The role of the right parietal cortex in sound localization: a chronometric single pulse transcranial magnetic stimulation study.

Auditory spatial functions, including the ability to discriminate between the positions of nearby sound sources, are subserved by a large temporo-parieto-frontal network. With the aim of determining whether and when the parietal contribution is critical for auditory spatial discrimination, we applied single pulse transcranial magnetic stimulation on the right parietal cortex 20, 80, 90 and 150 ms post-stimulus onset while participants completed a two-alternative forced choice auditory spatial discrimination task in the left or right hemispace. Our results reveal that transient TMS disruption of right parietal activity impairs spatial discrimination when applied at 20 ms post-stimulus onset for sounds presented in the left (controlateral) hemispace and at 80 ms for sounds presented in the right hemispace. We interpret our finding in terms of a critical role for controlateral temporo-parietal cortices over initial stages of the building-up of auditory spatial representation and for a right hemispheric specialization in integrating the whole auditory space over subsequent, higher-order processing stages.

Multisensory mechanisms in temporo-parietal cortex support self-location and first-person perspective.

Self-consciousness has mostly been approached by philosophical enquiry and not by empirical neuroscientific study, leading to an overabundance of diverging theories and an absence of data-driven theories. Using robotic technology, we achieved specific bodily conflicts and induced predictable changes in a fundamental aspect of self-consciousness by altering where healthy subjects experienced themselves to be (self-location). Functional magnetic resonance imaging revealed that temporo-parietal junction (TPJ) activity reflected experimental changes in self-location that also depended on the first-person perspective due to visuo-tactile and visuo-vestibular conflicts. Moreover, in a large lesion analysis study of neurological patients with a well-defined state of abnormal self-location, brain damage was also localized at TPJ, providing causal evidence that TPJ encodes self-location. Our findings reveal that multisensory integration at the TPJ reflects one of the most fundamental subjective feelings of humans: the feeling of being an entity localized at a position in space and perceiving the world from this position and perspective.

Temporo-parietal cortex encodes location of the self: joining fMRI with neuroscience robotics to study bodily self-consciousness

Neuroimaging of the self has focused on high-level mechanisms such as language, memory or imagery of the self and implicated widely distributed brain networks. Yet recent evidence suggests that low-level mechanisms such as multisensory and sensorimotor integration may play a fundamental role in self-related processing. In the present study we used visuotactile multisensory conflict, robotics, virtual reality, and fMRI to study such low-level mechanisms by experimentally inducing changes in self-location. Participants saw a video of a person's back (body) or an empty room (no-body) being stroked while a MR-compatible robotic device stroked their back. The latter tactile input was synchronous or asynchronous with respect to the seen stroking. Self-location was estimated behaviorally confirming previous data that self-location only differed between the two body conditions. fMRI results showed a bilateral activation of the temporo-parietal cortex with a significantly higher BOLD signal increase in the synchronous/body condition with respect to the other conditions. Sensorimotor cortex and extrastriate-body-area were also activated. We argue that temporo-parietal activity reflects the experience of the conscious 'I' as embodied and localized within bodily space, compatible with clinical data in neurological patients with out-of-body experiences.

Voluntary Explicit versus Involuntary Conceptual Memory Are Associated with Dissociable fMRI Responses in Hippocampus, Amygdala, and Parietal Cortex for Emotional and Neutral Word Pairs.

Although functional neuroimaging studies have supported the distinction between explicit and implicit forms of memory, few have matched explicit and implicit tests closely, and most of these tested perceptual rather than conceptual implicit memory. We compared event-related fMRI responses during an intentional test, in which a group of participants used a cue word to recall its associate from a prior study phase, with those in an incidental test, in which a different group of participants used the same cue to produce the first associate that came to mind. Both semantic relative to phonemic processing at study, and emotional relative to neutral word pairs, increased target completions in the intentional test, but not in the incidental test, suggesting that behavioral performance in the incidental test was not contaminated by voluntary explicit retrieval. We isolated the neural correlates of successful retrieval by contrasting fMRI responses to studied versus unstudied cues for which the equivalent "target" associate was produced. By comparing the difference in this repetition-related contrast across the intentional and incidental tests, we could identify the correlates of voluntary explicit retrieval. This contrast revealed increased bilateral hippocampal responses in the intentional test, but decreased hippocampal responses in the incidental test. A similar pattern in the bilateral amygdale was further modulated by the emotionality of the word pairs, although surprisingly only in the incidental test. Parietal regions, however, showed increased repetition-related responses in both tests. These results suggest that the neural correlates of successful voluntary explicit memory differ in directionality, even if not in location, from the neural correlates of successful involuntary implicit (or explicit) memory, even when the incidental test taps conceptual processes.

Multisensory anatomical pathways.

In order to interact with the multisensory world that surrounds us, we must integrate various sources of sensory information (vision, hearing, touch...). A fundamental question is thus how the brain integrates the separate elements of an object defined by several sensory components to form a unified percept. The superior colliculus was the main model for studying multisensory integration. At the cortical level, until recently, multisensory integration appeared to be a characteristic attributed to high-level association regions. First, we describe recently observed direct cortico-cortical connections between different sensory cortical areas in the non-human primate and discuss the potential role of these connections. Then, we show that the projections between different sensory and motor cortical areas and the thalamus enabled us to highlight the existence of thalamic nuclei that, by their connections, may represent an alternative pathway for information transfer between different sensory and/or motor cortical areas. The thalamus is in position to allow a faster transfer and even an integration of information across modalities. Finally, we discuss the role of these non-specific connections regarding behavioral evidence in the monkey and recent electrophysiological evidence in the primary cortical sensory areas.

The thalamocortical projection systems in primate: an anatomical support for multisensory and sensorimotor interplay.

Multisensory and sensorimotor integrations are usually considered to occur in superior colliculus and cerebral cortex, but few studies proposed the thalamus as being involved in these integrative processes. We investigated whether the organization of the thalamocortical (TC) systems for different modalities partly overlap, representing an anatomical support for multisensory and sensorimotor interplay in thalamus. In 2 macaque monkeys, 6 neuroanatomical tracers were injected in the rostral and caudal auditory cortex, posterior parietal cortex (PE/PEa in area 5), and dorsal and ventral premotor cortical areas (PMd, PMv), demonstrating the existence of overlapping territories of thalamic projections to areas of different modalities (sensory and motor). TC projections, distinct from the ones arising from specific unimodal sensory nuclei, were observed from motor thalamus to PE/PEa or auditory cortex and from sensory thalamus to PMd/PMv. The central lateral nucleus and the mediodorsal nucleus project to all injected areas, but the most significant overlap across modalities was found in the medial pulvinar nucleus. The present results demonstrate the presence of thalamic territories integrating different sensory modalities with motor attributes. Based on the divergent/convergent pattern of TC and corticothalamic projections, 4 distinct mechanisms of multisensory and sensorimotor interplay are proposed.

Prismatic adaptation changes visuospatial representation in the inferior parietal lobule.

Prismatic adaptation has been shown to induce a realignment of visuoproprioceptive representations and to involve parietocerebellar networks. We have investigated in humans how far other types of functions known to involve the parietal cortex are influenced by a brief exposure to prismatic adaptation. Normal subjects underwent an fMRI evaluation before and after a brief session of prismatic adaptation using rightward deviating prisms for one group or after an equivalent session using plain glasses for the other group. Activation patterns to three tasks were analyzed: (1) visual detection; (2) visuospatial short-term memory; and (3) verbal short-term memory. The prismatic adaptation-related changes were found bilaterally in the inferior parietal lobule when prisms, but not plain glasses, were used. This effect was driven by selective changes during the visual detection task: an increase in neural activity was induced on the left and a decrease on the right parietal side after prismatic adaptation. Comparison of activation patterns after prismatic adaptation on the visual detection task demonstrated a significant increase of the ipsilateral field representation in the left inferior parietal lobule and a significant decrease in the right inferior parietal lobule. In conclusion, a brief exposure to prismatic adaptation modulates differently left and right parietal activation during visual detection but not during short-term memory. Furthermore, the visuospatial representation within the inferior parietal lobule changes, with a decrease of the ipsilateral hemifield representation on the right and increase on the left side, suggesting thus a left hemispheric dominance.

The perception of touch and the ventral somatosensory pathway.

In humans, touching the skin is known to activate, among others, the contralateral primary somatosensory cortex on the postcentral gyrus together with the bilateral parietal operculum (i.e. the anatomical site of the secondary somatosensory cortex). But which brain regions beyond the postcentral gyrus specifically contribute to the perception of touch remains speculative. In this study we collected structural magnetic resonance imaging scans and neurological examination reports of patients with brain injuries or stroke in the left or right hemisphere, but not in the postcentral gyrus as the entry site of cortical somatosensory processing. Using voxel-based lesion-symptom mapping, we compared patients with impaired touch perception (i.e. hypoaesthesia) to patients without such touch impairments. Patients with hypoaesthesia as compared to control patients differed in one single brain cluster comprising the contralateral parietal operculum together with the anterior and posterior insular cortex, the putamen, as well as subcortical white matter connections reaching ventrally towards prefrontal structures. This finding confirms previous speculations on the 'ventral pathway of somatosensory perception' and causally links these brain structures to the perception of touch.

Temporo-Parietal Junction encodes the Embodied Self: Neuro-Robotics, fMRI, and Lesion mapping.

Introduction: Neuroimaging of the self focused on high-level mechanisms such as language, memory or imagery of the self. Recent evidence suggests that low-level mechanisms of multisensory and sensorimotor integration may play a fundamental role in encoding self-location and the first-person perspective (Blanke and Metzinger, 2009). Neurological patients with out-of body experiences (OBE) suffer from abnormal self-location and the first-person perspective due to a damage in the temporo-parietal junction (Blanke et al., 2004). Although self-location and the first-person perspective can be studied experimentally (Lenggenhager et al., 2009), the neural underpinnings of self-location have yet to be investigated. To investigate the brain network involved in self-location and first-person perspective we used visuo-tactile multisensory conflict, magnetic resonance (MR)-compatible robotics, and fMRI in study 1, and lesion analysis in a sample of 9 patients with OBE due to focal brain damage in study 2. Methods: Twenty-two participants saw a video showing either a person's back or an empty room being stroked (visual stimuli) while the MR-compatible robotic device stroked their back (tactile stimulation). Direction and speed of the seen stroking could either correspond (synchronous) or not (asynchronous) to those of the seen stroking. Each run comprised the four conditions according to a 2x2 factorial design with Object (Body, No-Body) and Synchrony (Synchronous, Asynchronous) as main factors. Self-location was estimated using the mental ball dropping (MBD; Lenggenhager et al., 2009). After the fMRI session participants completed a 6-item adapted from the original questionnaire created by Botvinick and Cohen (1998) and based on questions and data obtained by Lenggenhager et al. (2007, 2009). They were also asked to complete a questionnaire to disclose the perspective they adopted during the illusion. Response times (RTs) for the MBD and fMRI data were analyzed with a 3-way mixed model ANOVA with the in-between factor Perspective (up, down) and the two with-in factors Object (body, no-body) and Stroking (synchronous, asynchronous). Quantitative lesion analysis was performed using MRIcron (Rorden et al., 2007). We compared the distributions of brain lesions confirmed by multimodality imaging (Knowlton, 2004) in patients with OBE with those showing complex visual hallucinations involving people or faces, but without any disturbance of self-location and first person perspective. Nine patients with OBE were investigated. The control group comprised 8 patients. Structural imaging data were available for normalization and co-registration in all the patients. Normalization of each patient's lesion into the common MNI (Montreal Neurological Institute) reference space permitted simple, voxel-wise, algebraic comparisons to be made. Results: Even if in the scanner all participants were lying on their back and were facing upwards, analysis of perspective showed that half of the participants had the impression to be looking down at the virtual human body below them, despite any cues about their body position (Down-group). The other participants had the impression to be looking up at the virtual body above them (Up-group). Analysis of Q3 ("How strong was the feeling that the body you saw was you?") indicated stronger self-identification with the virtual body during the synchronous stroking. RTs in the MBD task confirmed these subjective data (significant 3-way interaction between perspective, object and stroking). fMRI results showed eight cortical regions where the BOLD signal was significantly different during at least one of the conditions resulting from the combination of Object and Stroking, relative to baseline: right and left temporo-parietal junction, right EBA, left middle occipito-temporal gyrus, left postcentral gyrus, right medial parietal lobe, bilateral medial occipital lobe (Fig 1). The activation patterns in right and left temporo-parietal junction and right EBA reflected changes in self-location and perspective as revealed by statistical analysis that was performed on the percentage of BOLD change with respect to the baseline. Statistical lesion overlap comparison (using nonparametric voxel based lesion symptom mapping) with respect to the control group revealed the right temporo-parietal junction, centered at the angular gyrus (Talairach coordinates x = 54, y =-52, z = 26; p>0.05, FDR corrected). Conclusions: The present questionnaire and behavioural results show that - despite the noisy and constraining MR environment) our participants had predictable changes in self-location, self-identification, and first-person perspective when robotic tactile stroking was applied synchronously with the robotic visual stroking. fMRI data in healthy participants and lesion data in patients with abnormal self-location and first-person perspective jointly revealed that the temporo-parietal cortex especially in the right hemisphere encodes these conscious experiences. We argue that temporo-parietal activity reflects the experience of the conscious "I" as embodied and localized within bodily space.

Role of the superior parietal lobules in letter-identity processing within strings: FMRI evidence from skilled and dyslexic readers.

Traditionally, the ventral occipito-temporal (vOT) area, but not the superior parietal lobules (SPLs), is thought as belonging to the neural system of visual word recognition. However, some dyslexic children who exhibit a visual attention span disorder - i.e. poor multi-element parallel processing - further show reduced SPLs activation when engaged in visual multi-element categorization tasks. We investigated whether these parietal regions further contribute to letter-identity processing within strings. Adult skilled readers and dyslexic participants with a visual attention span disorder were administered a letter-string comparison task under fMRI. Dyslexic adults were less accurate than skilled readers to detect letter identity substitutions within strings. In skilled readers, letter identity differs related to enhanced activation of the left vOT. However, specific neural responses were further found in the superior and inferior parietal regions, including the SPLs bilaterally. Two brain regions that are specifically related to substituted letter detection, the left SPL and the left vOT, were less activated in dyslexic participants. These findings suggest that the left SPL, like the left vOT, may contribute to letter string processing.

Subjective mental time: the functional architecture of projecting the self to past and future.

Abstract Human experience takes place in the line of mental time (MT) created through 'self-projection' of oneself to different time-points in the past or future. Here we manipulated self-projection in MT not only with respect to one's life events but also with respect to one's faces from different past and future time-points. Behavioural and event-related functional magnetic resonance imaging activity showed three independent effects characterized by (i) similarity between past recollection and future imagination, (ii) facilitation of judgements related to the future as compared with the past, and (iii) facilitation of judgements related to time-points distant from the present. These effects were found with respect to faces and events, and also suggest that brain mechanisms of MT are independent of whether actual life episodes have to be re-experienced or pre-experienced, recruiting a common cerebral network including the anteromedial temporal, posterior parietal, inferior frontal, temporo-parietal and insular cortices. These behavioural and neural data suggest that self-projection in time is a fundamental aspect of MT, relying on neural structures encoding memory, mental imagery and self.

Impaired early visual response modulations to spatial information in chronic schizophrenia.

Early visual processing stages have been demonstrated to be impaired in schizophrenia patients and their first-degree relatives. The amplitude and topography of the P1 component of the visual evoked potential (VEP) are both affected; the latter of which indicates alterations in active brain networks between populations. At least two issues remain unresolved. First, the specificity of this deficit (and suitability as an endophenotype) has yet to be established, with evidence for impaired P1 responses in other clinical populations. Second, it remains unknown whether schizophrenia patients exhibit intact functional modulation of the P1 VEP component; an aspect that may assist in distinguishing effects specific to schizophrenia. We applied electrical neuroimaging analyses to VEPs from chronic schizophrenia patients and healthy controls in response to variation in the parafoveal spatial extent of stimuli. Healthy controls demonstrated robust modulation of the VEP strength and topography as a function of the spatial extent of stimuli during the P1 component. By contrast, no such modulations were evident at early latencies in the responses from patients with schizophrenia. Source estimations localized these deficits to the left precuneus and medial inferior parietal cortex. These findings provide insights on potential underlying low-level impairments in schizophrenia.

Sub-cortical and brainstem sites associated with chemo-stimulated increases in ventilation in humans.

We investigated the neural basis for spontaneous chemo-stimulated increases in ventilation in awake, healthy humans. Blood oxygen level dependent (BOLD) functional MRI was performed in nine healthy subjects using T2 weighted echo planar imaging. Brain volumes (52 transverse slices, cortex to high spinal cord) were acquired every 3.9 s. The 30 min paradigm consisted of six, 5-min cycles, each cycle comprising 45 s of hypoxic-isocapnia, 45 s of isooxic-hypercapnia and 45 s of hypoxic-hypercapnia, with 55 s of non-stimulatory hyperoxic-isocapnia (control) separating each stimulus period. Ventilation was significantly (p<0.001) increased during hypoxic-isocapnia, isooxic-hypercapnia and hypoxic-hypercapnia (17.0, 13.8, 24.9 L/min respectively) vs. control (8.4 L/min) and was associated with significant (p<0.05, corrected for multiple comparisons) signal increases within a bilateral network that included the basal ganglia, thalamus, red nucleus, cerebellum, parietal cortex, cingulate and superior mid pons. The neuroanatomical structures identified provide evidence for the spontaneous control of breathing to be mediated by higher brain centres, as well as respiratory nuclei in the brainstem.

Relationship between dopamine D2 receptor occupancy, clinical response, and drug and monoamine metabolites levels in plasma and cerebrospinal fluid. A pilot study in patients suffering from first-episode schizophrenia treated with quetiapine.

Combining measurements of the monoamine metabolites in the cerebrospinal fluid (CSF) and neuroimaging can increase efficiency of drug discovery for treatment of brain disorders. To address this question, we examined five drug-naïve patients suffering from schizophrenic disorder. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS): at baseline and then at weekly intervals. Plasma and CSF levels of quetiapine and norquetiapine as well CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindole-acetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were obtained at baseline and again after at least a 4 week medication trail with 600 mg/day quetiapine. CSF monoamine metabolites levels were compared with dopamine D(2) receptor occupancy (DA-D(2)) using [(18)F]fallypride and positron emission tomography (PET). Quetiapine produced preferential occupancy of parietal cortex vs. putamenal DA-D(2), 41.4% (p<0.05, corrected for multiple comparisons). DA-D(2) receptor occupancies in the occipital and parietal cortex were correlated with CSF quetiapine and norquetiapine levels (p<0.01 and p<0.05, respectively). CSF monoamine metabolites were significantly increased after treatment and correlated with regional receptor occupancies in the putamen [DOPAC: (p<0.01) and HVA: (p<0.05)], caudate nucleus [HVA: (p<0.01)], thalamus [MHPG: (p<0.05)] and in the temporal cortex [HVA: (p<0.05) and 5-HIAA: (p<0.05)]. This suggests that CSF monoamine metabolites levels reflect the effects of quetiapine treatment on neurotransmitters in vivo and indicates that monitoring plasma and CSF quetiapine and norquetiapine levels may be of clinical relevance.

Acute Effects of Cannabis Smoking on Skills Related to Driving : an fMRI Study

Introduction : Driving is a complex everyday task requiring mechanisms of perception, attention, learning, memory, decision making and action control, thus indicating that involves numerous and varied brain networks. If many data have been accumulated over time about the effects of alcohol consumption on driving capability, much less is known about the role of other psychoactive substances, such as cannabis (Chang et al.2007, Ramaekers et al, 2006). Indeed, the solicited brain areas during safe driving which could be affected by cannabis exposure have not yet been clearly identified. Our aim is to study these brain regions during a tracking task related to driving skills and to evaluate the modulation due to the tolerance of cannabis effects. Methods : Eight non-smoker control subjects participated to an fMRI experiment based on a visuo-motor tracking task, alternating active tracking blocks with passive tracking viewing and rest condition. Half of the active tracking conditions included randomly presented traffic lights as distractors. Subjects were asked to track with a joystick with their right hand and to press a button with their left index at each appearance of a distractor. Four smoking subjects participated to the same fMRI sessions once before and once after smoking cannabis and a placebo in two independent cross-over experiments. We quantified the performance of the subjects by measuring the precision of the behavioural responses (i.e. percentage of time of correct tracking and reaction times to distractors). Functional MRI data were acquired using on a 3.0T Siemens Trio system equipped with a 32-channel head coil. BOLD signals will be obtained with a gradient-echo EPI sequence (TR=2s, TE=30ms, FoV=216mm, FA=90°, matrix size 72×72, 32 slices, thickness 3mm). Preprocessing, single subject analysis and group statistics were conducted on SPM8b. Results were thresholded at p<0.05 (FWE corrected) and at k>30 for spatial extent. Results : Behavioural results showed a significant impairment in task and cognitive test performance of the subjects after cannabis inhalation when comparing their tracking accuracy either to the controls subjects or to their performances before the inhalation or after the placebo inhalation (p<0.001 corrected). In controls, fMRI BOLD analysis of the active tracking condition compared to the passive one revealed networks of polymodal areas in superior frontal and parietal cortex dealing with attention and visuo-spatial coordination. In accordance to what is known of the visual and sensory motor networks we found activations in V4, frontal eye-field, right middle frontal gyrus, intra-parietal sulcus, temporo-parietal junction, premotor and sensory-motor cortex. The presence of distractors added a significant activation in the precuneus. Preliminary results on cannabis smokers in the acute phase, compared either to themselves before the cannabis inhalation or to control subjects, showed a decreased activation in large portions of the frontal and parietal attention network during the simple tracking task, but greater involvement of precuneus, of the superior part of intraparietal sulcus and middle frontal gyrus bilaterally when distractors were present in the task. Conclusions : Our preliminary results suggest that acute cannabis smoking alters performances and brain activity during active tracking tasks, partly reorganizing the recruitment of brain areas of the attention network.