Functional imaging of human crossmodal identification and object recognition

The perception of objects is a cognitive function of prime importance. In everyday life, object perception benefits from the coordinated interplay of vision, audition, and touch. The different sensory modalities provide both complementary and redundant information about objects, which may improve recognition speed and accuracy in many circumstances. We review crossmodal studies of object recognition in humans that mainly employed functional magnetic resonance imaging (fMRI). These studies show that visual, tactile, and auditory information about objects can activate cortical association areas that were once believed to be modality-specific. Processing converges either in multisensory zones or via direct crossmodal interaction of modality-specific cortices without relay through multisensory regions. We integrate these findings with existing theories about semantic processing and propose a general mechanism for crossmodal object recognition: The recruitment and location of multisensory convergence zones varies depending on the information content and the dominant modality.A. Amedi, K. von Kriegstein, N. M. van Atteveldt, M. S. Beauchamp and M. J. Naumeri contributed equally to this work     

Generators of electrical and magnetic mismatch responses in humans

Summary Studies bearing on generators of the electric and magnetic mismatch responses in humans to change in a repetitive sound are reviewed. It was concluded that the main contribution of the mismatch negativity (MMN) and of its magnetic equivalent MMNm, elicited even in the absence of attention, originates from auditory cortex on the supratemporal plane. In addition, those responses probably have one or two sources on the right lateral temporal cortex and, at least the MMN, a source also in the right frontal cortex. The activation caused by stimulus change in the sensory-specific cortex is, presumably, a manifestation of preperceptual change detection, whereas the frontal activation might be associated with conscious perception of, attention switch to, stimulus change.     

Role of DNA mismatch repair in apoptotic responses to therapeutic agents

Deficiencies in DNA mismatch repair (MMR) have been found in both hereditary cancer (i.e., hereditary nonpolyposis colorectal cancer) and sporadic cancers of various tissues. In addition to its primary roles in the correction of DNA replication errors and suppression of recombination, research in the last 10 years has shown that MMR is involved in many other processes, such as interaction with other DNA repair pathways, cell cycle checkpoint regulation, and apoptosis. Indeed, a cell's MMR status can influence its response to a wide variety of chemotherapeutic agents, such as temozolomide (and many other methylating agents), 6-thioguanine, cisplatin, ionizing radiation, etoposide, and 5-fluorouracil. For this reason, identification of a tumor's MMR deficiency (as indicated by the presence of microsatellite instability) is being utilized more and more as a prognostic indicator in the clinic. Here, we describe the basic mechanisms of MMR and apoptosis and investigate the literature examining the influence of MMR status on the apoptotic response following treatment with various therapeutic agents. Furthermore, using isogenic MMR-deficient (HCT116) and MMR-proficient (HCT116 3-6) cells, we demonstrate that there is no enhanced apoptosis in MMR-proficient cells following treatment with 5-fluoro-2'-deoxyuridine. In fact, apoptosis accounts for only a small portion of the induced cell death response.     

Functional and physical interaction between the mismatch repair and FA-BRCA pathways

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure and an increased risk for leukemia and cancer. Fifteen proteins thought to function in the repair of DNA interstrand crosslinks (ICLs) comprise what is known as the FA-BRCA pathway. Activation of this pathway leads to the monoubiquitylation and chromatin localization of FANCD2 and FANCI. It has previously been shown that FANCJ interacts with the mismatch repair (MMR) complex MutLα. Here we show that FANCD2 interacts with the MMR proteins MSH2 and MLH1. FANCD2 monoubiquitylation, foci formation and chromatin loading are greatly diminished in MSH2-deficient cells. Human or mouse cells lacking MSH2 or MLH1 display increased sensitivity and radial formation in response to treatment with DNA crosslinking agents. Studies in human cell lines and Drosophila mutants suggest an epistatic relationship between FANCD2, MSH2 and MLH1 with regard to ICL repair. Surprisingly, the interaction between MSH2 and MLH1 is compromised in multiple FA cell lines, and FA cell lines exhibit deficient MMR. These results suggest a significant role for MMR proteins in the activation of the FA pathway and repair of ICLs. In addition, we provide the first evidence for a defect in MMR in FA cell lines.     

Visual,haptic and crossmodal recognition of scenes

Real-world scene perception can often involve more than one sensory modality. Here we investigated the visual, haptic and crossmodal recognition of scenes of familiar objects. In three experiments participants first learned a scene of objects arranged in random positions on a platform. After learning, the experimenter swapped the position of two objects in the scene and the task for the participant was to identify the two swapped objects. In experiment 1, we found a cost in scene recognition performance when there was a change in sensory modality and scene orientation between learning and test. The cost in crossmodal performance was not due to the participants verbally encoding the objects (experiment 2) or by differences between serial and parallel encoding of the objects during haptic and visual learning, respectively (experiment 3). Instead, our findings suggest that differences between visual and haptic representations of space may affect the recognition of scenes of objects across these modalities.     

Using somatosensory mismatch responses as a window into somatotopic processing of tactile stimulation

Brain responses to tactile stimulation have often been studied through the examination of ERPs elicited to touch on the body surface. Here, we examined two factors potentially modulating the amplitude of the somatosensory mismatch negativity (sMMN) and P300 responses elicited by touch to pairs of body parts: (a) the distance between the representation of these body parts in somatosensory cortex, and (b) the physical distances between the stimulated points on the body surface. The sMMN and the P300 response were elicited by tactile stimulation in two oddball protocols. One protocol leveraged a discontinuity in cortical somatotopic organization, and involved stimulation of either the neck or the hand in relation to stimulation of the lip. The other protocol involved stimulation to the third or fifth finger in relation to the second finger. The neck‐lip pairing resulted in significantly larger sMMN responses (with shorter latencies) than the hand‐lip pairing, whereas the reverse was true for the amplitude of the P300. Mean sMMN amplitude and latency did not differ between finger pairings. However, larger P300 responses were elicited to stimulation of the fifth finger than the third finger. These results suggest that, for certain combinations of body parts, early automatic somatosensory mismatch responses may be influenced by distance between the cortical representations of these body parts, whereas the later P300 response may be more influenced by the distance between stimulated body parts on the body surface. Future investigations can shed more light on this novel suggestion.     

Sequential neural processes of tactile-visual crossmodal working memory

Working memory is essential to learning and performing sensory-motor behaviors that in many situations require the integration of stimuli of one modality with stimuli of another. In the present study, we focused on the neural mechanisms underlying crossmodal working memory. We hypothesized that in performance of the tactile crossmodal working memory task, there would be sequentially discrete task-correlated neural activities representing the processes of crossmodal working memory. Scalp-recorded event-related potentials were collected from 15 electrodes in humans performing each of four tasks: tactile-tactile unimodal delayed matching-to-sample task, tactile-visual crossmodal delayed matching-to-sample task, tactile unimodal control spatial task, and tactile crossmodal control spatial task. Two positive event-related potential peaks were observed during the delay of the task. One peak (late positive component-1) was at about 330 ms after the onset of the tactile stimulus, and the other (late positive component-2) was at about 600 ms. Late positive component-1 was observed in all four tasks. There was no significant difference in late positive component-1 either between the unimodal tasks, or between the crossmodal tasks, but late positive component-1 was significantly larger in the crossmodal tasks than that in the unimodal tasks, and showed a specific pattern of larger activity over parietal areas than activity over frontal areas. Late positive component-2 was not observed in the unimodal matching task but was observed in all other three tasks over parietal areas. During the late delay (1000 ms-1500 ms), significant differences in negative potentials (late negative component) were found between the tasks. The present study shows sequential changes in event-related potentials during the retention period of working memory tasks. It indicates that in performance of a crossmodal working memory task, there are sequentially discrete neural processes that may represent neural activities related to different cognitive functions, such as crossmodal transfer of information, and the working memory of the stimulus.     

Enhancement of visual perception by crossmodal visuo-auditory interaction

Neurophysiological studies have shown in animals that a sudden sound enhanced perceptual processing of subsequent visual stimuli. In the present study, we explored the possibility that such enhancement also exists in humans and can be explained through crossmodal integration effects, whereby the interaction occurs at the level of bimodal neurons. Subjects were required to detect visual stimuli in a unimodal visual condition or in crossmodal audio-visual conditions. The spatial and the temporal proximity of multisensory stimuli were systematically varied. An enhancement of the perceptual sensitivity (d') for luminance detection was found when the audiovisual stimuli followed a rather clear spatial and temporal rule, governing multisensory integration at the neuronal level. Electronic Publication     

The effect of schizophrenia risk factors on mismatch responses in a rat model

Reduced mismatch negativity (MMN), a robust finding in schizophrenia, has prompted interest in MMN as a preclinical biomarker of schizophrenia. The rat brain can generate human-like mismatch responses (MMRs) which therefore enables the exploration of the neurobiology of reduced MMRs. Given epidemiological evidence that two developmental factors, maternal infection and adolescent cannabis use, increase the risk of schizophrenia, we determined the effect of these two developmental risk factors on rat MMR amplitude in different auditory contexts. MMRs were assessed in awake adult male and female Wistar rats that were offspring of pregnant dams treated with either a viral infection mimetic (poly I:C) inducing maternal immune activation (MIA) or saline control. In adolescence, subgroups of the prenatal treatment groups were exposed to either a synthetic cannabinoid (adolescent cannabinoid exposure: ACE) or vehicle. The context under which MMRs were obtained was manipulated by employing two different oddball paradigms, one that manipulated the physical difference between rare and common auditory stimuli, and another that manipulated the probability of the rare stimulus. The design of the multiple stimulus sequences across the two paradigms also allowed an investigation of context on MMRs to two identical stimulus sequences. Male offspring exposed to each of the risk factors for schizophrenia (MIA, ACE or both) showed a reduction in MMR, which was evident only in the probability paradigm, with no effects seen in the physical difference. Our findings highlight the importance of contextual factors induced by paradigm manipulations and sex for modeling schizophrenia-like MMN impairments in rats.     

Preservation of crossmodal selective attention in healthy aging

The goal of the present study was to determine if older adults benefited from attention to a specific sensory modality in a voluntary attention task and evidenced changes in voluntary or involuntary attention when compared to younger adults. Suppressing and enhancing effects of voluntary attention were assessed using two cued forced-choice tasks, one that asked participants to localize and one that asked them to categorize visual and auditory targets. Involuntary attention was assessed using the same tasks, but with no attentional cues. The effects of attention were evaluated using traditional comparisons of means and Cox proportional hazards models. All analyses showed that older adults benefited behaviorally from selective attention in both visual and auditory conditions, including robust suppressive effects of attention. Of note, the performance of the older adults was commensurate with that of younger adults in almost all analyses, suggesting that older adults can successfully engage crossmodal attention processes. Thus, age-related increases in distractibility across sensory modalities are likely due to mechanisms other than deficits in attentional processing.     

Functional organization of parietal neuronal responses to optic-flow stimuli

We analyzed the dissimilarity matrix of neuronal responses to moving visual stimuli using tree clustering and multidimensional scaling (MDS). Single-cell activity was recorded in area 7a while random dots moving coherently in eight different kinds of motion (right-, left-, up-, and downward, clockwise, counterclockwise, expansion, contraction) were presented to behaving monkeys with eyes fixated. Tree clustering analyses showed that the [rightward, leftward], [upward, downward], and [clockwise, counterclockwise]] motions were clustered in three separate branches (i.e., horizontal, vertical, and rotatory motion, respectively). In contrast, expansion was in a lone branch, whereas contraction was also separate but within a larger cluster. The distances among these clusters were then subjected to an MDS analysis to identify the dimensions underlying the tree clustering observed. This analysis revealed two major factors in operation. The first factor separated expansion from all other stimulus motions, which seems to reflect the prominence of expansion during the common activity of locomotion. In contrast, the second factor separated planar motions from motion in depth, which suggests that the latter may hold a special place in visual motion processing.     

A mismatch repair-based model can explain some features of u.v. mutagenesis in yeast

Our studies on the REV2-dependent processes of DNA repair andu.v. mutagenesis in yeast are summarized and compared with thegeneral features of DNA damage-induced mutagenesis in yeast.On the basis of the data available, we propose that mismatchrepair is an essential process in u.v. mutagenesis. We assumethat a photoproduct site in double-stranded DNA can be handledas a replicative mismatch leading to misinsertion opposite thelesion.     

Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes

Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is caused by DNA variations in the DNA mismatch repair (MMR) genes MSH2, MLH1, MSH6, and PMS2. Many of the mutations identified result in premature termination of translation and thus in loss-of-function of the encoded mutated protein. These DNA variations are thought to be pathogenic mutations. However, some patients carry other DNA mutations, referred to as unclassified variants (UVs), which do not lead to such a premature termination of translation; it is not known whether these contribute to the disease phenotype or merely represent rare polymorphisms. This is a major problem which has direct clinical consequences. Several criteria can be used to classify these UVs, such as: whether they segregate with the disease within pedigrees, are absent in control individuals, show a change of amino acid polarity or size, provoke an amino acid change in a domain that is evolutionary conserved and/or shared between proteins belonging to the same protein family, or show altered function in an in vitro assay. In this review we discuss the various functional assays reported for the HNPCC-associated MMR proteins and the outcomes of these tests on UVs identified in patients diagnosed with or suspected of having HNPCC. We conclude that a large proportion of MMR UVs are likely to be pathogenic, suggesting that missense variants of MMR proteins do indeed play a role in HNPCC.     

Functional modulation of dendritic cells to suppress adaptive immune responses

In recent years, dendritic cells (DCs) have entered the center court of immune regulation. Dependent on their ontogeny, state of differentiation, and maturation and thereby a variable expression of membrane-bound and soluble molecules, DCs can induce immunostimulatory as well as immunoregulatory responses. This dual function has made them potential targets in vaccine development in cancer and infections as well as for the prevention and treatment of allograft rejection and autoimmune diseases. The present review is focused on the effect of immune-modulatory factors, such as cytokines and immunosuppressive drugs, and on the survival, differentiation, migration, and maturation of DC human subsets. A better understanding of DC immunobiology may lead to the development of specific therapies to prevent or dampen immune responses.     

Common features of light-evoked amacrine cell responses in vertebrate retina

The light-evoked electrical responses of a large number of amacrine cells in the roach retina have been observed by intracellular recording. Examination of response profiles suggests that amacrine cell responses possess a number of common features: combinations of sustained and transient components, light-dependent membrane noise and oscillations, afterpotentials. From these and other observations taken together, a unified view of light-evoked amacrine cell responses is presented, whereby response profiles are thought to reflect synaptic organizations rather than differences in inherent membrane properties.     

Neuroanatomical identification of crossmodal auditory inputs to interneurons in somatosensory cortex

Multisensory convergence is the first, requisite step in the process that generates neural responses to events involving more than one sensory modality. Although anatomical studies have documented the merging of afferents from different sensory modalities within a given area, they do not provide insight into the architecture of connectivity at the neuronal level that underlies multisensory processing. In fact, few anatomical studies of multisensory convergence at the neuronal level have been conducted. The present study used a combination of tract-tracing, immunocytochemistry, and confocal microscopic techniques to examine the connections related to crossmodal auditory cortical inputs to somatosensory area SIV. Axons labeled from auditory cortex were found in contact with immunolabeled interneurons in SIV, some of which also colocalized vesicular glutamate transporter 1, indicating the presence of an active, glutamatergic synapse. No specific subtype of inhibitory interneuron appeared to be targeted by the crossmodal contacts. These results provide insight into the structural basis for multisensory processing at the neuronal level and offer anatomical evidence for the direct involvement of inhibitory interneurons in multisensory processing.