Activity in the human superior colliculus associated with reaching for tactile targets.

The superior colliculus (SC) plays a major role in orienting movements of eyes and the head and in the allocation of attention. Functions of the SC have been mostly investigated in animal models, including non-human primates. Differences in the SC's anatomy and function between different species question extrapolations of these studies to humans without further validation. Few electrophysiological and neuroimaging studies in animal models and humans have reported a role of the SC in visually guided reaching movements. Using BOLD fMRI imaging, we sought to decipher if the SC is also active during reaching movements guided by tactile stimulation. Participants executed reaching movements to visual and tactile target positions. When contrasted against visual and tactile stimulation without reaching, we found increased SC activity with reaching not only for visual but also for tactile targets. We conclude that the SC's involvement in reaching does not rely on visual inputs. It is also independent from a specific sensory modality. Our results indicate a general involvement of the human SC in upper limb reaching movements.

Preserved Expert Object Recognition in a Case of Visual Hemiagnosia.

We examined a stroke patient (HWS) with a unilateral lesion of the right medial ventral visual stream, involving the right fusiform and parahippocampal gyri. In a number of object recognition tests with lateralized presentations of target stimuli, HWS showed significant symptoms of hemiagnosia with contralesional recognition deficits for everyday objects. We further explored the patient's capacities of visual expertise that were acquired before the current perceptual impairment became effective. We confronted him with objects he was an expert for already before stroke onset and compared this performance with the recognition of familiar everyday objects. HWS was able to identify significantly more of the specific ("expert") than of the everyday objects on the affected contralesional side. This observation of better expert object recognition in visual hemiagnosia allows for several interpretations. The results may be caused by enhanced information processing for expert objects in the ventral system in the affected or the intact hemisphere. Expert knowledge could trigger top-down mechanisms supporting object recognition despite of impaired basic functions of object processing. More importantly, the current work demonstrates that top-down mechanisms of visual expertise influence object recognition at an early stage, probably before visual object information propagates to modules of higher object recognition. Because HWS showed a lesion to the fusiform gyrus and spared capacities of expert object recognition, the current study emphasizes possible contributions of areas outside the ventral stream to visual expertise.

In-vivo quantitative structural imaging of the human midbrain and the superior colliculus at 9.4T.

We explored anatomical details of the superior colliculus (SC) by in vivo magnetic resonance imaging (MRI) at 9.4T. The high signal-to-noise ratio allowed the acquisition of high resolution, multi-modal images with voxel sizes ranging between 176 × 132 × 600 µm and (800)3µm. Quantitative mapping of the longitudinal relaxation rate R1, the effective transverse relaxation rate R2*, and the magnetic susceptibility QSM was performed in 14 healthy volunteers. The images were analyzed in native space as well as after normalization to a common brain space (MNI). The coefficient-of-variation (CoV) across subjects was evaluated in prominent regions of the midbrain, reaching the best reproducibility (CoV of 5%) in the R2* maps of the SC in MNI space, while the CoV in the QSM maps remained high regardless of brain-space. To investigate whether more complex neurobiological architectural features could be detected, depth profiles through the SC layers towards the red nucleus (RN) were evaluated at different levels of the SC along the rostro-caudal axis. This analysis revealed alterations of the quantitative MRI parameters concordant with previous post mortem histology studies of the cyto- and myeloarchitecture of the SC. In general, the R1 maps were hyperintense in areas characterized by the presence of abundant myelinated fibers, and likely enabled detection of the deep white layer VII of the SC adjacent to the periaqueductal gray. While R1 maps failed to reveal finer details, possibly due to the relatively coarse spatial sampling used for this modality, these could be recovered in R2* maps and in QSM. In the central part of the SC along its rostro-caudal axis, increased R2* values and decreased susceptibility values were observed 2 mm below the SC surface, likely reflecting the myelinated fibers in the superficial optic layer (layer III). Towards the deeper layers, a second increase in R2* was paralleled by a paramagnetic shift in QSM suggesting the presence of an iron-rich layer about 3 mm below the surface of the SC, attributed to the intermediate gray layer (IV) composed of multipolar neurons. These results dovetail observations in histological specimens and animal studies and demonstrate that high-resolution multi-modal MRI at 9.4T can reveal several microstructural features of the SC in vivo.

Depth-dependence of visual signals in the human superior colliculus at 9.4 T.

The superior colliculus (SC) is a layered structure located in the midbrain. We exploited the improved spatial resolution and BOLD signal strength available at 9.4 T to investigate the depth profile of visual BOLD responses in the human SC based on distortion-corrected EPI data with a 1 mm isotropic resolution. We used high resolution (350 µm in-plane) anatomical images to determine regions-of-interest of the SC and applied a semi-automated method to segment it into superficial, intermediate, and deep zones. A greater than linear increase in sensitivity of the functional signal at 9.4 T allowed us to detect a statistically significant depth pattern in a group analysis with a 20 min stimulation paradigm. Descriptive data showed consistent depth profiles also in single individuals. The highest signals were localized to the superficial layers of the right and left SC during contralateral stimulation, which was in good agreement with its functional architecture known from non-human primates. This study thus demonstrates the potential of 9.4 T MRI for functional neuroimaging even in deeply located, particularly challenging brain structures such as the SC. Hum Brain Mapp 38:574-587, 2017. © 2016 Wiley Periodicals, Inc.

Direct electrical stimulation of human cortex - the gold standard for mapping brain functions?

Despite its clinical relevance, direct electrical stimulation (DES) of the human brain is surprisingly poorly understood. Although we understand several aspects of electrical stimulation at the cellular level, surface DES evokes a complex summation effect in a large volume of brain tissue, and the effect is difficult to predict as it depends on many local and remote physiological and morphological factors. The complex stimulation effects are reflected in the heterogeneity of behavioural effects that are induced by DES, which range from evocation to inhibition of responses - sometimes even when DES is applied at the same cortical site. Thus, it is a misconception that DES - in contrast to other neuroscience techniques - allows us to draw unequivocal conclusions about the role of stimulated brain areas.

Anticipatory eye fixations reveal tool knowledge for tool interaction.

Action-oriented eye-tracking studies have shown that eye fixations reveal much about current behavioral intentions. The eyes typically fixate those positions of a tool or an object where the fingers will be placed next, or those positions in a scene, where obstacles need to be avoided to successfully reach or transport a tool or object. Here, we asked to what extent eye fixations can also reveal active cognitive inference processes, which are expected to integrate bottom-up visual information with internal knowledge for planning suitable object interactions task-dependently. In accordance to the available literature, we expected that task-relevant knowledge will include sensorimotor, semantic, and mechanical aspects. To investigate if and in which way this internal knowledge influences eye fixation behavior while planning an object interaction, we presented pictures of familiar and unfamiliar tools and instructed participants to either pantomime 'lifting' or 'using' the respective tool. When confronted with unfamiliar tools, participants fixated the tool's effector part closer and longer in comparison with familiar tools. This difference was particularly prominent during 'using' trials when compared with 'lifting' trials. We suggest that this difference indicates that the brain actively extracts mechanical information about the unknown tool in order to infer its appropriate usage. Moreover, the successive fixations over a trial indicate that a dynamic, task-oriented, active cognitive process unfolds, which integrates available tool knowledge with visually gathered information to plan and determine the currently intended tool interaction.

Involvement of the TPJ area in processing of novel global forms.

The neuropsychological syndrome "simultanagnosia" is characterized by the inability to integrate local elements into a global entity. This deficit in Gestalt perception is mainly apparent for novel global structures administered in clinical tests or unfamiliar visual scenes. Recognition of familiar complex objects or well-known visual scenes is often unaffected. Recent neuroimaging studies and reports from simultanagnosia patients suggest a crucial involvement of temporoparietal brain areas in processing of hierarchically organized visual material. In this study, we investigated the specific role of the TPJ in Gestalt perception. On the basis of perceptual characteristics known from simultanagnosia, we hypothesized that TPJ is dominantly involved in processing of novel object arrangements. To answer this question, we performed a learning study with hierarchical stimuli and tested behavioral and neuronal characteristics of Gestalt perception pre- and posttraining. The study included 16 psychophysical training sessions and two neuroimaging sessions. Participants improved their behavioral performance for trained global stimuli and showed limited transfer to untrained global material. We found significant training dependent neuronal signal modulations in anterior right hemispheric TPJ regions. These activation changes were specific to trained global stimuli, whereas no systematic neuronal response changes were observed for recognition of untrained global stimuli, local elements and regular objects that served as control stimuli. In line with perceptual characteristics in simultanagnosia, the results argue for an involvement of TPJ in processing of novel global structures. We discuss the signal modulations in the context of a more efficient or different neuronal strategy to process familiar global stimuli.

Fiber pathways connecting cortical areas relevant for spatial orienting and exploration.

By implementing a task that closely resembled a clinical test for diagnosing spatial neglect in stroke patients, Himmelbach et al. (: Neuroimage 32:1747-1759) found significantly increased activation during active exploration in those cortical areas in healthy subjects that are known to induce spatial neglect in case of a lesion. The present study investigated whether direct intra-hemispheric cortico-cortical connections could be found between these activated clusters using a probabilistic fiber-tracking approach in 52 healthy subjects. We found that parts of the extreme capsule (EmC) and the middle longitudinal fascicle (MdLF) connected the functional cluster in the prefrontal cortex with the superior temporal cortex and the temporo-parietal junction (TPJ) area in both hemispheres. The activation peak in the TPJ was additionally connected to the inferior frontal cortex by parts of the arcuate fascicle and the superior longitudinal fascicle (SLF II) in the right hemisphere. Our study elucidates the connections constituting the perisylvian network for spatial orienting and attention. Hence, we complement the knowledge from patients suffering from spatial neglect by giving first empirical evidence for the complete postulated network in healthy subjects.

Limb apraxia in acute ischemic stroke: a neglected clinical challenge?

Symptoms of limb apraxia and executive dysfunctions are currently not explicitly considered by the National Institutes of Health Stroke Scale and, thus, not routinely tested by clinicians in the acute care of patients with suspected stroke. Neuropsychological testing, clinical examination, MRI, and functional magnetic resonance imaging (fMRI) were performed in a right-handed patient with acute onset of left-sided sensorimotor hemiparesis due to a right hemisphere ischemic stroke. Deficits in the execution of meaningless and meaningful gestures were not detected properly on initial clinical examination but were revealed later on through neuropsychological testing. Instead, the patient's inability to respond to specific instructions in the acute care setting was mistaken to reflect severe deficits in auditory comprehension. fMRI revealed right-hemispheric localization of language in the right-handed patient. We suggest including a bedside test for limb apraxia symptoms in acute clinical care of stroke patients. The distinction between deficits in limb praxis and impairments of language can be complicated owing to the common hemispheric co-localization of the two functions.

The superior colliculus motor region does not respond to finger tapping movements in humans.

Electrophysiological studies in macaques and functional neuroimaging in humans revealed a motor region in the superior colliculus (SC) for upper limb reaching movements. Connectivity studies in macaques reported direct connections between this SC motor region and cortical premotor arm, hand, and finger regions. These findings motivated us to investigate if the human SC is also involved in sequential finger tapping movements. We analyzed fMRI task data of 130 subjects executing finger tapping from the Human Connectome Project. While we found strong signals in the SC for visual cues, we found no signals related to simple finger tapping. In subsequent experimental measurements, we searched for responses in the SC corresponding to complex above simple finger tapping sequences. We observed expected signal increases in cortical motor and premotor regions for complex compared to simple finger tapping, but no signal increases in the motor region of the SC. Despite evidence for direct anatomical connections of the SC motor region and cortical premotor hand and finger areas in macaques, our results suggest that the SC is not involved in simple or complex finger tapping in humans.

Signals from the deep: reach-related activity in the human superior colliculus.

Neurophysiological studies in nonhuman species indicated that neurons in the superior colliculus (SC) are involved in the control of upper limb movements. These findings suggested that the SC represents a crucial hub in a general sensorimotor network, including skeletomotor as much as oculomotor functions. In contrast to the SC in the various animal models, the human SC is largely unknown territory. In particular, it is unknown whether findings of reach-related activity in the nonhuman SC can be extrapolated to humans. Using fMRI we found signal increases at superficial/intermediate and deep locations at the SC during the execution of arm movements. In contrast, signals related to saccade execution were confined to the superficial and intermediate locations. Although targets for reaching were presented in the left and right hemifields under central fixation, we found a lateralization of reach-related signals with respect to the active arm. In contrast, saccade-related activity was bilateral, in agreement with the bilateral target presentation and the resulting directions of saccades. Our results suggest that the human SC not only contributes to the coordination of eye movements and spatial shifts of attentions but also to the sensorimotor control of arm movements.

Eye proprioception used for visual localization only if in conflict with the oculomotor plan.

Both the corollary discharge of the oculomotor command and eye muscle proprioception provide eye position information to the brain. Two contradictory models have been suggested about how these two sources contribute to visual localization: (1) only the efference copy is used whereas proprioception is a slow recalibrator of the forward model, and (2) both signals are used together as a weighted average. We had the opportunity to test these hypotheses in a patient (R.W.) with a circumscribed lesion of the right postcentral gyrus that overlapped the human eye proprioceptive representation. R.W. was as accurate and precise as the control group (n = 19) in locating a lit LED that she viewed through the eye contralateral to the lesion. However, when the task was preceded by a brief (<1 s), gentle push to the closed eye, which perturbed eye position and stimulated eye proprioceptors in the absence of a motor command, R.W.'s accuracy significantly decreased compared with both her own baseline and the healthy control group. The data suggest that in normal conditions, eye proprioception is not used for visual localization. Eye proprioception is, however, continuously monitored to be incorporated into the eye position estimate when a mismatch with the efference copy of the motor command is detected. Our result thus supports the first model and, furthermore, identifies the limits for its operation.

Dissociation of reach-related and visual signals in the human superior colliculus.

Electrophysiological and micro-stimulation studies in non-human animal species indicated that the superior colliculus (SC) plays a role in the control of upper limb movements. In our previous work we found reach-related signals in the deep superior colliculus in humans. Here we show that also signals in more dorsal locations are correlated with the execution of arm movements. We instructed healthy participants to reach for visual targets either presented in the left or in the right visual hemifield during an fMRI measurement. Visual stimulation was dissociated from movement execution using a pro- and anti-reaching task. Thereby, we successfully differentiated between signals at these locations induced by the visual input of target presentations on the one hand and by the execution of arm movements on the other hand. Extending our previous report, the results of this study are in good agreement with the observed anatomical distribution of reach-related neurons in macaques. Obviously, reach-related signals can be found across a considerable depth range also in humans.

Routine clinical testing underestimates proprioceptive deficits in Friedreich's ataxia.

Friedreich's ataxia (FA) is the most common recessive ataxia in the Western world with degeneration of dorsal root ganglia neurons as its major neuropathological hallmark. The sensitivity of clinical tools commonly used for the assessment of the proprioceptive component of FA is currently unknown. We hypothesised that current clinical testing underestimates proprioceptive deficits in FA patients. Such an underestimation would hamper our understanding of the components of FA, the monitoring of disease progression, and the detection of deficits in the current advent of drug trials. We compared clinical tests for joint position sense (JPS) and vibration sense (VS) to a test of spatial position sense (SPS) that examines localisation of both hands across a horizontal 2D space. We tested 22 healthy controls to derive a cut-off for the SPS. Eleven patients with genetically confirmed FA participated in this study. All 11 FA patients were impaired in the SPS test. Two patients showed unimpaired JPS and VS. Two additional patients showed unimpaired JPS, while two other patients unimpaired VS. The SPS test was more sensitive and revealed deficits potentially earlier than clinical screening tests. Only the SPS showed a positive correlation with ataxia severity. The SPS was more sensitive than the commonly used JPS and VS. Thus, our results indicate that proprioceptive deficits in FA start earlier and are more severe than indicated by routine standard clinical testing. The contribution of proprioceptive deficits to the impairment of FA patients might therefore indeed be underestimated today.

Characterization of the blood oxygen level dependent hemodynamic response function in human subcortical regions with high spatiotemporal resolution.

Subcortical brain regions are absolutely essential for normal human function. These phylogenetically early brain regions play critical roles in human behaviors such as the orientation of attention, arousal, and the modulation of sensory signals to cerebral cortex. Despite the critical health importance of subcortical brain regions, there has been a dearth of research on their neurovascular responses. Blood oxygen level dependent (BOLD) functional MRI (fMRI) experiments can help fill this gap in our understanding. The BOLD hemodynamic response function (HRF) evoked by brief (<4 s) neural activation is crucial for the interpretation of fMRI results because linear analysis between neural activity and the BOLD response relies on the HRF. Moreover, the HRF is a consequence of underlying local blood flow and oxygen metabolism, so characterization of the HRF enables understanding of neurovascular and neurometabolic coupling. We measured the subcortical HRF at 9.4T and 3T with high spatiotemporal resolution using protocols that enabled reliable delineation of HRFs in individual subjects. These results were compared with the HRF in visual cortex. The HRF was faster in subcortical regions than cortical regions at both field strengths. There was no significant undershoot in subcortical areas while there was a significant post-stimulus undershoot that was tightly coupled with its peak amplitude in cortex. The different BOLD temporal dynamics indicate different vascular dynamics and neurometabolic responses between cortex and subcortical nuclei.

Functional neuroimaging of the oculomotor brainstem network in humans.

The cortical systems involved in eye movement control in humans have been investigated extensively using fMRI. In contrast, there is virtually no data concerning the functional status of the human oculomotor brainstem nuclei. This lack of evidence has usually been explained by technical constraints of EPI based imaging and anatomical characteristics of the brainstem. Against this assumption, we successfully localised nuclei of the oculomotor system using high-resolution fMRI based on standard EPI sequences in a group of healthy subjects executing reflexive horizontal saccades. A random-effects group analysis revealed task-related BOLD increases in the superior colliculus, the oculomotor nucleus, the abducens nucleus and in the paramedian pontine reticular formation. This group analysis was complemented by individual positive findings in up to 94% of single subject analyses. A visual control paradigm led to increased signal levels in the superior colliculus consistent with its visual properties but no corresponding signal changes in other brainstem nuclei. These results are consistent with findings in animal studies and demonstrate the feasibility to detect BOLD signal increases associated with oculomotor tasks even in the human brainstem using conventional EPI imaging techniques.

The anatomy of object recognition--visual form agnosia caused by medial occipitotemporal stroke.

The influential model on visual information processing by Milner and Goodale (1995) has suggested a dissociation between action- and perception-related processing in a dorsal versus ventral stream projection. It was inspired substantially by the observation of a double dissociation of disturbed visual action versus perception in patients with optic ataxia on the one hand and patients with visual form agnosia (VFA) on the other. Unfortunately, almost all cases with VFA reported so far suffered from inhalational intoxication, the majority with carbon monoxide (CO). Since CO induces a diffuse and widespread pattern of neuronal and white matter damage throughout the whole brain, precise conclusions from these patients with VFA on the selective role of ventral stream structures for shape and orientation perception were difficult. Here, we report patient J.S., who demonstrated VFA after a well circumscribed brain lesion due to stroke etiology. Like the famous patient D.F. with VFA after CO intoxication studied by Milner, Goodale, and coworkers (Goodale et al., 1991, 1994; Milner et al., 1991; Servos et al., 1995; Mon-Williams et al., 2001a,b; Wann et al., 2001; Westwood et al., 2002; McIntosh et al., 2004; Schenk and Milner, 2006), J.S. showed an obvious dissociation between disturbed visual perception of shape and orientation information on the one side and preserved visuomotor abilities based on the same information on the other. In both hemispheres, damage primarily affected the fusiform and the lingual gyri as well as the adjacent posterior cingulate gyrus. We conclude that these medial structures of the ventral occipitotemporal cortex are integral for the normal flow of shape and of contour information into the ventral stream system allowing to recognize objects.

fMRI of global visual perception in simultanagnosia.

The integration of visual elements into global perception seems to be implemented separately to single object perception. This assumption is supported by the existence of patients with simultanagnosia who can identify single objects but are incapable of integrating multiple visual items. We investigated a case of simultanagnosia due to posterior cortical atrophy without structural brain damage who demonstrated an incomplete simultanagnosia. The patient successfully recognized a global stimulus in one trial but failed to do so just a few seconds later. Using event-related fMRI, we contrasted post hoc selected trials of successful global perception with trials of global recognition failure. We found circumscribed clusters of activity at the right and left primary intermediate sulci and a bilateral cluster at the ventral precuneus. The integration of multiple visual elements resulting in a conscious perception of their gestalt seems to rely on these bilateral structures in the human lateral and medial inferior parietal cortex.

Effects of arm weight and target height on hand selection: A low-cost virtual reality paradigm.

We evaluated the ability of a virtual reality (VR) system to reliably detect the reaching frequency midline position of a user; the distinguishing plane between free-choice use of the left and right hand. The paradigm utilized the Leap Motion Hand Tracker along with a custom script written in C# and was realized through a Unity3D application. Stimuli appeared in random locations on the computer screen and required the participant to reach with the hand of their choice to contact them with a virtually coupled hand inside the virtual space. We investigated the effects of two manipulations of effort on the free-choice reaching of either the left or right hand. We varied the height of target positions and applied an additional weight to the non-dominant, left hand. We observed main effects of height and weight on reaching frequency midline positions across the group. We found increased use of the dominant hand as stimuli height increased, as well as a significant increase in overall use of the dominant, right hand when a weighted-glove was worn by the non-dominant, left hand. Our results are in line with previously published research on hand selection from similar paradigms, supporting the use of our VR paradigm in future experiments and applications.

Hemifield coding in ventral object-sensitive areas - Evidence from visual hemiagnosia.

Electrophysiological monkey and human neuroimaging studies have reported a lateralization of signal processing in object perception. However, it is unclear whether these results point to a unique topographically organized signal processing in either hemisphere, or if these results represent a rather negligible spatial organization of otherwise redundant object perception systems in both hemispheres. We tested a group of 10 patients with lesions to ventral object processing regions and spared primary visual functions with lateral presentations of different categories of object stimuli. Object perception in the contralesional visual field was impaired while object perception on the ipsilesional hemifield was intact. These results demonstrate that the object perception system needs two intact ventral pathways for unimpaired object perception across the whole visual field; the loss of one system cannot be fully compensated by its contralateral homolog or spared parts of the lesioned ventral stream.