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.

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.

Dissociating frontal and temporal correlates of phonological and semantic fluency in a large sample of left hemisphere stroke patients.

Previous lesion studies suggest that semantic and phonological fluency are differentially subserved by distinct brain regions in the left temporal and the left frontal cortex, respectively. However, as of yet, this often implied double dissociation has not been explicitly investigated due to mainly two reasons: (i) the lack of sufficiently large samples of brain-lesioned patients that underwent assessment of the two fluency variants and (ii) the lack of tools to assess interactions in factorial analyses of non-normally distributed behavioral data. In addition, previous studies did not control for task resource artifacts potentially introduced by the generally higher task difficulty of phonological compared to semantic fluency. We addressed these issues by task-difficulty adjusted assessment of semantic and phonological fluency in 85 chronic patients with ischemic stroke of the left middle cerebral artery. For classical region-based lesion-behavior mapping patients were grouped with respect to their primary lesion location. Building on the extension of the non-parametric Brunner-Munzel rank-order test to multi-factorial designs, ANOVA-type analyses revealed a significant two-way interaction for cue type (semantic vs. phonological) by lesion location (left temporal vs. left frontal vs. other as stroke control group). Subsequent contrast analyses further confirmed the proposed double dissociation by demonstrating that (i) compared to stroke controls, left temporal lesions led to significant impairments in semantic but not in phonological fluency, whereas left frontal lesions led to significant impairments in phonological but not in semantic fluency, and that (ii) patients with frontal lesions showed significantly poorer performance in phonological than in semantic fluency, whereas patients with temporal lesions showed significantly poorer performance in semantic than in phonological fluency. The anatomical specificity of these findings was further assessed in voxel-based lesion-behavior mapping analyses using the multi-factorial extension of the Brunner-Munzel test. Voxel-wise ANOVA-type analyses identified circumscribed parts of left inferior frontal gyrus and left superior and middle temporal gyrus that significantly double-dissociated with respect to their differential contribution to phonological and semantic fluency, respectively. Furthermore, a main effect of lesion with significant impairments in both fluency types was found in left inferior frontal regions adjacent to but not overlapping with those showing the differential effect for phonological fluency. The present study hence not only provides first explicit evidence for the anatomical double dissociation in verbal fluency at the group level but also clearly underlines that its formulation constitutes an oversimplification as parts of left frontal cortex appear to contribute to both semantic and phonological fluency.

Joint EEG/fMRI state space model for the detection of directed interactions in human brains--a simulation study.

An often addressed challenge in neuroscience research is the assignment of different tasks to specific brain regions. In many cases several brain regions are activated during a single task. Therefore, one is also interested in the temporal evolution of brain activity to infer causal relations between activated brain regions. These causal relations may be described by a directed, task specific network which consists of activated brain regions as vertices and directed edges. The edges describe the causal relations. Inference of the task specific brain network from measurements like electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) is challenging, due to the low spatial resolution of the former and the low temporal resolution of the latter. Here, we present a simulation study investigating a possible combined analysis of simultaneously measured EEG and fMRI data to address the challenge specified above. A nonlinear state space model is used to distinguish between the underlying brain states and the (simulated) EEG/fMRI measurements. We make use of a modified unscented Kalman filter and a corresponding unscented smoother for the estimation of the underlying neural activity. Model parameters are estimated using an expectation-maximization algorithm, which exploits the partial linearity of our model. Inference of the brain network structure is then achieved using directed partial correlation, a measure for Granger causality. The results indicate that the convolution effect of the fMRI forward model imposes a big challenge for the parameter estimation and reduces the influence of the fMRI in combined EEG-fMRI models. It remains to be investigated whether other models or similar combinations of other modalities such as, e.g., EEG and magnetoencephalography can increase the profit of the promising idea of combining various modalities.

How the ventral pathway got lost: and what its recovery might mean.

Textbooks dealing with the anatomical representation of language in the human brain display two language-related zones, Broca's area and Wernicke's area, connected by a single dorsal fiber tract, the arcuate fascicle. This classical model is incomplete. Modern imaging techniques have identified a second long association tract between the temporal and prefrontal language zones, taking a ventral course along the extreme capsule. This newly identified ventral tract connects brain regions needed for language comprehension, while the well-known arcuate fascicle is used for "sensorimotor mapping" during speech production. More than 130 years ago, Carl Wernicke already described a ventral connection for language, almost identical to the present results, but during scientific debate in the following decades either its function or its existence were rejected. This article tells the story of how this knowledge was lost and how the ventral connection, and in consequence the dual system, fits into current hypotheses and how language relates to other systems.

Word order processing in the bilingual brain.

One of the issues debated in the field of bilingualism is the question of a "critical period" for second language acquisition. Recent studies suggest an influence of age of onset of acquisition (AOA) particularly on syntactic processing; however, the processing of word order in a sentence context has not yet been examined specifically. We used functional MRI to examine word order processing in two groups of highly proficient German-French bilinguals who had either acquired French or German after the age of 10, and a third group which had acquired both languages before the age of three. Subjects listened to French and German sentences in which the order of subject and verb was systematically varied. In both groups of late bilinguals, processing of L2 compared to L1 resulted in higher levels of activation mainly of the left inferior frontal cortex while early bilinguals showed no activation difference in any of these areas. A selective increase in activation for late bilinguals only suggests that AOA contributes to modulating overall syntactic processing in L2. In addition, native speakers of French showed significantly higher activation for verb-subject-order than native German speakers. These data suggest that AOA effects may in particular affect those grammatical structures which are marked in the first language.