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.

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.

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.

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.

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.

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.

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.

Clinical assessment of dysphagia in neurodegeneration (CADN): development, validity and reliability of a bedside tool for dysphagia assessment.

Screening assessments for dysphagia are essential in neurodegenerative disease. Yet there are no purpose-built tools to quantify swallowing deficits at bedside or in clinical trials. A quantifiable, brief, easy to administer assessment that measures the impact of dysphagia and predicts the presence or absence of aspiration is needed. The Clinical Assessment of Dysphagia in Neurodegeneration (CADN) was designed by a multidisciplinary team (neurology, neuropsychology, speech pathology) validated against strict methodological criteria in two neurodegenerative diseases, Parkinson's disease (PD) and degenerative ataxia (DA). CADN comprises two parts, an anamnesis (part one) and consumption (part two). Two-thirds of patients were assessed using reference tests, the SWAL-QOL symptoms subscale (part one) and videofluoroscopic assessment of swallowing (part two). CADN has 11 items and can be administered and scored in an average of 7 min. Test-retest reliability was established using correlation and Bland-Altman plots. 125 patients with a neurodegenerative disease were recruited; 60 PD and 65 DA. Validity was established using ROC graphs and correlations. CADN has sensitivity of 79 and 84% and specificity 71 and 69% for parts one and two, respectively. Significant correlations with disease severity were also observed (p < 0.001) for PD with small to large associations between disease severity and CADN scores for DA. Cutoff scores were identified that signal the presence of clinically meaningful dysphagia symptomatology and risk of aspiration. The CADN is a reliable, valid, brief, quantifiable, and easily deployed assessment of swallowing in neurodegenerative disease. It is thus ideally suited for both clinical bedside assessment and future multicentre clinical trials in neurodegenerative disease.

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.

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.

Memory-guided reaching in a patient with visual hemiagnosia.

The two-visual-systems hypothesis (TVSH) postulates that memory-guided movements rely on intact functions of the ventral stream. Its particular importance for memory-guided actions was initially inferred from behavioral dissociations in the well-known patient DF. Despite of rather accurate reaching and grasping movements to visible targets, she demonstrated grossly impaired memory-guided grasping as much as impaired memory-guided reaching. These dissociations were later complemented by apparently reversed dissociations in patients with dorsal damage and optic ataxia. However, grasping studies in DF and optic ataxia patients differed with respect to the retinotopic position of target objects, questioning the interpretation of the respective findings as a double dissociation. In contrast, the findings for reaching errors in both types of patients came from similar peripheral target presentations. However, new data on brain structural changes and visuomotor deficits in DF also questioned the validity of a double dissociation in reaching. A severe visuospatial short-term memory deficit in DF further questioned the specificity of her memory-guided reaching deficit. Therefore, we compared movement accuracy in visually-guided and memory-guided reaching in a new patient who suffered a confined unilateral damage to the ventral visual system due to stroke. Our results indeed support previous descriptions of memory-guided movements' inaccuracies in DF. Furthermore, our data suggest that recently discovered optic-ataxia like misreaching in DF is most likely caused by her parieto-occipital and not by her ventral stream damage. Finally, multiple visuospatial memory measurements in HWS suggest that inaccuracies in memory-guided reaching tasks in patients with ventral damage cannot be explained by visuospatial short-term memory or perceptual deficits, but by a specific deficit in visuomotor processing.

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.

Revisiting the cortical system for peripheral reaching at the parieto-occipital junction.

Optic ataxia (OA) is a neurological disorder that is characterised by misreaching to targets in the visual periphery. The anatomy of OA thus provides important information for the neural representation of visually guided reaching in humans. In 2005 a lesion mapping analysis of OA localised the critical lesion site at the parieto-occipital junction (POJ) (Karnath & Perenin, 2005). This work was accompanied by the discovery of a peripheral reaching module at the POJ in an fMRI study (Prado et al., 2005). The ostensible overlap between the territory typically affected in patients with OA and the findings of Prado et al. (2005) had a tremendous influence on the search for a cortical peripheral reaching module. However, a close inspection of the functional Magnetic Resonance Imaging (fMRI) study revealed that a comparison between reaching towards visible targets in the peripheral visual field and reaching to visible targets in the central visual field--which is the key aspect in clinical examinations of OA--was not conducted. Moreover, whereas main effects of reaching overlapped with the OA lesion site, specific interaction effects did not overlap. We performed a direct comparison between reaching to visible peripheral targets and reaching to visible central targets to address the inconsistencies between the aforementioned studies. Our analysis shows that Prado et al.'s study cannot be taken as evidence for a delineated module for peripheral reaching. In contrast to Prado et al. we found a combined system of POJ, IPS and SPL areas--the posterior human 7A, mIPS, V6A and the posterior IPS--with increased signals during reaching to peripheral targets.

The influence of object height on maximum grip aperture in empirical and modeled data.

During a grasping movement, the maximum grip aperture (MGA) is almost linearly scaled to the dimension of the target along which it is grasped. There is still a surprising uncertainty concerning the influence of the other target dimensions on the MGA. We asked healthy participants to grasp cuboids always along the object's width with their thumb and index finger. Independent from variations of object width, we systematically varied height and depth of these target objects. We found that taller objects were generally grasped with a larger MGA. At the same time, the slope of the regression of MGA on object width decreased with increasing target height. In contrast, we found no effect of varying target depth on the MGA. Simulating these movements with a grasping model in which the objective to avoid contact of the digits with the target object at positions other than the goal positions was implemented yielded larger effects of target height than of target depth on MGA. We concluded that MGA does not only depend on the dimension of the target object along which it is grasped. Furthermore, the effects of the other 2 dimensions are considerably different. This pattern of results can partially be explained by the aim to avoid contacting the target object at positions other than the goal positions.

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 temporo-parietal junction contributes to global gestalt perception-evidence from studies in chess experts.

In a recent neuroimaging study the comparison of intact vs. disturbed perception of global gestalt indicated a significant role of the temporo-parietal junction (TPJ) in the intact perception of global gestalt (Huberle and Karnath, 2012). This location corresponded well with the areas known to be damaged or impaired in patients with simultanagnosia after stroke or due to neurodegenerative diseases. It was concluded that the TPJ plays an important role in the integration of individual items to a holistic percept. Thus, increased BOLD signals should be found in this region whenever a task calls for the integration of multiple visual items. Behavioral experiments in chess experts suggested that their superior skills in comparison to chess novices are partly based on fast holistic processing of chess positions with multiple pieces. We thus analyzed BOLD data from four fMRI studies that compared chess experts with chess novices during the presentation of complex chess-related visual stimuli (Bilalic et al., 2010, 2011a,b, 2012). Three regions of interests were defined by significant TPJ clusters in the abovementioned study of global gestalt perception (Huberle and Karnath, 2012) and BOLD signal amplitudes in these regions were compared between chess experts and novices. These cross-paradigm ROI analyses revealed higher signals at the TPJ in chess experts in comparison to novices during presentations of complex chess positions. This difference was consistent across the different tasks in five independent experiments. Our results confirm the assumption that the TPJ region identified in previous work on global gestalt perception plays an important role in the processing of complex visual stimulus configurations.

Guidelines and quality measures for the diagnosis of optic ataxia.

Since the first description of a systematic mis-reaching by Bálint in 1909, a reasonable number of patients showing a similar phenomenology, later termed optic ataxia (OA), has been described. However, there is surprising inconsistency regarding the behavioral measures that are used to detect OA in experimental and clinical reports, if the respective measures are reported at all. A typical screening method that was presumably used by most researchers and clinicians, reaching for a target object in the peripheral visual space, has never been evaluated. We developed a set of instructions and evaluation criteria for the scoring of a semi-standardized version of this reaching task. We tested 36 healthy participants, a group of 52 acute and chronic stroke patients, and 24 patients suffering from cerebellar ataxia. We found a high interrater reliability and a moderate test-retest reliability comparable to other clinical instruments in the stroke sample. The calculation of cut-off thresholds based on healthy control and cerebellar patient data showed an unexpected high number of false positives in these samples due to individual outliers that made a considerable number of errors in peripheral reaching. This study provides first empirical data from large control and patient groups for a screening procedure that seems to be widely used but rarely explicitly reported and prepares the grounds for its use as a standard tool for the description of patients who are included in single case or group studies addressing optic ataxia similar to the use of neglect, extinction, or apraxia screening tools.

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.

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.