The Role of Ascending Ventral-Tegmental Fibers for Recovery after Stroke.

OBJECTIVES: The integrity of cortical motor networks and their descending effector pathway (the corticospinal tract [CST]) is a major determinant motor recovery after stroke. However, this view neglects the importance of ascending tracts and their modulatory effects on cortical physiology. Here, we explore the role of such a tract that connects dopaminergic ventral tegmental midbrain nuclei to the motor cortex (the VTMC tract) for post-stroke recovery. METHODS: Lesion data and diffusivity parameters (fractional anisotropy) of the ipsi- and contralesional VTMC tract and CST were obtained from 133 patients (63.9 ± 13.4 years, 45 women) during the acute and chronic stage after the first ever ischemic stroke in the middle cerebral artery territory. Degeneration of VTMC tract and CST was quantified and related to clinical outcome parameters (National Institute of Health Stroke Scale with motor and cortical symptom subscores; modified Fugl-Meyer upper extremity score; modified Ranking Scale [mRS]). RESULTS: A significant post-stroke degeneration occurred in both tracts, but only VTMC degeneration was associated with lesion size. Using multiple regression models, we dissected the impact of particular tracts on recovery: Changes in VTMC tract integrity were stronger associated with independence in daily activities (mRS), upper limb motor impairment (modified Fugl-Meyer upper extremity score) and cortical symptoms (aphasia, neglect) captured by National Institute of Health Stroke Scale compared to CST. Changes in CST integrity merely were associated with the degree of hemiparesis (National Institute of Health Stroke Scale motor subscale). INTERPRETATION: Post-stroke outcome is influenced by ascending (VTMC) and descending (CST) fiber tracts. Favorable outcome regarding independence (modified Ranking Scale), upper limb motor function (modified Fugl-Meyer upper extremity score), and cortical symptoms (aphasia, neglect) was more strongly related to the ascending than descending tract. ANN NEUROL 2023;93:922-933.

Speaking in gestures: Left dorsal and ventral frontotemporal brain systems underlie communication in conducting.

Conducting constitutes a well-structured system of signs anticipating information concerning the rhythm and dynamic of a musical piece. Conductors communicate the musical tempo to the orchestra, unifying the individual instrumental voices to form an expressive musical Gestalt. In a functional magnetic resonance imaging (fMRI) experiment, 12 professional conductors and 16 instrumentalists conducted real-time novel pieces with diverse complexity in orchestration and rhythm. For control, participants either listened to the stimuli or performed beat patterns, setting the time of a metronome or complex rhythms played by a drum. Activation of the left superior temporal gyrus (STG), supplementary and premotor cortex and Broca's pars opercularis (F3op) was shared in both musician groups and separated conducting from the other conditions. Compared to instrumentalists, conductors activated Broca's pars triangularis (F3tri) and the STG, which differentiated conducting from time beating and reflected the increase in complexity during conducting. In comparison to conductors, instrumentalists activated F3op and F3tri when distinguishing complex rhythm processing from simple rhythm processing. Fibre selection from a normative human connectome database, constructed using a global tractography approach, showed that the F3op and STG are connected via the arcuate fasciculus, whereas the F3tri and STG are connected via the extreme capsule. Like language, the anatomical framework characterising conducting gestures is located in the left dorsal system centred on F3op. This system reflected the sensorimotor mapping for structuring gestures to musical tempo. The ventral system centred on F3Tri may reflect the art of conductors to set this musical tempo to the individual orchestra's voices in a global, holistic way.

The dual-loop model for combining external and internal worlds in our brain.

Intelligible communication with others as well as covert conscious thought requires us to combine a representation of the external world with inner abstract concepts. Interaction with the external world through sensory perception and motor execution is arranged as sequences in time and space, whereas abstract thought and invariant categories are independent of the moment. Using advanced MRI-based fibre tracking on high resolution data from 183 participants in the Human Connectome Project, we identified two large supramodal systems comprising specific cortical regions and their connecting fibre tracts; a dorsal one for processing of sequences in time and space, and a ventral one for concepts and categories. We found that two hub regions exist in the executive front and the perceptive back of the brain where these two cognitive processes converge, constituting a dual-loop model. The hubs are located in the onto- and phylogenetically youngest regions of the cortex. We propose that this hub feature serves as the neural substrate for the more abstract sense of syntax in humans, i.e. for the system populating sequences with content in all cognitive domains. The hubs bring together two separate systems (dorsal and ventral) at the front and the back of the brain and create a closed-loop. The closed-loop facilitates recursivity and forethought, which we use twice; namely, for communication with others about things that are not there and for covert thought.

Speech apraxia and oral apraxia: association or dissociation? A multivariate lesion-symptom mapping study in acute stroke patients.

The anatomical relationship between speech apraxia (SA) and oral apraxia (OA) is still unclear. To shed light on this matter we studied 137 patients with acute ischaemic left-hemisphere stroke and performed support vector regression-based, multivariate lesion-symptom mapping. Thirty-three patients presented with either SA or OA. These two symptoms mostly co-occurred (n = 28), except for few patients with isolated SA (n = 2) or OA (n = 3). All patient with either SA or OA presented with aphasia (p < 0.001) and these symptoms were highly associated with apraxia (p < 0.001). Co-occurring SA and OA were predominantly associated with insular lesions, while the insula was completely spared in the five patients with isolated SA or OA. Isolated SA occurred in case of frontal lesions (prefrontal gyrus and superior longitudinal fasciculus), while isolated OA occurred in case of either temporoparietal or striatocapsular lesions. Our study supports the notion of a predominant, but not exclusive, role of the insula in verbal and non-verbal oral praxis, and indicates that frontal regions may contribute exclusively to verbal oral praxis, while temporoparietal and striatocapsular regions contribute to non-verbal oral praxis. However, since tests for SA and OA so far intrinsically also investigate aphasia and apraxia, refined tests are warranted.

Neurobiological signature of intimacy in anorexia nervosa.

BACKGROUND: Intimacy and psychosexual development represent core problems of anorexia nervosa (AN). Experiential and neurobiological evidence however is scarce. MATERIAL AND METHODS: Thirty-one female AN patients were compared with 35 non-patients (NP) and 22 recovered participants (REC) by using functional magnetic resonance imaging. Participants viewed pictures of couples in intimate relationships and control stimuli. RESULTS: AN patients experienced intimate stimuli with lower valence and dominance. AN showed decreased activation of parietal cortices. NP decreased the prefrontal cortex response, which AN patients did not. REC participants did not differ from NP on a behavioural level, though with regard to the neural signature. DISCUSSION: Parietal cortices are related to processing of erotic themes, which seems to be deficient in AN. Dysfunction of prefrontal cortices likely mirrors dysfunctional control in AN. The neural signature does not seem to be state-related considering results of REC.

Do all visual deficits cause pure alexia? Dissociations between visual processing and reading suggest "no".

Pure alexia is a deficit of reading affecting the ability to process a word's letters in parallel. Instead, a slow, effortful letter-by-letter reading strategy is employed. It has been claimed that a visual impairment caused the reading impairment. The present study compares visual processing and word reading of a patient with severe visuospatial deficits due to probable posterior cortical atrophy (PCA) to two patients with pure alexia. A double dissociation emerged between visual processing and word reading: The participant with PCA was severely impaired in all visual tasks but read fluently while the patients with pure alexia read slowly but exhibited better preserved visual processing. It is concluded that a visual impairment does not inevitably lead to pure alexia, and that this syndrome is more plausibly conceived of as an orthographic deficit. In addition, the PCA patient's hypometabolism was assessed, and the interaction of the dorsal and ventral visual stream in word reading is discussed.

Frequency and Chunking in Derived Words: A Parametric fMRI Study.

In usage-based linguistic theories, the assumption that high-frequency language strings are mentally represented as unitary chunks has been invoked to account for a wide range of phenomena. However, neurocognitive evidence in support of this assumption is still lacking. In line with Gestalt psychological assumptions, we propose that a language string qualifies as a chunk if the following two conditions are simultaneously satisfied: The perception of the whole string does not involve strong activation of its individual component parts, but the component parts in isolation strongly evoke the whole. Against this background, we explore the relationship between different frequency metrics and the chunk status of derived words (e.g., "government," "worthless") in a masked visual priming experiment with two conditions of interest. One condition investigates "whole-to-part" priming (worthless-WORTH), whereas the other one analyzes "part-to-whole" priming (tear-TEARLESS). Both conditions combine mixed-effects regression analyses of lexical decision RTs with a parametric fMRI design. Relative frequency (the frequency of the whole word relative to that of its onset-embedded part) emerges as the only frequency metric to correlate with chunk status in behavioral terms. The fMRI results show that relative frequency modulates activity in regions that have been related to morphological (de)composition or general task performance difficulty (notably left inferior frontal areas) and in regions associated with competition between whole, undecomposed words (right inferior frontal areas). We conclude that relative frequency affects early stages of processing, thereby supporting the usage-based concept of frequency-induced chunks.

The Dual-Loop Model and the Human Mirror Neuron System: an Exploratory Combined fMRI and DTI Study of the Inferior Frontal Gyrus.

The inferior frontal gyrus (IFG) is active during both goal-directed action and while observing the same motor act, leading to the idea that also the meaning of a motor act (action understanding) is represented in this "mirror neuron system" (MNS). However, in the dual-loop model, based on dorsal and ventral visual streams, the MNS is thought to be a function of the dorsal steam, projecting to pars opercularis (BA44) of IFG, while recent studies suggest that conceptual meaning and semantic analysis are a function of ventral connections, projecting mainly to pars triangularis (BA45) of IFG. To resolve this discrepancy, we investigated action observation (AO) and imitation (IMI) using fMRI in a large group of subjects. A grasping task (GR) assessed the contribution from movement without AO. We analyzed connections of the MNS-related areas within IFG with postrolandic areas with the use of activation-based DTI. We found that action observation with imitation are mainly a function of the dorsal stream centered on dorsal part of BA44, but also involve BA45, which is dorsally and ventrally connected to the same postrolandic regions. The current finding suggests that BA45 is the crucial part where the MNS and the dual-loop system interact.

The ventral fiber pathway for pantomime of object use.

The current concept of a dual loop system of brain organization predicts a domain-general dual-pathway architecture involving dorsal and ventral fiber connections. We investigated if a similar dichotomy of brain network organization applies for pantomime (P) and imitation of meaningless gestures (I). Impairments of these tasks occur after left hemispheric brain lesions causing apraxia. Isolated impairments and double-dissociations point towards an anatomical segregation. Frontal and parietal areas seem to contribute differently. A special role of the inferior frontal gyrus and underlying fiber pathways was suggested recently. Using a combined fMRI/DTI-approach, we compared the fiber pathway architecture of left hemispheric frontal, temporal and parietal network components of pantomime and imitation. Thereby, we separated object effects from pantomime-specific effects. P and I both engage a fronto-temporo-parietal network of cortical areas interconnected by a dorsal fiber system (superior longitudinal fascicle) for direct sensory-motor interactions. The pantomime-specific effect additionally involved the triangular part of the inferior frontal gyrus, the middle temporal gyrus, the inferior parietal cortex and the intraparietal sulcus, interconnected by ventral fibers of the extreme capsule, likely related to higher-order conceptual and semantic operations. We discuss this finding in the context of the dual loop model and recent anatomical concepts.

Self-perspective leads to increased activation of pain processing brain regions in fibromyalgia.

BACKGROUND: Dysfunction of central nervous pain processing is assumed to play a key role in primary fibromyalgia (FM) syndrome. This pilot study examined differences of pain processing associated with adopting different interpersonal perspectives. METHODS: Eleven FM patients and 11 healthy controls (HC) were scanned with functional magnetic resonance imaging. Participants were trained to take either a self-perspective or another person's perspective when viewing the visual stimuli. Stimuli showed body parts in painful situations of varying intensity (low, medium, and high) and visually similar but neutral situations. RESULTS: Patients with FM showed a higher increase in blood oxygen level dependent (BOLD) response, particularly in the supplementary motor area (SMA). All pain-related regions of interest (anterior insula, somatosensory cortices, anterior cingulate cortex, and SMA) showed stronger modulation of BOLD responses in FM patients in the self-perspective. In contrast to pain processing regions, perspective-related regions (e.g. temporoparietal junction) did not differ between FM and HC. CONCLUSIONS: The stronger response of all four pain processing cerebral regions during self-perspective is discussed in the light of disturbed bottom-up processing. Furthermore, the results confirm earlier reports of augmented pain processing in FM, and provide evidence for sensitization of central nervous pain processing.

Attention-network specific alterations of structural connectivity in the undamaged white matter in acute neglect.

Visual neglect results from dysfunction within the spatial attention network. The structural connectivity in undamaged brain tissue in neglect has barely been investigated until now. In the present study, we explored the microstructural white matter characteristics of the contralesional hemisphere in relation to neglect severity and recovery in acute stroke patients. We compared age-matched healthy subjects and three groups of acute stroke patients (9 ± 0.5 days after stroke): (i) patients with nonrecovered neglect (n = 12); (ii) patients with rapid recovery from initial neglect (within the first week post-stroke, n = 7), (iii) stroke patients without neglect (n = 17). We analyzed the differences between groups in grey and white matter density and fractional anisotropy (FA) and used fiber tracking to identify the affected fibers. Patients with nonrecovered neglect differed from those with rapid recovery by FA-reduction in the left inferior parietal lobe. Fibers passing through this region connect the left-hemispheric analogues of the ventral attention system. Compared with healthy subjects, neglect patients with persisting neglect had FA-reduction in the left superior parietal lobe, optic radiation, and left corpus callosum/cingulum. Fibers passing through these regions connect centers of the left dorsal attention system. FA-reduction in the identified regions correlated with neglect severity. The study shows for the first time white matter changes within the spatial attention system remote from the lesion and correlating with the extent and persistence of neglect. The data support the concept of neglect as disintegration within the whole attention system and illustrate the dynamics of structural-functional correlates in acute stroke.

Damage to ventral and dorsal language pathways in acute aphasia.

Converging evidence from neuroimaging studies and computational modelling suggests an organization of language in a dual dorsal-ventral brain network: a dorsal stream connects temporoparietal with frontal premotor regions through the superior longitudinal and arcuate fasciculus and integrates sensorimotor processing, e.g. in repetition of speech. A ventral stream connects temporal and prefrontal regions via the extreme capsule and mediates meaning, e.g. in auditory comprehension. The aim of our study was to test, in a large sample of 100 aphasic stroke patients, how well acute impairments of repetition and comprehension correlate with lesions of either the dorsal or ventral stream. We combined voxelwise lesion-behaviour mapping with the dorsal and ventral white matter fibre tracts determined by probabilistic fibre tracking in our previous study in healthy subjects. We found that repetition impairments were mainly associated with lesions located in the posterior temporoparietal region with a statistical lesion maximum in the periventricular white matter in projection of the dorsal superior longitudinal and arcuate fasciculus. In contrast, lesions associated with comprehension deficits were found more ventral-anterior in the temporoprefrontal region with a statistical lesion maximum between the insular cortex and the putamen in projection of the ventral extreme capsule. Individual lesion overlap with the dorsal fibre tract showed a significant negative correlation with repetition performance, whereas lesion overlap with the ventral fibre tract revealed a significant negative correlation with comprehension performance. To summarize, our results from patients with acute stroke lesions support the claim that language is organized along two segregated dorsal-ventral streams. Particularly, this is the first lesion study demonstrating that task performance on auditory comprehension measures requires an interaction between temporal and prefrontal brain regions via the ventral extreme capsule pathway.

Time to bury the chisel: a continuous dorsal association tract system.

The arcuate fasciculus may be subdivided into a tract directly connecting frontal and temporal lobes and a pair of indirect subtracts in which the fronto-temporal connection is mediated by connections to the inferior parietal lobe. This tripartition has been advanced as an improvement over the centuries-old consensus that the lateral dorsal association fibers form a continuous system with no discernible discrete parts. Moreover, it has been used as the anatomical basis for functional hypotheses regarding linguistic abilities. Ex hypothesi, damage to the indirect subtracts leads to deficits in the repetition of multi-word sequences, whereas damage to the direct subtract leads to deficits in the immediate reproduction of single multisyllabic words. We argue that this partitioning of the dorsal association tract system enjoys no special anatomical status, and the search for the anatomical substrates of linguistic abilities should not be constrained by it. Instead, the merit of any postulated partitioning should primarily be judged on the basis of whether it enlightens or obfuscates our understanding of the behavior of patients in which individual subtracts are damaged.

Action semantics and movement characteristics engage distinct processing streams during the observation of tool use.

The cortical motor system follows a modular organization in which different features of executed movements are supported by distinct streams. Accordingly, different levels of action recognition, such as movement characteristics or action semantics may be processed within distinct networks. The present study aimed to differentiate areas related to the analysis of action features involving semantic knowledge from regions concerned with the evaluation of movement characteristics determined by structural object properties. To this end, the assessment of (i) tool-associated actions in relation to semantically, but not functionally inappropriate recipients (factor "Semantics"), and the evaluation of (ii) tool-associated movements performed with awkward versus correct hand postures (factor "Hand") were experimentally manipulated in an fMRI study with an event-related 2 × 2 factorial design. The videos used as stimuli displayed actions performed with the right hand in third-person perspective. Conjunction analysis of all four experimental conditions showed that observing videos depicting tool-related actions compared to rest was associated with widespread bilateral activity within the frontal lobes, inferior and superior parietal lobules, parts of the temporal lobes, as well as the occipital lobes. Viewing actions executed with incorrect compared to correct hand postures (factor "Hand") elicited significantly more activity within right primary sensory cortex (Brodmann area 2) and superior parietal lobule. Conversely, tool-associated actions displayed after semantically incorrect compared to correct recipients elicited higher activation within a left-lateralized network comprising the ventro-lateral prefrontal cortex (VLPFC), parts of the intraparietal sulcus and the angular gyrus (AG), as well as the supplementary motor area (SMA) and pre-SMA. Probabilistic diffusion tensor imaging-based tractography revealed two distinct fiber connections between AG and the frontal activation: A dorsal pathway via the superior longitudinal fascicle to the caudal part of VLPFC and a ventral pathway reaching the more rostral parts of VLPFC via the extreme capsule. The task-dependent relative modulation of activity within these brain networks composed of activated cortical areas connected by specific white matter tracts may indicate that the assessment of semantic action features relies on both dorso-ventral and ventral processing streams, whereas the analysis of hand postures with respect to objects depends on areas within the dorso-dorsal stream.

Dynamic gray matter changes within cortex and striatum after short motor skill training are associated with their increased functional interaction.

Gray matter (GM) changes have been described after short learning tasks that lasted for 7 days or after external stimulation that lasted for 5 days. However, the early time course of training-dependent GM changes is still unknown. We investigated whether shorter motor training sessions (four times of 30 min training) would induce GM changes. Therefore, T1-weighted MRIs were acquired daily. Because reported GM changes were induced by learning, a close relationship was assumed between the functional activity and the GM changes. Therefore, fMRI was performed in addition to daily T1-weighted MRIs. At the end of the four training sessions (at time point "post"), the test results of the trained motor skill were associated with an increase of GM in secondary cortical motor areas (dPMC(right), dPMC(left), SMA(left) and the right inferior parietal lobule, IPL(right)). The earliest time point at which a GM change was detected was 1day before in the right ventral striatum (by contrasting daily T1-weighted MRI vs. baseline). To analyze whether this very early GM change within the right ventral striatum is associated with those GM changes at time point post (which were associated with motor skill performance), their functional connectivity was investigated over the time period of motor skill training. This analysis revealed an increase of functional coupling between these regions (striatum and cortex) over the training days. The current data demonstrate training-induced short GM plasticity is paralleled by their temporally dynamical process of functional interaction between the cortex and the striatum in response to a motor skill training.

Ventral and dorsal fiber systems for imagined and executed movement.

Although motor imagery is an entirely cognitive process, it shows remarkable similarity to overt movement in behavioral and physiological studies. In concordance, brain imaging studies reported shared fronto-parietal sensorimotor networks commonly engaged by both tasks. However, differences in prefrontal and parietal regions point toward additional cognitive mechanisms in the context of imagery. Within the perspective of a general dichotomization into dorsal and ventral processing streams in the brain, the question arises whether motor imagery and overt movement could differentially involve the dorsal or ventral system. Therefore, we combined fMRI and DTI data of 20 healthy subjects to analyze the anatomical characteristics of connecting fronto-parietal association pathways of imagined and overt movements. We found a dichotomy of fiber pathways into dorsal and ventral systems: the superior longitudinal fascicle (SLF II-III) was found to connect frontal and parietal regions involved in both overt and imagined movements, whereas a ventral tract via the extreme/external capsule (EmC/EC) connects cortical regions specific for motor imagery that were situated more anteriorly and posteriorly. We suppose that motor imagery-related kinesthetic emulations are embedded into dorsal sensorimotor networks, and imagery-specific cognitive functions are implemented in the ventral system. These findings have implications for models of motor cognition.

Acute visual neglect and extinction: distinct functional state of the visuospatial attention system.

The neural mechanisms underlying spatial neglect are still disputed. Abnormal left parietal hyperactivation is proposed to lead to the rightward attentional bias, a clinical hallmark of neglect. Extinction, another deficit of visuospatial attention, is regarded as either a 'mild' form of neglect or a distinct syndrome. Although both neglect and extinction are typical syndromes of acute right hemispheric stroke, all imaging studies investigating these syndromes were conducted at least several weeks after stroke onset, in a phase when brain reorganization has already progressed. The present study aimed at comparing the activation patterns in acute stroke patients with neglect and extinction during visuospatial processing. Using functional magnetic resonance imaging, we examined the functional state of the attention system in 33 patients with a first ever stroke (53 ± 5 h after stroke onset) and age-matched healthy subjects (n = 15). All patients had embolic infarcts within the territory of the right middle cerebral artery. Patients were divided into three groups: (i) normal visuospatial processing (control patients, n = 11); (ii) patients with visual extinction but with no signs of neglect (n = 9); and (iii) patients with visual neglect (n = 13). While undergoing functional magnetic resonance imaging, patients performed a Posner-like task for visuospatial attention with detection of the targets in the left and right visual hemifields. Patients with neglect showed the expected imbalance in the left versus right parietal activation, which however, was present also in control and extinction patients, thus representing an epiphenomenon of the acute structural lesion in the right hemisphere. Compared with control patients, neglect was characterized by reduced activation in the right parietal and lateral occipital cortex, as well as in the left frontal eye field. In contrast, the activation pattern in patients with extinction differed from all other groups by an increased activation of the left prefrontal cortex. In both patients with neglect and extinction, detection of targets in the left hemifield correlated with an activation in the left prefrontal and parietal cortex. Thus at least in acute stroke, a relative hyperactivation of the left parietal cortex is not a particular characteristic of neglect. The specific signature of neglect is represented by the dysfunction of the right parietal and lateral occipital cortex. The function of the left attentional centres might provide a compensatory role after critical right hemisphere lesions and be relevant for the contralesional spatial processing.

Amygdala hyperreactivity in restrictive anorexia nervosa.

Functional imaging studies had often investigated heterogeneous samples of anorexia nervosa (AN) patients with varying paradigms and methodologies that had resulted in divergent results. The present study aimed to examine these issues by studying a well-defined sample of restrictive AN patients with a disorder-specific paradigm which had been used previously. Subjects showed increased blood oxygen level dependent responses of the cingulate, frontal, insular and parietal cortices. Group comparisons demonstrated increased activity of the right amygdala in the sample of restrictive AN patients. Our results are in support of other recently published functional imaging studies and point to a pivotal role of the right amygdala in AN. Signals of the midcingulum were reduced in comparison to healthy controls. The constellation of increased activity of the amygdala and decreased activity of the cingulate cortex likely represents parts of a negative feedback loop of emotional processing. Disgust ratings correlated with the amygdala signal negatively, which points to the complex role of this structure within eating disorders.