Network Architecture of Verticality Processing in the Human Thalamus.

OBJECTIVE: Thalamic dysfunction in lesions or neurodegeneration may alter verticality perception and lead to postural imbalance and falls. The aim of the current study was to delineate the structural and functional connectivity network architecture of the vestibular representations in the thalamus by multimodal magnetic resonance imaging. METHODS: Seventy-four patients with acute unilateral isolated thalamic infarcts were studied prospectively with emphasis on the perception of verticality (tilts of the subjective visual vertical [SVV]). We used multivariate lesion-symptom mapping based on support-vector regression to determine the thalamic nuclei associated with ipsiversive and contraversive tilts of the SVV. The lesion maps were used to evaluate the white matter disconnection and whole brain functional connectivity in healthy subjects. RESULTS: Contraversive SVV tilts were associated with lesions of the ventral posterior lateral/medial, ventral lateral, medial pulvinar, and medial central/parafascicular nuclei. Clusters associated with ipsiversive tilts were located inferiorly (ventral posterior inferior nucleus) and laterally (ventral lateral, ventral posterior lateral, and reticular nucleus) to these areas. Distinct ascending vestibular brainstem pathways terminated in the subnuclei for ipsi- or contraversive verticality processing. The functional connectivity analysis showed specific patterns of cortical connections with the somatomotor network for lesions with contraversive tilts, and with the core multisensory vestibular representations (areas Ri, OP2-3, Ig, 3av, 2v) for lesions with ipsiversive tilts. INTERPRETATION: The functional specialization may allow both a stable representation of verticality for sensorimotor integration and flexible adaption to sudden changes in the environment. A targeted modulation of this circuitry could be a novel therapeutic strategy for higher level balance disorders of thalamocortical origin. ANN NEUROL 2023;94:133-145.

Vestibular compensation of otolith graviceptive dysfunction in stroke patients.

BACKGROUND AND PURPOSE: A sensitive and frequent clinical sign of a vestibular tone imbalance is the tilt of the perceived subjective visual vertical (SVV). There are no data yet focusing on lesion location at the cortical level as a factor for predicting compensation from the tilt of the SVV. METHODS: With modern voxelwise lesion behavior mapping analysis, the present study determines whether lesion location in 23 right-hemispheric cortical stroke patients with an otolith dysfunction could predict the compensation of a vestibular tone imbalance in the chronic stage. RESULTS: Our statistical anatomical lesion analysis revealed that lesions of the posterior insular cortex are involved in vestibular otolith compensation. CONCLUSION: The insular cortex appears to be a critical anatomical region for predicting a tilt of the SVV as a chronic disorder in stroke patients.

The importance of the insular cortex for vestibular and spatial syndromes.

BACKGROUND AND PURPOSE: The aim of the study was to identify the neuroanatomical correlates and associations of neuropsychological syndromes after acute unilateral right-hemisphere brain lesions. The neuropsychological syndromes considered were orientation in three-dimensional space such as tilts of the subjective visual vertical or of the subjective haptic vertical, pusher syndrome, visual neglect and unawareness of paresis (anosognosia for hemiparesis). These neuropsychological phenomena have been found to occur separately or in different combinations after lesions to the right insular cortex. METHOD: Magnetic resonance imaging scans were obtained from 82 patients with acute right-hemispheric stroke. A lesion-behavior mapping analysis was conducted to specify the neuroanatomical correlates of the above-mentioned neuropsychological syndromes. RESULTS: In all analyses of the individual neuropsychological syndromes the insular cortex was affected. CONCLUSIONS: Thus, the insular cortex is involved in (self-)perception and orientation within a three-dimensional space. Since isolated lesions of the insular cortex did not induce the above neuropsychological phenomena, there have to be other regions involved.

What part of the cerebellum contributes to a visuospatial working memory task?

Although there is evidence that the cerebellum is involved in working memory (WM), it remains unclear which functions within WM the cerebellum supports and which structures are involved in WM. We tested whether the cerebellum is involved in the filtering of incoming information or in its storage. Using a statistical brain mapping approach in 29 patients with cerebellar ischemic stroke, we found that the cerebellum plays a gatekeeper role, as lesions of the tonsil, the lobus semilunaris inferior, and parts of the vermal pyramid rendered WM susceptible to irrelevant information. We conclude that the cerebellum controls incoming WM information.

Brain connectivity networks underlying resting heart rate variability in acute ischemic stroke.

Acute strokes can affect heart rate variability (HRV), the mechanisms how are not well understood. We included 42 acute stroke patients (2-7 days after ischemic stroke, mean age 66 years, 16 women). For analysis of HRV, 20 matched controls (mean age 60.7, 10 women) were recruited. HRV was assessed at rest, in a supine position and individual breathing rhythmus for 5 min. The coefficient of variation (VC), the root mean square of successive differences (RMSSD), the powers of low (LF, 0.04-0.14 Hz) and high (HF, 0.15-0.50 Hz) frequency bands were extracted. HRV parameters were z-transformed related to age- and sex-matched normal subjects. Z-values < -1 indicate reduced HRV. Acute stroke lesions were marked on diffusion-weighted images employing MRIcroN and co-registered to a T1-weighted structural volume-dataset. Using independent component analysis (ICA), stroke lesions were related to HRV. Subsequently, we used the ICA-derived lesion pattern as a seed and estimated the connectivity between these brain regions and seven common functional networks, which were obtained from 50 age-matched healthy subjects (mean age 68.9, 27 women). Especially, LF and VC were frequently reduced in patients. ICA revealed one covarying lesion pattern for LF and one similar for VC, predominantly affecting the right hemisphere. Activity in brain areas corresponding to these lesions mainly impact on limbic (r = 0.55 ± 0.08) and salience ventral attention networks (0.61 ± 0.10) in the group with reduced LF power (z-score < -1), but on control and default mode networks in the group with physiological LF power (z-score > -1). No different connectivity could be found for the respective VC groups. Our results suggest that HRV alteration after acute stroke might be due to affecting resting-state brain networks.

A pathway in the brainstem for roll-tilt of the subjective visual vertical: evidence from a lesion-behavior mapping study.

The perceived subjective visual vertical (SVV) is an important sign of a vestibular otolith tone imbalance in the roll plane. Previous studies suggested that unilateral pontomedullary brainstem lesions cause ipsiversive roll-tilt of SVV, whereas pontomesencephalic lesions cause contraversive roll-tilts of SVV. However, previous data were of limited quality and lacked a statistical approach. We therefore tested roll-tilt of the SVV in 79 human patients with acute unilateral brainstem lesions due to stroke by applying modern statistical lesion-behavior mapping analysis. Roll-tilt of the SVV was verified to be a brainstem sign, and for the first time it was confirmed statistically that lesions of the medial longitudinal fasciculus (MLF) and the medial vestibular nucleus are associated with ipsiversive tilt of the SVV, whereas contraversive tilts are associated with lesions affecting the rostral interstitial nucleus of the MLF, the superior cerebellar peduncle, the oculomotor nucleus, and the interstitial nucleus of Cajal. Thus, these structures constitute the anatomical pathway in the brainstem for verticality perception. Present data indicate that graviceptive otolith signals present a predominant role in the multisensory system of verticality perception.

Insular strokes cause no vestibular deficits.

BACKGROUND AND PURPOSE: In previous imaging studies, the posterior insular cortex (IC) was identified as an essential part for vestibular otolith perception and considered as a core region of a human vestibular cortical network. However, it is still unknown whether lesions exclusively restricted to the posterior IC suffice to provoke signs of vestibular otolith dysfunction. Thus, present data aimed to test whether patients with lesions restricted to the IC showed vestibular otolith dysfunction. METHODS: We studied 10 acute unilateral stroke patients with lesions restricted to the IC which were tested for signs of vestibular otolith dysfunction, such as tilts of subjective visual vertical, out of 475 stroke patients. RESULTS: None of the patients was with stroke exclusively affecting the IC-specified vertigo as a symptom. In addition, neither showed a deficit in the perception of verticality (subjective visual vertical tilts) nor showed any further vestibular otolith deficits, such as ocular torsion or skew deviation. CONCLUSIONS: It seems that lesions of the posterior IC might have to be combined with lesions of adjacent regions of the cortical and subcortical vestibular network to cause vestibular otolith deficits.

A Comparison of Immersive vs. Non-Immersive Virtual Reality Exercises for the Upper Limb: A Functional Near-Infrared Spectroscopy Pilot Study with Healthy Participants.

Functional near-infrared spectroscopy (fNIRS) allows for a reliable assessment of oxygenated blood flow in relevant brain regions. Recent advancements in immersive virtual reality (VR)-based technology have generated many new possibilities for its application, such as in stroke rehabilitation. In this study, we asked whether there is a difference in oxygenated hemoglobin (HbO2) within brain motor areas during hand/arm movements between immersive and non-immersive VR settings. Ten healthy young participants (24.3 ± 3.7, three females) were tested using a specially developed VR paradigm, called "bus riding", whereby participants used their hand to steer a moving bus. Both immersive and non-immersive conditions stimulated brain regions controlling hand movements, namely motor cortex, but no significant differences in HbO2 could be found between the two conditions in any of the relevant brain regions. These results are to be interpreted with caution, as only ten participants were included in the study.

Anatomical correlate of impaired covert visual attentional processes in patients with cerebellar lesions.

In the past years, claims of cognitive and attentional function of the cerebellum have first been raised but were later refuted. One reason for this controversy might be that attentional deficits only occur when specific cerebellar structures are affected. To further elucidate this matter and to determine which cerebellar regions might be involved in deficits of covert visual attention, we used new brain imaging tools of lesion mapping that allow a direct comparison with control patients. A total of 26 patients with unilateral right-sided cerebellar infarcts were tested on a covert visual attention task. Eight (31%) patients showed markedly slowed responses, especially in trials in which an invalid cue necessitated reorienting of the focus of attention for target detection. Compared with the 18 patients who performed within the range of healthy control subjects, only the impaired patients had lesions of cerebellar vermal structures such as the pyramid. We suggest that these midcerebellar regions are indirectly involved in covert visual attention via oculomotor control mechanisms. Thus, specific cerebellar structures do influence attentional orienting, whereas others do not.

Keeping memory clear and stable--the contribution of human basal ganglia and prefrontal cortex to working memory.

Successful remembering involves both hindering irrelevant information from entering working memory (WM) and actively maintaining relevant information online. Using a voxelwise lesion-behavior brain mapping approach in stroke patients, we observed that lesions of the left basal ganglia render WM susceptible to irrelevant information. Lesions of the right prefrontal cortex on the other hand make it difficult to keep more than a few items in WM. These findings support basal ganglia-prefrontal cortex models of WM whereby the basal ganglia play a gatekeeper role and allow only relevant information to enter prefrontal cortex where this information then is actively maintained in WM.

Line bisection error and its anatomic correlate.

BACKGROUND AND PURPOSE: Patients with chronic visual field defects typically show a contralesional line bisection error (LBE). However, in the acute phase of the disease, it has been suggested that the LBE points to the ipsilesional side. The aims of the current study were first, to test whether specific lesions are associated with LBE, and second, to determine whether there is a difference in the LBE between the acute and the chronic phase. METHODS: Twenty-two patients with visual field defects due to stroke without neglect were tested for line bisection and for the anatomic lesion site by voxelwise lesion-behavior mapping analysis. RESULTS: Patients with visual field defects in the acute and chronic phases differed in neither the direction nor the extent of their LBE. An association between lesions of the lingual gyrus, the cuneus, and the extent of contralesional LBE was found. CONCLUSIONS: Present data support the view that a contralesional LBE is due rather to lesions of the lingual gyrus and the cuneus and not to an adaptive attentional mechanism over time.

Evidence for modulation of opioidergic activity in central vestibular processing: A [(18)F] diprenorphine PET study.

Animal and functional imaging studies had identified cortical structures such as the parieto-insular vestibular cortex, the retro-insular cortex, or the anterior cingulate cortex belonging to a vestibular cortical network. Basic animal studies revealed that endorphins might be important transmitters involved in cerebral vestibular processing. The aim of the present study was therefore to analyse whether the opioid system is involved in vestibular neurotransmission of humans or not. Changes in opioid receptor availability during caloric air stimulation of the right ear were studied with [(18)F] Fluoroethyl-diprenorphine ([(18)F]FEDPN) PET scans in 10 right-handed healthy volunteers and compared to a control condition. Decrease in receptor availability to [(18)F]FEDPN during vestibular stimulation in comparison to the control condition was significant at the right posterior insular cortex and the postcentral region indicating more endogenous opioidergic binding in these regions during stimulation. These data give evidence that the opioidergic system plays a role in the right hemispheric dominance of the vestibular cortical system in right-handers.

Tight link between our sense of limb ownership and self-awareness of actions.

BACKGROUND AND PURPOSE: Hemiparetic stroke patients with disturbed awareness for their motor weakness (anosognosia for hemiparesis/-plegia [AHP]) may exhibit further abnormal attitudes toward or perceptions of the affected limb(s). The present study investigated the clinical relationship and the anatomy of such abnormal attitudes and AHP. METHODS: In a new series of 79 consecutively admitted acute stroke patients with right brain damage and hemiparesis/-plegia, different types of abnormal attitudes toward the hemiparetic/plegic limb (asomatognosia, somatoparaphrenia, anosodiaphoria, misoplegia, personification, kinaesthetic hallucinations, supernumerary phantom limb) were investigated. RESULTS: Ninty-two percent of the patients with AHP showed additional "disturbed sensation of limb ownership" (DSO) for the paretic/plegic limb. The patients had the feeling that their contralesional limb(s) do not belong to their body or even belong to another person. Analysis of lesion location revealed that the right posterior insula is a crucial structure involved in these phenomena. CONCLUSIONS: DSO for hemiparetic/-plegic limbs and AHP are tightly linked both clinically and anatomically. The right posterior insula seems to be a crucial structure involved in the genesis of our sense of limb ownership and self-awareness of actions.

Mechanisms and modulators of cognitive training gain transfer in cognitively healthy aging: study protocol of the AgeGain study.

BACKGROUND: Cognitively healthy older people can increase their performance in cognitive tasks through training. However, training effects are mostly limited to the trained task; thus, training effects only poorly transfer to untrained tasks or other contexts, which contributes to reduced adaptation abilities in aging. Stabilizing transfer capabilities in aging would increase the chance of persistent high performance in activities of daily living including longer independency, and prolonged active participation in social life. The trial AgeGain aims at elaborating the physiological brain mechanisms of transfer in aging and supposed major modulators of transfer capability, especially physical activity, cerebral vascular lesions, and amyloid burden. METHODS: This 4-year interventional, multicenter, phase 2a cognitive and physical training study will enroll 237 cognitively healthy older subjects in four recruiting centers. The primary endpoint of this trial is the prediction of transfer of cognitive training gains. Secondary endpoints are the structural connectivity of the corpus callosum, Default Mode Network activity, brain-derived neurotrophic factors, motor fitness, and maximal oxygen uptake. DISCUSSION: Cognitive transfer allows making use of cognitive training gains in everyday life. Thus, maintenance of transfer capability with aging increases the chance of persistent self-guidance and prolonged active participation in social life, which may support a good quality of life. The AgeGain study aims at identifying older people who will most benefit from cognitive training. It will increase the understanding of the neurobiological mechanisms of transfer in aging and will help in determining the impact of physical activity and sport as well as pathologic factors (such as cerebrovascular disease and amyloid load) on transfer capability. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), ID: DRKS00013077 . Registered on 19 November 2017.

Cross-modal processing in early visual and auditory cortices depends on expected statistical relationship of multisensory information.

Previous studies have shown that processing information in one sensory modality can either be enhanced or attenuated by concurrent stimulation of another modality. Here, we reconcile these apparently contradictory results by showing that the sign of cross-modal interactions depends on whether the content of two modalities is associated or not. When concurrently presented auditory and visual stimuli are paired by chance, cue-induced preparatory neural activity is strongly enhanced in the task-relevant sensory system and suppressed in the irrelevant system. Conversely, when information in the two modalities is reliably associated, activity is enhanced in both systems regardless of which modality is task relevant. Our findings illustrate an ecologically optimal flexibility of the neural mechanisms that govern multisensory processing: facilitation occurs when integration is expected, and suppression occurs when distraction is expected. Because thalamic structures were more active when the senses needed to operate separately, we propose them to serve gatekeeper functions in early cross-modal interactions.

Deep brain stimulation of the nucleus ventralis intermedius: a thalamic site of graviceptive modulation.

Based on animal studies, it has been shown that the nucleus ventralis intermedius (VIM) of the thalamus plays an important role within the vestibular system. A few human studies support the vestibular role of the VIM. In this study, we aimed to test the hypothesis whether changing the stimulation status in patients with unilateral deep brain stimulation in the VIM causally modulates the vestibular system, i.e., the graviceptive vertical perception. We tested six tremor patients for tilt of subjective visual vertical (SVV) with unilateral DBS in the VIM (mean age 67 years; mean time since electrode implantation 55 months). The mean tilt of the patients during the stimulator "on" condition was 1.4° to the contraversive side [standard deviation (SD) ± 0.4°] whereas during the "off" period a mean contraversive tilt of 4.4° (SD ± 3.0°) was obtained (p = 0.02). Thus, we were able to show that otolith-dominated graviceptive vertical perception can be directly modulated by changing the status of DBS VIM stimulation, indicating that the VIM is directly involved in (contraversive) vertical perception and its thalamic pathways.

Awareness of the functioning of one's own limbs mediated by the insular cortex?

Normally, we are aware of the current functions of our arms and legs. However, this self-evident status may change dramatically after brain damage. Some patients with "anosognosia" typically are convinced that their limbs function normally, although they have obvious motor defects after stroke. Such patients may experience their own paretic limbs as strange or as not belonging to them and may even attribute ownership to another person and try to push their paralyzed limb out of bed. These odd beliefs have been attributed to disturbances somewhere in the right hemisphere. Here, we use lesion mapping in 27 stroke patients to show that the right posterior insula is commonly damaged in patients with anosognosia for hemiplegia/hemiparesis but is significantly less involved in hemiplegic/hemiparetic patients without anosognosia. The function of the posterior insular cortex has been controversially discussed. Recent neuroimaging results in healthy subjects revealed specific involvement of this area in the subject's feeling of being versus not being involved in a movement. Our finding corresponds with this observation and suggests that the insular cortex is integral to self-awareness and to one's beliefs about the functioning of body parts.

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.

Functional Plasticity after Unilateral Vestibular Midbrain Infarction in Human Positron Emission Tomography.

The aim of the study was to uncover mechanisms of central compensation of vestibular function at brainstem, cerebellar, and cortical levels in patients with acute unilateral midbrain infarctions presenting with an acute vestibular tone imbalance. Eight out of 17 patients with unilateral midbrain infarctions were selected on the basis of signs of a vestibular tone imbalance, e.g., graviceptive (tilts of perceived verticality) and oculomotor dysfunction (skew deviation, ocular torsion) in F18-fluordeoxyglucose (FDG)-PET at two time points: A) in the acute stage, and B) after recovery 6 months later. Lesion-behavior mapping analyses with MRI verified the exact structural lesion sites. Group subtraction analyses and comparisons with healthy controls were performed with Statistic Parametric Mapping for the PET data. A comparison of PET A of acute-stage patients with that of healthy controls showed increases in glucose metabolism in the cerebellum, motion-sensitive visual cortex areas, and inferior temporal lobe, but none in vestibular cortex areas. At the supratentorial level bilateral signal decreases dominated in the thalamus, frontal eye fields, and anterior cingulum. These decreases persisted after clinical recovery in contrast to the increases. The transient activations can be attributed to ocular motor and postural recovery (cerebellum) and sensory substitution of vestibular function for motion perception (visual cortex). The persisting deactivation in the thalamic nuclei and frontal eye fields allows alternative functional interpretations of the thalamic nuclei: either a disconnection of ascending sensory input occurs or there is a functional mismatch between expected and actual vestibular activity. Our data support the view that both thalami operate separately for each hemisphere but receive vestibular input from ipsilateral and contralateral midbrain integration centers. Normally they have gatekeeper functions for multisensory input to the cortex and automatic motor output to subserve balance and locomotion, as well as sensorimotor integration.