White matter volume loss drives cortical reshaping after thalamic infarcts.

OBJECTIVE: The integration of somatosensory, ocular motor and vestibular signals is necessary for self-location in space and goal-directed action. We aimed to detect remote changes in the cerebral cortex after thalamic infarcts to reveal the thalamo-cortical connections necessary for multisensory processing and ocular motor control. METHODS: Thirteen patients with unilateral ischemic thalamic infarcts presenting with vestibular, somatosensory, and ocular motor symptoms were examined longitudinally in the acute phase and after six months. Voxel- and surface-based morphometry were used to detect changes in vestibular and multisensory cortical areas and known hubs of central ocular motor processing. The results were compared with functional connectivity data in 50 healthy volunteers. RESULTS: Patients with paramedian infarcts showed impaired saccades and vestibular perception, i.e., tilts of the subjective visual vertical (SVV). The most common complaint in these patients was double vision or vertigo / dizziness. Posterolateral thalamic infarcts led to tilts of the SVV and somatosensory deficits without vertigo. Tilts of the SVV were higher in paramedian compared to posterolateral infarcts (median 11.2° vs 3.8°). Vestibular and ocular motor symptoms recovered within six months. Somatosensory deficits persisted. Structural longitudinal imaging showed significant volume reduction in subcortical structures connected to the infarcted thalamic nuclei (vestibular nuclei region, dentate nucleus region, trigeminal root entry zone, medial lemniscus, superior colliculi). Volume loss was evident in connections to the frontal, parietal and cingulate lobes. Changes were larger in the ipsilesional hemisphere but were also detected in homotopical regions contralesionally. The white matter volume reduction led to deformation of the cortical projection zones of the infarcted nuclei. CONCLUSIONS: White matter volume loss after thalamic infarcts reflects sensory input from the brainstem as well the cortical projections of the main affected nuclei for sensory and ocular motor processing. Changes in the cortical geometry seem not to reflect gray matter atrophy but rather reshaping of the cortical surface due to the underlying white matter atrophy.

Multisensory vestibular, vestibular-auditory, and auditory network effects revealed by parametric sound pressure stimulation.

Multisensory convergence and sensorimotor integration are important aspects for the mediation of higher vestibular cognitive functions at the cortical level. In contrast to the integration of vestibulo-visual or vestibulo-tactile perception, much less is known about the neural mechanism that mediates the integration of vestibular-otolith (linear acceleration/translation/gravity detection) and auditory processing. Vestibular-otolith and auditory afferents can be simultaneously activated using loud sound pressure stimulation, which is routinely used for testing cervical and ocular vestibular evoked myogenic potentials (VEMPs) in clinical neurotological testing. Due to the simultaneous activation of afferents there is always an auditory confound problem in fMRI studies of the neural topology of these systems. Here, we demonstrate that the auditory confounding problem can be overcome in a novel way that does not require the assumption of simple subtraction and additionally allows detection of non-linear changes in the response due to vestibular-otolith interference. We used a parametric sound pressure stimulation design that took each subject's vestibular stimulation threshold into account and analyzed for changes in BOLD-response below and above vestibular-otolith threshold. This approach helped to investigate the functional neuroanatomy of sound-induced auditory and vestibular integration using functional magnetic resonance imaging (fMRI). Results revealed that auditory and vestibular convergence are contained in overlapping regions of the caudal part of the superior temporal gyrus (STG) and the posterior insula. In addition, there are regions that were responsive only to suprathreshold stimulations, suggesting vestibular (otolith) signal processing in these areas. Based on these parametric analyses, we suggest that the caudal part of the STG and posterior insula could contain areas of vestibular contribution to auditory processing, i.e., higher vestibular cortices that provide multisensory integration that is important for tasks such as spatial localization of sound.

Human Exploration of Enclosed Spaces through Echolocation.

Some blind humans have developed echolocation, as a method of navigation in space. Echolocation is a truly active sense because subjects analyze echoes of dedicated, self-generated sounds to assess space around them. Using a special virtual space technique, we assess how humans perceive enclosed spaces through echolocation, thereby revealing the interplay between sensory and vocal-motor neural activity while humans perform this task. Sighted subjects were trained to detect small changes in virtual-room size analyzing real-time generated echoes of their vocalizations. Individual differences in performance were related to the type and number of vocalizations produced. We then asked subjects to estimate virtual-room size with either active or passive sounds while measuring their brain activity with fMRI. Subjects were better at estimating room size when actively vocalizing. This was reflected in the hemodynamic activity of vocal-motor cortices, even after individual motor and sensory components were removed. Activity in these areas also varied with perceived room size, although the vocal-motor output was unchanged. In addition, thalamic and auditory-midbrain activity was correlated with perceived room size; a likely result of top-down auditory pathways for human echolocation, comparable with those described in echolocating bats. Our data provide evidence that human echolocation is supported by active sensing, both behaviorally and in terms of brain activity. The neural sensory-motor coupling complements the fundamental acoustic motor-sensory coupling via the environment in echolocation.SIGNIFICANCE STATEMENT Passive listening is the predominant method for examining brain activity during echolocation, the auditory analysis of self-generated sounds. We show that sighted humans perform better when they actively vocalize than during passive listening. Correspondingly, vocal motor and cerebellar activity is greater during active echolocation than vocalization alone. Motor and subcortical auditory brain activity covaries with the auditory percept, although motor output is unchanged. Our results reveal behaviorally relevant neural sensory-motor coupling during echolocation.

Vestibular thalamus: Two distinct graviceptive pathways.

OBJECTIVE: To determine whether there are distinct thalamic regions statistically associated with either contraversive or ipsiversive disturbance of verticality perception measured by subjective visual vertical (SVV). METHODS: We used modern statistical lesion behavior mapping on a sample of 37 stroke patients with isolated thalamic lesions to clarify which thalamic regions are involved in graviceptive otolith processing and whether there are distinct regions associated with contraversive or ipsiversive SVV deviation. RESULTS: We found 2 distinct systems of graviceptive processing within the thalamus. Contraversive tilt of SVV was associated with lesions to the nuclei dorsomedialis, intralamellaris, centrales thalami, posterior thalami, ventrooralis internus, ventrointermedii, ventrocaudales and superior parts of the nuclei parafascicularis thalami. The regions associated with ipsiversive tilt of SVV were located in more inferior regions, involving structures such as the nuclei endymalis thalami, inferior parts of the nuclei parafascicularis thalami, and also small parts of the junction zone of the nuclei ruber tegmenti and brachium conjunctivum. CONCLUSIONS: Our data indicate that there are 2 anatomically distinct graviceptive signal processing mechanisms within the vestibular network in humans that lead, when damaged, to a vestibular tone imbalance either to the contraversive or to the ipsiversive side.

Human hippocampal activation during stance and locomotion: fMRI study on healthy, blind, and vestibular-loss subjects.

The hippocampal formation, including the parahippocampal gyrus, is known to be involved in different aspects of navigation and spatial orientation. Recently, bilateral parahippocampal activation during mental imagery of walking and running was demonstrated in fMRI. For the current study the question was whether distinct functional regions within the hippocampal formation could be defined from the analysis of brain activity during imagery of stance and locomotion in healthy, blind, and vestibular-loss subjects. Using the same experimental paradigm in all groups (fMRI during mental imagery of stance and locomotion after training of actual performance, regions of interest [ROI] analysis), activations were found in the hippocampal formation, predominantly on the right side, in all subjects. In healthy subjects, standing was associated with anterior hippocampal activation; during locomotion widespread activity was found in the right parahippocampal gyrus. Compared to healthy controls, blind subjects showed less activity in the right dorsal parahippocampal region, whereas vestibular-loss subjects had less activity in the anterior hippocampal formation. The findings show that the hippocampal formation in humans processes visual and vestibular signals in different regions. The data support the assumption that the anterior hippocampus and the entorhinal cortex in the parahippocampal region are input areas for vestibular and somatosensory signals. Posterior parahippocampal and fusiform gyri, which are connected to visual cortical areas, are more important for visually guided locomotion and landmark recognition during navigation. The right-sided dominance reflects the importance of the right hemisphere for spatial orientation.

Mind the bend: cerebral activations associated with mental imagery of walking along a curved path.

The use of functional magnetic resonance imaging (fMRI) to examine mental imagery of locomotion has become an attractive way to investigate supraspinal gait control in humans. Whereas cerebral activation patterns associated with walking along a straight line have already been investigated, data on activations associated with the initiation of turns and the maintenance of a curved path are sparse. Electrophysiological findings in animals show that electrical stimulation of the striatum induces a contraversive turn of eyes, head, and body. In the present study, fMRI was used to investigate brain activity in 12 healthy volunteers during mental imagery of walking along a curved path, walking straight ahead, and upright stance. The major findings were as follows: (1) A shift of activation to the hemisphere contralateral to the turn was found in the putamen, and-for initiation of the turn-in the caudate nucleus. These findings confirm the important role of the striatum in the initiation of movement and the execution of contraversive body turns. (2) Parahippocampal and fusiform gyri, known to be involved in visually guided navigation, showed more activity when walking along a curved path than when walking straight ahead. (3) Deactivations were found in the superior and medial temporal gyri, areas belonging to the multisensory and vestibular cortical network. This reduced activity may reflect the suppression of vestibular signal processing in favour of-potentially conflicting-visual input. (4) Mental imagery of walking along a curved path induced ipsiversive eye movements in most subjects, as did actually walking along a curve. These data complement earlier findings on the role of anticipatory eye movements during initiation of turns and suggest that there is a very close neurophysiologic relation between locomotion and its mental imagery.

Supraspinal locomotor control in quadrupeds and humans.

Locomotion in humans and other vertebrates is based on spinal pattern generators, which are regulated by supraspinal control. Most of our knowledge about the hierarchical network of supraspinal locomotion centres derives from animal experiments, mainly in the cat. Here we summarize evidence that the supraspinal network of quadrupeds is conserved in humans despite their transition to bipedalism. By use of mental imagery of locomotion in fMRI we found (1), locomotion modulates sensory systems and is itself modulated by sensory signals. During automated locomotion in healthy subjects cortical sensory inhibition occurs in vestibular and somatosensory areas; this inhibition is cancelled in the congenitally blind; (2), we delineated separate and distinct areas in the brainstem and cerebellum which are remarkably similar to the feline locomotor network. The activations found here include homologues to the pacemakers for gait initiation and speed regulation in the interfastigial cerebellum and bilateral midbrain tegmentum (cerebellar and mesencephalic locomotor regions), their descending target regions in the pontine reticular formation, and the rhythm generators in the cerebellar vermis and paravermal cerebellar cortex. This conservation of the basic organization of supraspinal locomotor control during vertebrate phylogeny opens new perspectives for both, the diagnosis and treatment of common gait disorders. It is conceivable that electrical stimulation of locomotor brain stem centres may initiate and improve gait in selected patients suffering from Parkinson's disease or progressive supranuclear palsy.

Imaging human supraspinal locomotor centers in brainstem and cerebellum.

An erect posture with bipedal locomotion is a characteristic feature of humans compared to other mammals. Most of our knowledge about the hierarchical network of supraspinal locomotor centers derives from animal experiments, mainly in the cat. We posed the question of whether evolutionary transition from quadrupedal to bipedal locomotion--with associated change of foreleg function--caused reorganization of these supraspinal locomotor centers. Using functional magnetic resonance imaging, we identified separate and distinct cerebellar and brainstem BOLD signal increases related to posture and gait during mental imagery of standing, walking, and running in healthy volunteers (n=26). Comparison with the locomotion centers in the cat showed that these activations include the pacemakers for gait initiation and speed regulation in the interfastigial cerebellum and bilateral midbrain tegmentum (cerebellar and mesencephalic locomotor regions), their descending target regions in the pontine reticular formation, and the rhythm generators in the cerebellar vermis and paravermal cortex. Moreover, during mental imagery of stance, a BOLD signal increase was observed in the dorsal pons, reflecting an activation of the dorsal tegmental field, a locomotion-suppressing site in the cat. These results support the view that the organization of supraspinal locomotor centers was preserved during the transition to bipedal locomotion. The clinical relevance of these centers has so far been largely neglected. However, Parkinson's disease, for example, is associated with reduced cell counts in the pedunculopontine nucleus, a part of the mesencephalic locomotor region. This association suggests that deep brain stimulation of locomotion centers may provide new therapeutic approaches for common gait disorders.