Typicality in the brain during semantic and episodic memory decisions.

Concept typicality is a key semantic dimension supporting the categorical organization of items based on their features, such that typical items share more features with other members of their category than atypical items, which are more distinctive. Typicality effects manifest in better accuracy and faster response times during categorization tasks, but higher performance for atypical items in episodic memory tasks, due to their distinctiveness. At a neural level, typicality has been linked to the anterior temporal lobe (ATL) and the inferior frontal gyrus (IFG) in semantic decision tasks, but patterns of brain activity during episodic memory tasks remain to be understood. We investigated the neural correlates of typicality in semantic and episodic memory to determine the brain regions associated with semantic typicality and uncover effects arising when items are reinstated during retrieval. In an fMRI study, 26 healthy young subjects first performed a category verification task on words representing typical and atypical concepts (encoding), and then completed a recognition memory task (retrieval). In line with previous literature, we observed higher accuracy and faster response times for typical items in the category verification task, while atypical items were better recognized in the episodic memory task. During category verification, univariate analyses revealed a greater involvement of the angular gyrus for typical items and the inferior frontal gyrus for atypical items. During the correct recognition of old items, regions belonging to the core recollection network were activated. We then compared the similarity of the representations from encoding to retrieval (ERS) using Representation Similarity Analyses. Results showed that typical items were reinstated more than atypical ones in several regions including the left precuneus and left anterior temporal lobe (ATL). This suggests that the correct retrieval of typical items requires finer-grained processing, evidenced by greater item-specific reinstatement, which is needed to resolve their confusability with other members of the category due to their higher feature similarity. Our findings confirm the centrality of the ATL in the processing of typicality while extending it to memory retrieval.

Familiarity in Mild Cognitive Impairment as a Function of Patients' Clinical Outcome 4 Years Later.

OBJECTIVES: The current study addresses the nature of memory difficulties in amnestic mild cognitive impairment (aMCI). Whereas recollection is consistently found to be impaired in aMCI, the results on familiarity are divergent. One potential factor that could explain this divergence in findings relates to the heterogeneity of aMCI patients, so that only those aMCI patients who develop Alzheimer disease (AD) may present with impaired familiarity. The present study aimed at testing this hypothesis. METHODS: A group of 45 aMCI patients and a group of 26 healthy older adults performed a verbal recognition memory test with the Remember/Know paradigm to assess recollection and familiarity processes. All participants were followed for 4 years with clinical and neuropsychological testing. At the end of follow-up, 22 aMCI patients progressed to AD and 23 aMCI patients remained stable. Initial memory performance was compared between the 3 groups. RESULTS: Whereas recollection was severely diminished in all aMCI patients, familiarity accuracy (and consequently global recognition accuracy) was found to be impaired only in aMCI patients who subsequently developed AD. CONCLUSION: These findings suggest that the enrichment of the aMCI population with predementia stage patients may modulate the likelihood to observe familiarity deficits, and impaired global recognition accuracy may accompany incipient AD.

Auditory localization should be considered as a sign of minimally conscious state based on multimodal findings.

Auditory localization (i.e. turning the head and/or the eyes towards an auditory stimulus) is often part of the clinical evaluation of patients recovering from coma. The objective of this study is to determine whether auditory localization could be considered as a new sign of minimally conscious state, using a multimodal approach. The presence of auditory localization and the clinical outcome at 2 years of follow-up were evaluated in 186 patients with severe brain injury, including 64 with unresponsive wakefulness syndrome, 28 in minimally conscious state minus, 71 in minimally conscious state plus and 23 who emerged from the minimally conscious state. Brain metabolism, functional connectivity and graph theory measures were investigated by means of 18F-fluorodeoxyglucose positron emission tomography, functional MRI and high-density electroencephalography in two subgroups of unresponsive patients, with and without auditory localization. These two subgroups were also compared to a subgroup of patients in minimally conscious state minus. Auditory localization was observed in 13% of unresponsive patients, 46% of patients in minimally conscious state minus, 62% of patients in minimally conscious state plus and 78% of patients who emerged from the minimally conscious state. The probability to observe an auditory localization increased along with the level of consciousness, and the presence of auditory localization could predict the level of consciousness. Patients with auditory localization had higher survival rates (at 2-year follow-up) than those without localization. Differences in brain function were found between unresponsive patients with and without auditory localization. Higher connectivity in unresponsive patients with auditory localization was measured between the fronto-parietal network and secondary visual areas, and in the alpha band electroencephalography network. Moreover, patients in minimally conscious state minus significantly differed from unresponsive patients without auditory localization in terms of brain metabolism and alpha network centrality, whereas no difference was found with unresponsive patients who presented auditory localization. Our multimodal findings suggest differences in brain function between unresponsive patients with and without auditory localization, which support our hypothesis that auditory localization should be considered as a new sign of minimally conscious state. Unresponsive patients showing auditory localization should therefore no longer be considered unresponsive but minimally conscious. This would have crucial consequences on these patients' lives as it would directly impact the therapeutic orientation or end-of-life decisions usually taken based on the diagnosis.

Anosognosia and default mode subnetwork dysfunction in Alzheimer's disease.

Research on the neural correlates of anosognosia in Alzheimer's disease varied according to methods and objectives: they compared different measures, used diverse neuroimaging modalities, explored connectivity between brain networks, addressed the role of specific brain regions or tried to give support to theoretical models of unawareness. We used resting-state fMRI connectivity with two different seed regions and two measures of anosognosia in different patient samples to investigate consistent modifications of default mode subnetworks and we aligned the results with the Cognitive Awareness Model. In a first study, patients and their relatives were presented with the Memory Awareness Rating Scale. Anosognosia was measured as a patient-relative discrepancy score and connectivity was investigated with a parahippocampal seed. In a second study, anosognosia was measured in patients with brain amyloid (taken as a disease biomarker) by comparing self-reported rating with memory performance, and connectivity was examined with a hippocampal seed. In both studies, anosognosia was consistently related to disconnection within the medial temporal subsystem of the default mode network, subserving episodic memory processes. Importantly, scores were also related to disconnection between the medial temporal and both the core subsystem (participating to self-reflection) and the dorsomedial subsystem of the default mode network (the middle temporal gyrus that might subserve a personal database in the second study). We suggest that disparity in connectivity within and between subsystems of the default mode network may reflect impaired functioning of pathways in cognitive models of awareness.

Brain, Behavior, and Cognitive Interplay in Disorders of Consciousness: A Multiple Case Study.

Patients with prolonged disorders of consciousness (DoC) after severe brain injury may present residual behavioral and cognitive functions. Yet the bedside assessment of these functions is compromised by patients' multiple impairments. Standardized behavioral scales such as the Coma Recovery Scale-Revised (CRS-R) have been developed to diagnose DoC, but there is also a need for neuropsychological measurement in these patients. The Cognitive Assessment by Visual Election (CAVE) was therefore recently created. In this study, we describe five patients in minimally conscious state (MCS) or emerging from the MCS (EMCS). Their cognitive profiles, derived from the CRS-R and CAVE, are presented alongside their neuroimaging results using structural magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET). Scores on the CAVE decreased along with the CRS-R total score, establishing a consistent behavioral/cognitive profile for each patient. Out of these five cases, the one with highest CRS-R and CAVE performance had the least extended cerebral hypometabolism. All patients showed structural and functional brain impairments that were consistent with their behavioral/cognitive profile as based on previous literature. For instance, the presence of visual and motor residual functions was respectively associated with a relative preservation of occipital and motor cortex/cerebellum metabolism. Moreover, residual language comprehension skills were found in the presence of preserved temporal and angular cortex metabolism. Some patients also presented structural impairment of hippocampus, suggesting the presence of memory impairments. Our results suggest that brain-behavior relationships might be observed even in severely brain-injured patients and they highlight the importance of developing new tools to assess residual cognition and language in MCS and EMCS patients. Indeed, a better characterization of their cognitive profile will be helpful in preparation of rehabilitation programs and daily routines.

BCI Performance and Brain Metabolism Profile in Severely Brain-Injured Patients Without Response to Command at Bedside.

Detection and interpretation of signs of "covert command following" in patients with disorders of consciousness (DOC) remains a challenge for clinicians. In this study, we used a tactile P3-based BCI in 12 patients without behavioral command following, attempting to establish "covert command following." These results were then confronted to cerebral metabolism preservation as measured with glucose PET (FDG-PET). One patient showed "covert command following" (i.e., above-threshold BCI performance) during the active tactile paradigm. This patient also showed a higher cerebral glucose metabolism within the language network (presumably required for command following) when compared with the other patients without "covert command-following" but having a cerebral glucose metabolism indicative of minimally conscious state. Our results suggest that the P3-based BCI might probe "covert command following" in patients without behavioral response to command and therefore could be a valuable addition in the clinical assessment of patients with DOC.

Prevalence of increases in functional connectivity in visual, somatosensory and language areas in congenital blindness.

There is ample evidence that congenitally blind individuals rely more strongly on non-visual information compared to sighted controls when interacting with the outside world. Although brain imaging studies indicate that congenitally blind individuals recruit occipital areas when performing various non-visual and cognitive tasks, it remains unclear through which pathways this is accomplished. To address this question, we compared resting state functional connectivity in a group of congenital blind and matched sighted control subjects. We used a seed-based analysis with a priori specified regions-of-interest (ROIs) within visual, somato-sensory, auditory and language areas. Between-group comparisons revealed increased functional connectivity within both the ventral and the dorsal visual streams in blind participants, whereas connectivity between the two streams was reduced. In addition, our data revealed stronger functional connectivity in blind participants between the visual ROIs and areas implicated in language and tactile (Braille) processing such as the inferior frontal gyrus (Broca's area), thalamus, supramarginal gyrus and cerebellum. The observed group differences underscore the extent of the cross-modal reorganization in the brain and the supra-modal function of the occipital cortex in congenitally blind individuals.

Recognition of personally familiar faces and functional connectivity in Alzheimer's disease.

Studies have reported that patients in the severe stages of Alzheimer's disease (AD) experience difficulties recognizing their own faces in recent photographs. Two case reports of late-stage AD showed that this loss of self-face recognition was temporally graded: photographs from the remote past were recognized more easily than more recent photographs. Little is known about the neural correlates of own face recognition abilities in AD patients, while neuroimaging studies in healthy adults have related these abilities to a bilateral fronto-parieto-occipital network. In this study, two behavioral experiments (experiments 1 and 2) and one functional magnetic resonance imaging (fMRI) experiment (second part of experiment 2) were conducted to compare mild AD patients (experiment 1) and moderate AD patients (experiment 2) with healthy older participants in a recognition task involving self and familiar faces from different decades of the participants' life. In moderate AD patients, variable performance allowed us to examine correlations between scores and resting-state fMRI in order to link behavioral data to cerebral activity. At the behavioral level, the results revealed that, in mild AD, self and familiar face recognition was preserved. Moreover, mild AD patients and healthy older participants showed an inverse temporal gradient, with faster recognition of self and familiar recent photographs than self and familiar remote photographs. However, in moderate AD, both self and familiar face recognition were affected. fMRI results showed that the higher the connectivity between the dorsomedial prefrontal cortex (dMPFC) and the right superior frontal gyrus (rSFG), the lower the self and familiar face recognition scores in moderate AD patients. Given that previous studies have related the superior frontal region to control processes rather than face recognition processes, these results might reflect less segregation and more interference between brain networks in AD. In other words, impaired face recognition in AD may be related to functional dedifferentiation of specific brain regions.

Changes in cerebral metabolism in patients with a minimally conscious state responding to zolpidem.

BACKGROUND: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of arousal and cognitive abilities. We here assessed zolpidem-induced changes in regional brain metabolism in three patients with known zolpidem response in chronic post-anoxic minimally conscious state (MCS). METHODS: [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and standardized clinical assessments using the Coma Recovery Scale-Revised were performed after administration of 10 mg zolpidem or placebo in a randomized double blind 2-day protocol. PET data preprocessing and comparison with a healthy age-matched control group were performed using statistical parametric mapping (SPM8). RESULTS: Behaviorally, all patients recovered functional communication after administration of zolpidem (i.e., emergence from the MCS). FDG-PET showed increased metabolism in dorsolateral prefrontal and mesiofrontal cortices after zolpidem but not after placebo administration. CONCLUSION: Our data show a metabolic activation of prefrontal areas, corroborating the proposed mesocircuit hypothesis to explain the paradoxical effect of zolpidem observed in some patients with DOC. It also suggests the key role of the prefrontal cortices in the recovery of functional communication and object use in hypoxic patients with chronic MCS.

Brain energization in response to deep brain stimulation of subthalamic nuclei in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment in a subgroup of medically refractory patients with Parkinson's disease (PD). Here, we compared resting-state (18)F-fluorodeoxyglucose (FDG) positron emission tomography images in the stimulator off (DBS_OFF) and on (DBS_ON) conditions in eight PD patients in an unmedicated state, on average 2 years after bilateral electrode implantation. Global standardized uptake value (SUV) significantly increased by ∼11% in response to STN-DBS. To avoid any bias in the voxel-based analysis comparing DBS_ON and DBS_OFF conditions, individual scan intensity was scaled to a region where FDG-SUV did not differ significantly between conditions. The resulting FDG-SUV ratio (FDG-SUVR) was found to increase in many regions in response to STN-DBS including the target area of surgery, caudate nuclei, primary sensorimotor, and associative cortices. Contrary to previous studies, we could not find any regional decrease in FDG-SUVR. These findings were indirectly supported by comparing the extent of areas with depressed FDG-SUVR in DBS_OFF and DBS_ON relatively to 10 normal controls. Altogether, these novel results support the prediction that the effect of STN-DBS on brain activity in PD is unidirectional and consists in an increase in many subcortical and cortical regions.

NEMA NU4-2008 image quality performance report for the microPET focus 120 and for various transmission and reconstruction methods.

UNLABELLED: This work aimed to evaluate the image quality and accuracy of attenuation and scatter corrections provided with the microPET Focus 120 scanner using the National Electrical Manufacturers Association NU4-2008 image quality phantom. METHODS: Attenuation correction was obtained from transmission measurements using either a (68)Ge or a (57)Co point source. Fully corrected emission images were reconstructed using Fourier rebinning (FORE) and filtered backprojection (FBP). For attenuation data obtained with the (57)Co source, fully corrected emission images were also reconstructed using FORE and 2-dimensional (2D) ordered-subset expectation maximization (OSEM), 3-dimensional (3D) filtered backprojection (3DRP), 3D OSEM, and 3D maximum a posteriori methods. The mean activity, the coefficients of variation (COVs) of the uniform slices, the recovery coefficients (RCs) for hot rods, and the spillover ratio (SOR) for nonemitting water and air compartments were measured. RESULTS: For (57)Co-based attenuation correction, the mean activity value differed by less than 3% from the true activity. Measuring the attenuation with (68)Ge resulted in lower reconstructed activity and higher COV. On the basis of (57)Co measurements, the SORs for air and water nonemitting compartments were the closest to zero for attenuation correction. The RC measured on emission images corrected for attenuation but not for scatter did not show any significant difference linked to the transmission method. However, higher RCs were noted for transmission measurement with (68)Ge in coincidence with windowing when emission data were corrected for attenuation and scatter. This resulted from a lower mean value in the uniform area. 2D and 3DRP reconstruction methods showed little effect on the mean activity value, whereas iterative 3D methods gave 7% higher values. Higher RCs were found with iterative reconstruction than with FBP and 3DRP. However, the SOR seemed to be optimal with FBP. SORs were higher with iterative methods and decreased with the number of iterations. CONCLUSION: For studies of small rodents with the Focus 120, (57)Co transmission seems to be the most suitable method for attenuation correction. FORE and 2D reconstruction methods appear to be a good compromise between overall image quality and reconstruction time: OSEM provides the largest contrasts, but FBP provides superior attenuation and scatter correction.

Does propofol alter membrane fluidity at clinically relevant concentrations? An ESR spin label study.

General anesthetics have been shown to perturb the membrane properties of excitable tissues. Due to their lipid solubility, anesthetics dissolve in every membrane, penetrate into organelles and interact with numerous cellular structures in multiple ways. Several studies indicate that anesthetics alter membrane fluidity and decrease the phase-transition temperature. However, the required concentrations to induce such effects on the properties of membrane lipids are by far higher than clinically relevant concentrations. In the present study, the fluidizing effect of the anesthetic agent propofol (2,6-diisopropyl phenol: PPF), a general anesthetic extensively used in clinical practice, has been investigated on liposome dimyristoyl-L-alpha phosphatidylcholine (DMPC) and cell (erythrocyte, Neuro-2a) membranes using electron spin resonance spectroscopy (ESR) of nitroxide labeled fatty acid probes (5-, 16-doxyl stearic acid). A clear effect of PPF at concentrations higher than the clinically relevant ones was quantified both in liposome and cell membranes, while no evident fluidity effect was measured at the clinical PPF doses. However, absorption spectroscopy of merocyanine 540 (MC540) clearly indicates a PPF fluidizing capacity in liposome membrane even at these clinical concentrations. PPF may locally influence the structure and dynamics of membrane domains, through the formation of small-scale lipid domains, which would explain the lack of ESR information at low PPF concentrations.

Quantification of lipid bilayer effective microviscosity and fluidity effect induced by propofol.

Electron spin resonance (ESR) spectroscopy with nitroxide spin probes was used as a method to probe the liposome microenvironments. The effective microviscosities have been determined from the calibration of the ESR spectra of the probes in solvent mixtures of known viscosities. In the first time, by measuring ESR order parameter (S) and correlation time (tau(c)) of stearic spin probes, we have been able to quantify the value of effective microviscosity at different depths inside the liposome membrane. At room temperature, local microviscosities measured in dimyristoyl-l-alpha phosphatidylcholine (DMPC) liposome membrane at the different depths of 7.8, 16.95, and 27.7 A were 222.53, 64.09, and 62.56 cP, respectively. In the gel state (10 degrees C), those microviscosity values increased to 472.56, 370.61, and 243.37 cP. In a second time, we have applied this technique to determine the modifications in membrane microviscosity induced by 2,6-diisopropyl phenol (propofol; PPF), an anaesthetic agent extensively used in clinical practice. Propofol is characterized by a unique phenolic structure, absent in the other conventional anaesthetics. Indeed, given its lipophilic property, propofol is presumed to penetrate into and interact with membrane lipids and hence to induce changes in membrane fluidity. Incorporation of propofol into dimyristoyl-l-alpha phosphatidylcholine liposomes above the phase-transition temperature (23.9 degrees C) did not change microviscosity. At 10 degrees C, an increase of propofol concentration from 0 to 1.0 x 10(-2) M for a constant lipid concentration mainly induced a decrease in microviscosity. This fluidity effect of propofol has been qualitatively confirmed using merocyanine 540 (MC540) as lipid packing probe. Above 10(-2) M propofol, no further decrease in microviscosity was observed, and the microviscosity at the studied depths (7.8, 16.95, and 27.7 A) amounted 260.21, 123.87, and 102.27 cP, respectively. The concentration 10(-2) M was identified as the saturation limit of propofol in dimyristoyl-l-alpha phosphatidylcholine liposomes.