibits the reuptake of serotonin, and dextroamphetamine enhances presynaptic release of monoamines. Although the excitatory effect of both noradrenaline and dopamine on motor behavior generally is accepted, the role of serotonin on motor output is under debate. In the current investigation, the authors evidenced a putative role of monoamines and, more specifically, of serotonin in the regulation of cerebral motor activity in healthy subjects. The effects on cerebral motor activity of a single dose of fluoxetine (20 mg), an inhibitor of serotonin reuptake, and fenozolone (20 mg/50 kg), an amphetamine-like drug, were assessed by functional magnetic resonance imaging. Subjects performed sensorimotor tasks with the right hand. Functional magnetic resonance imaging studies were performed in two sessions on two different days. The first session, with two scan experiments separated by 5 hours without any drug administration, served as time-effect control. A second, similar session but with drug administration after the first scan assessed drug effects. A large increase in evoked signal intensity occurred in the ipsilateral cerebellum, and a parallel, large reduction occurred in primary and secondary motor cortices (P < 10(-3)). These results are consistent with the known effects of habituation. Both drugs elicited comparable effects, that is, a more focused activation in the contralateral sensorimotor area, a greater involvement of posterior supplementary motor area, and a widespread decrease of bilateral cerebellar activation (P < 10(-3)). The authors demonstrated for the first time that cerebral motor activity can be modulated by a single dose of fluoxetine or fenozolone in healthy subjects. Drug effects demonstrated a direct or indirect involvement of monoamines and serotonin in the facilitation of cerebral motor activity.

ERP correlates of phoneme perception in speech and sound contexts.

To address the question of the existence of a phonetic module for speech perception, event-related potentials were recorded using a 32 channel system in subjects performing a detection task where the target was the ambiguous, noise-like phoneme /f/ presented either among syllables (speech context) or among environmental sounds (non-speech context). Significant context effects were observed on the N2/P3 complex elicited by the target. In particular, a well localized N2b (250-280 ms) appeared at the left temporoparietal sites on the difference wave between contexts as the result of an enhanced negativity when the target was presented among non-speech stimuli. These findings suggest the involvement of the left temporoparietal region in autonomous, modular processes of speech perception.

Differential fMRI responses in the left posterior superior temporal gyrus and left supramarginal gyrus to habituation and change detection in syllables and tones.

Using a habituation-recovery paradigm adapted to functional magnetic resonance imaging, we investigated the brain responses to syllables and tones in six right-handed male subjects. We opposed a standard condition (STD) in which the subjects were listening to homogeneous sequences of four identical stimuli, to a deviant condition (DEV) in which the fourth stimulus of the sequence differed in pitch or spectral content for tones and in the initial stop consonant for syllables. The corresponding runs alternated four rest periods with two STD and two DEV conditions. In addition to a marked rightward asymmetry in the primary and secondary auditory cortex for tones and a right inferior frontal activation for the tone condition where the deviant had increased spectral content, the experiment revealed differential activations in the left posterior superior temporal gyrus and in the left supramarginal gyrus. Activations within the left posterior superior temporal gyrus were observed for the DEV condition with tones and for the STD and DEV conditions with syllables. Activation within the inferior part of the left supramarginal gyrus was only observed for the DEV condition with syllables. The analysis of the decreases and increases in the BOLD signal across the STD, DEV, and rest conditions suggests that the left posterior superior temporal gyrus is implicated in the preattentive change detection of acoustic changes in speech as well as nonspeech stimuli, whereas the left supramarginal gyrus is more specifically engaged in the detection of changes in phonological units.

Event-related potentials elicited by passive movements in humans: characterization, source analysis, and comparison to fMRI.

Cortical areas responsive to proprioceptive stimulation were assessed by ERP technique in normals and in selected patients with stroke and were compared to fMRI data. Repetitive extension of right and left forefinger elicited a P1/N1/P2 complex wave pattern. This pattern was absent in patient with complete sensory loss and present but spatially modified in patient with recovered sensory deficit. Source localization with a simple model showed three sources starting in the contralateral rolandic area (SI), then involving the inferior parietal lobe unilaterally and the supplementary motor area (10 to 134 ms). It was followed by a bilaterally distributed pattern of two sources located in the ipsilateral parietal region and in the contralateral insula. Right and left stimulation led to very symmetrical patterns. Comparison to fMRI obtained from passive extension of the wrist in normals showed very compatible data. We described in this paper, a sequential processing of proprioceptive inputs after passive movements involving primary and secondary sensory motor areas.

Normal frontal perfusion in patients with frozen gait.

We have studied the frontal perfusion in the resting condition of two groups of patients with frozen gait: 10 patients with the syndrome of "isolated gait ignition failure" (IGIF) and 8 patients with idiopathic Parkinson's disease (PD) and severe "off" freezing. These patients were compared with two other groups: one including 20 age-matched volunteers as normal control subjects and the other one including 12 patients with progressive supranuclear palsy (PSP) as a positive control with expected frontal hypoperfusion. Frontal perfusion was assessed using single photon emission computed tomography (SPECT) regional cerebral blood flow measurement with intravenous 133Xenon. A significant frontal hypoperfusion was only present in the PSP group but not in the three others. These results do not support the hypothesis that start hesitations and freezing when walking are related to a frontal lobe dysfunction. However, it is possible that frontal neuronal dysfunction occurs without measurable cerebral blood flow changes in the resting condition.

Cortical motor overactivation in parkinsonian patients with L-dopa-induced peak-dose dyskinesia.

We have studied the regional cerebral blood flow (rCBF) changes induced by the execution of a finger-to-thumb opposition motor task in the supplementary and primary motor cortex of two groups of parkinsonian patients on L-dopa medication, the first one without L-dopa induced dyskinesia (n = 23) and the other with moderate peak-dose dyskinesia (n = 15), and of a group of 14 normal subjects. Single photon emission tomography with i.v. 133Xe was used to measure the rCBF changes. The dyskinetic parkinsonian patients exhibited a pattern of response which was markedly different from those of the normal subjects and non-dyskinetic parkinsonian patients, with a significant overactivation in the supplementary motor area and the ipsi- and contralateral primary motor areas. These results are compatible with the hypothesis that an hyperkinetic abnormal involuntary movement, like L-dopa-induced peak dose dyskinesia, is due to a disinhibition of the primary and associated motor cortex secondary to an excessive outflow of the pallidothalamocortical motor loop.

Brain correlates of memory processes in patients with dementia of Alzheimer's type: a SPECT Activation Study.

Task-induced changes in regional cerebral blood flow (rCBF) during verbal episodic memory activation were compared in 17 right-handed patients with dementia of the Alzheimer's type (DAT) and 20 healthy volunteers. Regional cerebral blood flow was assessed using single photon emission computed tomography (SPECT) and an injection of 133Xe (xenon, isotope of mass 133) in 21 regions of interest (ROI) during rest, passive listening to 36 words, and memorizing of a 12-word list repeated three times. In healthy subjects, memory-listening comparison showed activation of a distributed system involving several left-sided ROI, especially the posterior inferior frontal region. In patients with DAT, the same pattern of activation was found for listening-rest comparison, and no significant changes were found in memory-listening comparison. During listening compared with rest, significant activation was observed in left-sided hypoperfused regions. A significant correlation between memory performance and rCBF recorded in patients with DAT during the memory task was found only in the right lateral frontal region, a region that was not hypoperfused significantly in patients. The involvement of this region might relate to either retrieval effort or actual performance of patients with DAT on the memory task.