Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.

Autoimmune encephalitis and gastrointestinal dysmotility: achalasia, gastroparesis, and slow transit constipation.

BACKGROUND: Neurological autoimmune disorders (NAD) are caused by autoimmune inflammation triggered by specific antibody subtypes. NAD may disturb the gut-brain axis at several levels including brain, spinal cord, peripheral, or enteric nervous system. CASE REPORT: We present a case with antinuclear neuronal Hu (ANNA-1)- and antiglial nuclear (SOX-1) autoimmune antibody-positive limbic encephalitis and significant gastrointestinal dysmotility consisting of achalasia type II, gastroparesis, altered small intestinal interdigestive motility, and severe slow transit constipation. The autoantibodies of the patient's serum labeled enteric neurons and interstitial cells of Cajal but no other cells in the gut wall. Achalasia was treated successfully by pneumatic cardia dilation and gastrointestinal dysmotility successfully with prucalopride. CONCLUSION: NAD may disturb gastrointestinal motility by altering various levels of the gut-brain axis.

Semantic Congruence Alters Functional Connectivity during Olfactory-Visual Perception.

Previous research has shown that humans struggle to interpret multiple perceptual signals when the information provided by these signals is incongruent. In the context of olfactory-visual integration, behavioral and neuronal differences in response to congruent and incongruent stimulus pairs have been established. Here, we explored functional connectivity of the human brain with regard to the perception of congruent and incongruent food stimuli. Participants were simultaneously presented olfactory and visual stimuli of 4 different food objects, 2 healthy and 2 unhealthy objects. Stimulus pairs were grouped into "congruent" (olfactory and visual presentation of the same object), "semi-congruent" (stimuli of similar "healthiness"), and "incongruent" (healthy-unhealthy stimulus combination). Using functional magnetic resonance imaging and psychophysiological interaction (PPI) analyses, we revealed part of a neural network, the nodes of which show differential connectivity depending on the level of congruency of the presented stimulus combinations. This network relies strongly on, mostly left, inferior frontal gyrus. The analysis of such network transcends standard subtractive designs and indicates the need for more detailed formulations of neuronal models and increased specificity in functional imaging.

Metacognitive Confidence Increases with, but Does Not Determine, Visual Perceptual Learning.

While perceptual learning increases objective sensitivity, the effects on the constant interaction of the process of perception and its metacognitive evaluation have been rarely investigated. Visual perception has been described as a process of probabilistic inference featuring metacognitive evaluations of choice certainty. For visual motion perception in healthy, naive human subjects here we show that perceptual sensitivity and confidence in it increased with training. The metacognitive sensitivity-estimated from certainty ratings by a bias-free signal detection theoretic approach-in contrast, did not. Concomitant 3Hz transcranial alternating current stimulation (tACS) was applied in compliance with previous findings on effective high-low cross-frequency coupling subserving signal detection. While perceptual accuracy and confidence in it improved with training, there were no statistically significant tACS effects. Neither metacognitive sensitivity in distinguishing between their own correct and incorrect stimulus classifications, nor decision confidence itself determined the subjects' visual perceptual learning. Improvements of objective performance and the metacognitive confidence in it were rather determined by the perceptual sensitivity at the outset of the experiment. Post-decision certainty in visual perceptual learning was neither independent of objective performance, nor requisite for changes in sensitivity, but rather covaried with objective performance. The exact functional role of metacognitive confidence in human visual perception has yet to be determined.

Cortical representations of confidence in a visual perceptual decision.

To date the exact neuronal implementation of decision confidence has been subject to little research. Here we explore electroencephalographic correlates of human choice certainty in a visual motion discrimination task for either spatial attention or motor effector cue instructions. We demonstrate electrophysiological correlates of choice certainty that evolve as early as 300 ms after stimulus onset and resemble the primary visual motion representations in early visual cortex. These correlates do not emerge unless or until the subject unambiguously knows which of the competing visual stimuli is actually relevant to behaviour. They extend beyond stimulus presentation up to the motor response but are independent of the motor effector. Our findings suggest that perceptual confidence evolves in parallel with representations of stimulus properties and is dedicated to one specific aspect of the visual world. Its electroencephalographic correlates can be disentangled from representations of sensory evidence, objective discrimination performance and overt motor behaviour.

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.

Electrical stimulation of the human homolog of the medial superior temporal area induces visual motion blindness.

Despite tremendous advances in neuroscience research, it is still unclear how neuronal representations of sensory information give rise to the contents of our perception. One of the first and also the most compelling pieces of evidence for direct involvement of cortical signals in perception comes from electrical stimulation experiments addressing the middle temporal (MT) area and the medial superior temporal (MST) area: two neighboring extrastriate cortical areas of the monkey brain housing direction-sensitive neurons. Here we have combined fMRI with electrical stimulation in a patient undergoing awake brain surgery, to separately probe the functional significance of the human homologs, i.e., area hMT and hMST, on motion perception. Both the stimulation of hMT and hMST made it impossible for the patient to perceive the global visual motion of moving random dot patterns. Although visual motion blindness was predominantly observed in the contralateral visual field, stimulation of hMST also affected the ipsilateral hemifield. These results suggest that early visual cortex up to the stage of MT is not sufficient for the perception of global visual motion. Rather, visual motion information must be mediated to higher-tier cortical areas, including hMST, to gain access to conscious perception.

Losing the sound of concepts: damage to auditory association cortex impairs the processing of sound-related concepts.

Conceptual knowledge is classically supposed to be abstract and represented in an amodal unitary system, distinct from the sensory and motor brain systems. A more recent embodiment view of conceptual knowledge, however, proposes that concepts are grounded in distributed modality-specific brain areas which typically process sensory or action-related object information. Recent neuroimaging evidence suggested the significance of left auditory association cortex encompassing posterior superior and middle temporal gyrus in coding conceptual sound features of everyday objects. However, a causal role of this region in processing conceptual sound information has yet to be established. Here we had the unique chance to investigate a patient, JR, with a focal lesion in left posterior superior and middle temporal gyrus. To test the necessity of this region in conceptual and perceptual processing of sound information we administered four different experimental tasks to JR: Visual word recognition, category fluency, sound recognition and voice classification. Compared with a matched control group, patient JR was consistently impaired in conceptual processing of sound-related everyday objects (e.g., "bell"), while performance for non-sound-related everyday objects (e.g., "armchair"), animals, whether they typically produce sounds (e.g., "frog") or not (e.g., "tortoise"), and musical instruments (e.g., "guitar") was intact. An analogous deficit pattern in JR was also obtained for perceptual recognition of the corresponding sounds. Hence, damage to left auditory association cortex specifically impairs perceptual and conceptual processing of sounds from everyday objects. In support of modality-specific theories, these findings strongly evidence the necessity of auditory association cortex in coding sound-related conceptual information.

Processing of coherent visual motion in topographically organized visual areas in human cerebral cortex.

Recent imaging studies in human subjects have demonstrated representations of global visual motion in medial parieto-occipital cortex (area V6) and posterior parietal cortex, the latter containing at least seven topographically organized areas along the intraparietal sulcus (IPS0-IPS5, SPL1). In this fMRI study we used topographic mapping procedures to delineate a total of 18 visual areas in human cerebral cortex and tested their responsiveness to coherent visual motion under conditions of controlled attention and fixation. Preferences for coherent visual motion as compared to motion noise as well as hemispheric asymmetries were assessed for contralateral, ipsilateral, and bilateral visual motion presentations. Except for areas V1-V4 and IPS3-5, all other areas showed stronger responses to coherent motion with the most significant activations found in V6, followed by MT/MST, V3A, IPS0-2 and SPL1. Hemispheric differences were negligible altogether suggesting that asymmetries in parietal cortex observed in cognitive tasks do not reflect differences in basic visual response properties. Interestingly, areas V6, MST, V3A, and areas along the intraparietal sulcus showed specific representations of coherent visual motion not only when presented in the hemifield primarily covered by the given visual representation but also when presented in the ipsilateral visual field. This finding suggests that coherent motion induces a switch in spatial representation in specialized motion areas from contralateral to full-field coding.

Selective attention increases choice certainty in human decision making.

Choice certainty is a probabilistic estimate of past performance and expected outcome. In perceptual decisions the degree of confidence correlates closely with choice accuracy and reaction times, suggesting an intimate relationship to objective performance. Here we show that spatial and feature-based attention increase human subjects' certainty more than accuracy in visual motion discrimination tasks. Our findings demonstrate for the first time a dissociation of choice accuracy and certainty with a significantly stronger influence of voluntary top-down attention on subjective performance measures than on objective performance. These results reveal a so far unknown mechanism of the selection process implemented by attention and suggest a unique biological valence of choice certainty beyond a faithful reflection of the decision process.

Central oscillators in a patient with neuropathic tremor: evidence from intraoperative local field potential recordings.

Present pathophysiological concepts of neuropathic tremor assume mistimed and defective afferent input resulting in deregulation of cerebello-thalamo-cortical motor networks. Here, we provide direct evidence of central tremor processing in a 76-year-old female who underwent bilateral deep brain stimulation of the ventral intermedial nucleus of the thalamus (Vim-DBS) because of neuropathic tremor associated with IgM paraproteinemia. Electrophysiological recordings of EEG and EMG were performed in three perioperative sessions: (1) preoperatively, (2) intraoperatively, and (3) 4 days after surgery in both rest and postural tremor conditions. Tremor-related synchronization (coherence) between motor cortex (M1) and muscles (M. extensor digitorum, M. flexor digitorum) was assessed, and additional intraoperative local field potential (LFP) recordings from Vim allowed comprehensive coherence mapping in thalamo-cortico-muscular networks. Directionality of information flow was determined by directed transfer function (DTF) and phase analyses. Stimulation effects on tremor and corticomuscular coherence were assessed and the patient was followed for 12 months on clinical outcome measures (Tremor Rating Scale, CADET-Score). Vim-DBS reduced tremor (59%) and improved motor functionality in daily activities (31%, CADET-A) after 12 months. Intraoperative recordings demonstrated significant coherence in the tremor frequency (4 Hz) between M1 and contralateral muscle, Vim and ipsilateral M1, Vim and contralateral muscle, but not between Vim and contralateral M1. Information flow was directed from M1 to Vim and bidirectional between M1 and muscle and between Vim and muscle, respectively. Corticomuscular coherence at tremor frequency was completely suppressed by Vim-DBS. Our case study demonstrates central oscillators underlying neuropathic tremor and implies a strong pathophysiological rationale for Vim-DBS.

Alpha oscillations correlate with the successful inhibition of unattended stimuli.

Because the human visual system is continually being bombarded with inputs, it is necessary to have effective mechanisms for filtering out irrelevant information. This is partly achieved by the allocation of attention, allowing the visual system to process relevant input while blocking out irrelevant input. What is the physiological substrate of attentional allocation? It has been proposed that alpha activity reflects functional inhibition. Here we asked if inhibition by alpha oscillations has behavioral consequences for suppressing the perception of unattended input. To this end, we investigated the influence of alpha activity on motion processing in two attentional conditions using magneto-encephalography. The visual stimuli used consisted of two random-dot kinematograms presented simultaneously to the left and right visual hemifields. Subjects were cued to covertly attend the left or right kinematogram. After 1.5 sec, a second cue tested whether subjects could report the direction of coherent motion in the attended (80%) or unattended hemifield (20%). Occipital alpha power was higher contralateral to the unattended side than to the attended side, thus suggesting inhibition of the unattended hemifield. Our key finding is that this alpha lateralization in the 20% invalidly cued trials did correlate with the perception of motion direction: Subjects with pronounced alpha lateralization were worse at detecting motion direction in the unattended hemifield. In contrast, lateralization did not correlate with visual discrimination in the attended visual hemifield. Our findings emphasize the suppressive nature of alpha oscillations and suggest that processing of inputs outside the field of attention is weakened by means of increased alpha activity.

Effect of TMS on oculomotor behavior but not perceptual stability during smooth pursuit eye movements.

During smooth pursuit eye movements, we do not mistake the shift of the retinal image induced by the visual background for motion of the world around us but instead perceive a stable world. The goal of this study was to search for the neuronal substrates providing perceptual stability. To this end, pursuit eye movements across a background stimulus and perceptual stability were measured in the absence and presence, respectively, of transcranial magnetic stimulation (TMS) applied to 6 different brain regions, that is, primary visual cortex (V1), area MT+/V5, left and right temporoparietal junctions (TPJs), medial parieto-occipital cortex (POC), and the lateral cerebellum (LC). Stimulation of MT+/V5 and the cerebellum induced significant decreases in pursuit gain independent of background presentation, whereas stimulation of TPJ impaired the suppression of the optokinetic reflex induced by background stimulation. In contrast to changes in pursuit, only nonsignificant modifications in perceptual stability were observed. We conclude that MT+/V5, TPJ, and the LC contribute to pursuit eye movements and that TPJ supports the suppression of optokinesis. The lack of significant influences of TMS on perception suggests that motion perception invariance is not based on a localized but rather a highly distributed network featuring parallel processing.

Visual motion perception deficits due to cerebellar lesions are paralleled by specific changes in cerebro-cortical activity.

Recent anatomical studies have revealed strong cerebellar projections into parietal and prefrontal cortex. These findings suggest that the cerebellum might not only play a functional role in motor control but also cognitive domains, an idea also supported by neuropsychological testing of patients with cerebellar lesions that has revealed specific deficits. The goal of the present study was to test whether or not cognitive impairments after cerebellar damage are resulting from changes in cerebro-cortical signal processing. The detection of global visual motion embedded in noise, a faculty compromised after cerebellar lesions, was chosen as a model system. Using magnetoencephalography, cortical responses were recorded in a group of patients with cerebellar lesions (n = 8) and controls (n = 13) who observed visual motion of varied coherence, i.e., motion strength, presented in the peripheral visual field during controlled stationary fixation. Corroborating earlier results, the patients showed a significant impairment in global motion discrimination despite normal fixation behavior. This deficit was paralleled by qualitative differences in responses recorded from parieto-temporal cortex, including a reduced responsiveness to coherent visual motion and a striking loss of bilateral representations of motion coherence. Moreover, the perceptual thresholds correlated with the cortical representation of motion strength on single subject basis. These results demonstrate that visual motion processing in cerebral cortex critically depends on an intact cerebellum and establish a correlation between cortical activity and impaired visual perception resulting from cerebellar damage.

Demonstration of an eye-movement-induced visual motion illusion (Filehne illusion) in Rhesus monkeys.

During pursuit eye movements, the world around us remains perceptually stable despite the retinal-image slip induced by the eye movement. It is commonly held that this perceptual invariance is achieved by subtracting an internal reference signal, reflecting the eye movement, from the retinal motion signal. However, if the reference signal is too small or too large, a false eye-movement-induced motion of the external world, the Filehne illusion (FI), will be perceived. A reference signal of inadequate size can be simulated experimentally by asking human subjects to pursue a target across backgrounds with externally added motion that are perceived as moving. In the present study we asked if non-human primates respond to such manipulation in a way comparable to humans. Using psychophysical methods, we demonstrate that Rhesus monkeys do indeed experience a percept of pursuit-induced background motion. In this study we show that an FI can be predictably induced in Rhesus monkeys. The monkey FI shows dependencies on the size and direction of background movement, which is very similar to the ones characterizing the human FI. This congruence suggests that the perception of self-induced visual motion is based on similar inferential mechanisms in non-human and human primates.

Cross-frequency coupling of brain oscillations indicates the success in visual motion discrimination.

Cortical activity such as recorded by EEG or MEG is characterized by ongoing rhythms that encompass a wide range of temporal and spatial scales. Recent studies have suggested an oscillatory hierarchy with faster oscillations being locked to preferred phases of underlying slower waves, a functional principle applied up to the level of action potential generation. We here tested the idea that amplitude-phase coupling between frequencies might serve the detection of weak sensory signals. To this end we recorded neuromagnetic responses during a motion discrimination task using near-threshold stimuli. Amplitude modulation of occipital high-frequency oscillations in the gamma range (63+/-5 Hz) was phase locked to a slow-frequency oscillation in the delta band (1-5 Hz). Most importantly, the strength of gamma amplitude modulation reflected the success in visual discrimination. This correlation provides evidence for the hypothesis that coupling between low- and high-frequency brain oscillations subserves signal detection.

Differential dependency on motion coherence in subregions of the human MT+ complex.

The detection of coherent motion embedded in noise has been widely used as a measure of global visual motion processing. Animal studies have demonstrated that this performance is closely linked to the responses of direction-sensitive neurons in the macaque middle temporal (MT) and medial superior temporal (MST) areas. Despite the strong similarities between the visual cortex of human and that of non-human primates, the human middle temporal complex (area MT+), located in the posterior part of the inferior temporal sulcus and presumably comprising both area MT and area MST, has not consistently been found to share the functional hallmark of MT and MST neurons, i.e. their preference for coherent rather than incoherent visual motion. In order to search for such preferences in human area MT+, blood oxygen level-dependent responses to random dot kinematograms presented in the right visual hemifield were studied here as a function of stimulus size and dot density. The stimulus extensions were varied in such a way as to cover an area either equaling, exceeding or falling below the mean receptive field size of macaque area MT. Unlike the posterior part of human area MT+, the anterior part and its right-hemisphere homolog showed significantly stronger responses to coherent than to incoherent motion. These differences were only present for large stimuli that presumably exceeded the receptive field size of neurons in area MT. Our results suggest that functional magnetic resonance imaging may reveal stronger responses to coherent visual motion in human area MST, provided that the stimulus allows for sufficient summation within the receptive fields. In contrast, functional magnetic resonance imaging may fail to reveal the same dependency for human area MT.