Sylviane Confort-Gouny

Decreased basal fMRI functional connectivity in epileptogenic networks and contralateral compensatory mechanisms.

A better understanding of interstructure relationship sustaining drug‐resistant epileptogenic networks is crucial for surgical perspective and to better understand the consequences of epileptic processes on cognitive functions. We used resting‐state fMRI to study basal functional connectivity within temporal lobes in medial temporal lobe epilepsy (MTLE) during interictal period. Two hundred consecutive single‐shot GE‐EPI acquisitions were acquired in 37 right‐handed subjects (26 controls, eight patients presenting with left and three patients with right MTLE). For each hemisphere, normalized correlation coefficients were computed between pairs of time‐course signals extracted from five regions involved in MTLE epileptogenic networks (Brodmann area 38, amygdala, entorhinal cortex (EC), anterior hippocampus (AntHip), and posterior hippocampus (PostHip)). In controls, an asymmetry was present with a global higher connectivity in the left temporal lobe. Relative to controls, the left MTLE group showed disruption of the left EC‐AntHip link, and a trend of decreased connectivity of the left AntHip‐PostHip link. In contrast, a trend of increased connectivity of the right AntHip‐PostHip link was observed and was positively correlated to memory performance. At the individual level, seven out of the eight left MTLE patients showed decreased or disrupted functional connectivity. In this group, four patients with left TLE showed increased basal functional connectivity restricted to the right temporal lobe spared by seizures onset. A reverse pattern was observed at the individual level for patients with right TLE. This is the first demonstration of decreased basal functional connectivity within epileptogenic networks with concomitant contralateral increased connectivity possibly reflecting compensatory mechanisms. Hum Brain Mapp 2009.

Compensatory cortical activation observed by fMRI during a cognitive task at the earliest stage of MS.

Recent functional magnetic resonance imaging (fMRI) studies have suggested that functional cortical changes seen in patients with early relapsing‐remitting multiple sclerosis (MS) can have an adaptive role to limit the clinical impact of tissue injury. To determine whether cortical reorganization occurs during high cognitive processes at the earliest stage of multiple sclerosis (MS), we performed an fMRI experiment using the conventional Paced Auditory Serial Addition Test (PASAT) as paradigm in a population of ten patients with clinically isolated syndrome suggestive of multiple sclerosis (CISSMS). At the time of the fMRI exploration, mean disease duration was 6.8 ± 3.3 months. We compared these results to those obtained in a group of ten education‐, age‐, and sex‐matched healthy controls. Subjects were explored on a 1.5 T MRI system using single‐shot gradient‐echo EPI sequence. Performances of the two groups during PASAT recorded inside the MR scanner were not different. Statistical assessment of brain activation was based on the random effect analysis (between‐group analysis two‐sample t‐test P < 0.005 confirmed by individual analyses performed in the surviving regions P < 0.05 Mann Whitney U‐test). Compared to controls, patients showed significantly greater activation in the right frontopolar cortex, the bilateral lateral prefrontal cortices, and the right cerebellum. Healthy controls did not show greater activation compared to CISSMS patients. The present study argues in favor of the existence of compensatory cortical activations at the earliest stage of MS mainly located in regions involved in executive processing in patients performing PASAT. It also suggests that fMRI can evidence the active processes of neuroplasticity contributing to mask the clinical cognitive expression of brain pathology at the earliest stage of MS. Hum. Brain Mapping 20:51–58, 2003.

Magnetic resonance study of the influence of tissue damage and cortical reorganization on PASAT performance at the earliest stage of multiple sclerosis.

We sought to determine the influence of tissue damage and the potential impact of cortical reorganization on the performance to the Paced Auditory Serial Addition Test (PASAT) in patients at the earliest stage of multiple sclerosis (MS). Magnetization transfer ratio (MTR) imaging and functional magnetic resonance imaging (fMRI) experiments using PASAT as paradigm were carried out in 18 patients with clinically isolated syndrome suggestive of MS (CISSMS) compared to 18 controls. MTR histogram analyses showed structural abnormalities in patients involving the normal‐appearing white matter (NAWM) but also the gray matter (GM). Mean PASAT scores were significantly lower in the group of patients taken as a whole, and were correlated with the mean NAWM MTR value. No correlation was observed between PASAT scores and GM MTR. However, in the subgroup of patients with normal PASAT performance (n = 9), fMRI showed larger activations in bilateral Brodmann area 45 (BA45) and right BA44 compared to that in controls (n = 18). In these areas with potentially compensatory reorganization, the whole group of patients (n = 18) showed significantly greater activation than controls (n = 18). Activation in the right BA45 was inversely correlated with the mean NAWM MTR and the peak position of GM MTR histograms of patients. This study indicates that even at the earliest stage of MS, cortical reorganization is present inside the executive system of working memory and could tend to limit the determinant functional impact of NAWM injury on the execution of the PASAT. Hum. Brain Mapping 24:216–228, 2005.

Compensatory cortical activation observed by fMRI during a cognitive task at the earliest stage of multiple sclerosis

Recent functional magnetic resonance imaging (fMRI) studies have suggested that functional cortical changes seen in patients with early relapsing‐remitting multiple sclerosis (MS) can have an adaptive role to limit the clinical impact of tissue injury. To determine whether cortical reorganization occurs during high cognitive processes at the earliest stage of multiple sclerosis (MS), we performed an fMRI experiment using the conventional Paced Auditory Serial Addition Test (PASAT) as paradigm in a population of ten patients with clinically isolated syndrome suggestive of multiple sclerosis (CISSMS). At the time of the fMRI exploration, mean disease duration was 6.8 ± 3.3 months. We compared these results to those obtained in a group of ten education‐, age‐, and sex‐matched healthy controls. Subjects were explored on a 1.5 T MRI system using single‐shot gradient‐echo EPI sequence. Performances of the two groups during PASAT recorded inside the MR scanner were not different. Statistical assessment of brain activation was based on the random effect analysis (between‐group analysis two‐sample t‐test P < 0.005 confirmed by individual analyses performed in the surviving regions P < 0.05 Mann Whitney U‐test). Compared to controls, patients showed significantly greater activation in the right frontopolar cortex, the bilateral lateral prefrontal cortices, and the right cerebellum. Healthy controls did not show greater activation compared to CISSMS patients. The present study argues in favor of the existence of compensatory cortical activations at the earliest stage of MS mainly located in regions involved in executive processing in patients performing PASAT. It also suggests that fMRI can evidence the active processes of neuroplasticity contributing to mask the clinical cognitive expression of brain pathology at the earliest stage of MS. Hum. Brain Mapping 20:51–58, 2003.

Imaging Experimental Cerebral Malaria In Vivo: Significant Role of Ischemic Brain Edema

The first in vivo magnetic resonance study of experimental cerebral malaria is presented. Cerebral involvement is a lethal complication of malaria. To explore the brain of susceptible mice infected with Plasmodium berghei ANKA, multimodal magnetic resonance techniques were applied (imaging, diffusion, perfusion, angiography, spectroscopy). They reveal vascular damage including blood-brain barrier disruption and hemorrhages attributable to inflammatory processes. We provide the first in vivo demonstration for blood-brain barrier breakdown in cerebral malaria. Major edema formation as well as reduced brain perfusion was detected and is accompanied by an ischemic metabolic profile with reduction of high-energy phosphates and elevated brain lactate. In addition, angiography supplies compelling evidence for major hemodynamics dysfunction. Actually, edema further worsens ischemia by compressing cerebral arteries, which subsequently leads to a collapse of the blood flow that ultimately represents the cause of death. These findings demonstrate the coexistence of inflammatory and ischemic lesions and prove the preponderant role of edema in the fatal outcome of experimental cerebral malaria. They improve our understanding of the pathogenesis of cerebral malaria and may provide the necessary noninvasive surrogate markers for quantitative monitoring of treatment.

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.

Role of resting state functional connectivity MRI in presurgical investigation of mesial temporal lobe epilepsy

Objective The authors aimed to determine the ability of resting-state functional connectivity MRI (fcMRI) to lateralise/localise the epileptogenic zone in patients presenting with mesial temporal lobe epilepsy (MTLE) at the individual level. Methods Basal functional connectivity (BFC) was evaluated in each hemisphere of 22 MTLE patients. 200 volumes were acquired using a single-shot GE-EPI sequence during a resting period of 10 min at 1.5 T. The signal time-course was extracted from 10 regions of interest (ROIs), five ROIs in each hemisphere, usually involved in epileptogenic networks of MTLE. Normalised correlation coefficients between pairs of ROIs signal time-courses were computed to reflect BFC. Based on normative BFC values obtained from 36 controls, the number of BFC decreases and increases were determined in each hemisphere for each patient. Results BFC decreases were found bilaterally, although the number of decreased links was significantly higher in the epileptogenic side (p=0.025). Conversely, BFC increases were found almost exclusively in the contralateral lobe leading to a strong test effect for locating the non-epileptic lobe with a sensitivity of 64% and a specificity of 91% (p<0.001). The most frequently disconnected areas were the entorhinal cortex and the anterior hippocampus in the epileptic lobe, while contralateral BFC increases involved preferentially hippocampus and amygdala. Conclusions This study demonstrates that the presence of BFC increases in the non-epileptic side was paradoxically the most specific marker of epileptogenic zone localisation, and suggests that a single resting-state fcMRI could be useful in the presurgical assessment of MTLE at an individual level.

Atrophy mainly affects the limbic system and the deep grey matter at the first stage of multiple sclerosis

Background The existence of grey matter (GM) atrophy right after the first clinical event suggestive of multiple sclerosis (MS) remains controversial. The aim of this study was therefore to establish whether regional GM atrophy is already present in the earliest stage of MS assessing regional GM atrophy in a large group of patients. Methods Sixty-two patients with a clinically isolated syndrome (CIS) were examined on a 1.5 T MR imager within 6 months after their first clinical events. A group of 37 matched healthy control subjects were also included in the study. An optimised voxel-based morphometry (VBM) method customised for MS was applied on volumetric T1-weighted images. The functional status of patients was assessed using the Expanded Disability Status Scale (EDSS) and the Brief Repeatable Battery. Results VBM analysis (p<0.005, familywise error corrected) on patients versus control subjects showed the presence of significant focal GM atrophy in patients involving the bilateral insula, the bilateral orbitofrontal cortices, the bilateral internal and inferior temporal regions, the posterior cingulate cortex, the bilateral thalami, the bilateral caudate nuclei, the bilateral lenticular nuclei and the bilateral cerebellum. EDSS was slightly correlated (ρ=−0.37 p=0.0027) with the atrophy of the right cerebellum. No correlations have been evidenced between the cognitive status of patients and the regional GM atrophy. Conclusion The present study performed on a large group of CIS patients demonstrated that regional GM atrophy is present right after the first clinical event of multiple sclerosis and mainly affects the deep GM and the limbic system.

Heterogeneity of metabolic response to muscular exercise in humans: New criteria of invariance defined by in vivo phosphorus-31 NMR spectroscopy

31P NMR spectroscopy at 4.7 T has been used in vivo to follow metabolic changes associated with exercise and subsequent recovery in the forearm flexor digitorum superficial muscle of 14 healthy volunteers. The muscle content in phosphomonoesters at rest provides an index of glycogenolytic activity. Quantitative linear correlations have been shown to link end‐of‐exercise acidosis to recovery kinetics of phosphocreatine and phosphocreatine/organic phosphate ratio. These linear relationships constitute new metabolic invariants to be used in the study of myopathies and muscle adaptation to exercise.

31P NMR spectroscopy and ergometer exercise test as evidence for muscle oxidative performance improvement with coenzyme Q in mitochondrial myopathies

Two patients with mitochondrial encephalomyopathy due to complexes I and IV deficiencies received 150 mg/d of coenzyme Q10 (CoQ). We studied them with a bicycle ergometer exercise test and 31P NMR spectroscopy before and after 10 months of treatment. Before treatment, we observed a low phosphocreatine/inorganic phosphate (PCr/Pi) resting value along with abnormally high resting lactate concentration. During exercise, there was a pronounced acidosis with delayed kinetics of postexercise recovery for blood lactate, pH, PCr, and PCr/Pi ratio. Oxygen uptake during exercise was reduced while the lowering of the ventilatory threshold indicated an early activation of glycolysis. After treatment, the bicycle ergometer exercise test indicated a significant improvement with a decrease in resting blood lactate level, an increase in oxygen consumption during exercise, and an increase in the kinetics of lactate disappearance during the recovery period. A shift of the ventilatory threshold to higher workload was present. 31P NMR spectroscopy confirmed the improvement, showing a significant increase in the PCr/Pi ratio at rest and in the kinetics of recovery for pH, PCr, and PCr/Pi ratio following exercise in patient 1. For patient 2, we observed a less pronounced acidosis correlated with a lesser amount of Pi produced during exercise. These observations indicate an improvement of mitochondrial function and a shift from high to low glycolytic activity in both patients consequent to CoQ treatment.