Glioblastoma remodelling of human neural circuits decreases survival.

Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.

Distributed Sensitivity to Syntax and Semantics throughout the Language Network.

Human language is expressive because it is compositional: The meaning of a sentence (semantics) can be inferred from its structure (syntax). It is commonly believed that language syntax and semantics are processed by distinct brain regions. Here, we revisit this claim using precision fMRI methods to capture separation or overlap of function in the brains of individual participants. Contrary to prior claims, we find distributed sensitivity to both syntax and semantics throughout a broad frontotemporal brain network. Our results join a growing body of evidence for an integrated network for language in the human brain within which internal specialization is primarily a matter of degree rather than kind, in contrast with influential proposals that advocate distinct specialization of different brain areas for different types of linguistic functions.

No evidence of theory of mind reasoning in the human language network.

Language comprehension and the ability to infer others' thoughts (theory of mind [ToM]) are interrelated during development and language use. However, neural evidence that bears on the relationship between language and ToM mechanisms is mixed. Although robust dissociations have been reported in brain disorders, brain activations for contrasts that target language and ToM bear similarities, and some have reported overlap. We take another look at the language-ToM relationship by evaluating the response of the language network, as measured with fMRI, to verbal and nonverbal ToM across 151 participants. Individual-participant analyses reveal that all core language regions respond more strongly when participants read vignettes about false beliefs compared to the control vignettes. However, we show that these differences are largely due to linguistic confounds, and no such effects appear in a nonverbal ToM task. These results argue against cognitive and neural overlap between language processing and ToM. In exploratory analyses, we find responses to social processing in the "periphery" of the language network-right-hemisphere homotopes of core language areas and areas in bilateral angular gyri-but these responses are not selectively ToM-related and may reflect general visual semantic processing.

Functional alterations in cortical processing of speech in glioma-infiltrated cortex.

Recent developments in the biology of malignant gliomas have demonstrated that glioma cells interact with neurons through both paracrine signaling and electrochemical synapses. Glioma-neuron interactions consequently modulate the excitability of local neuronal circuits, and it is unclear the extent to which glioma-infiltrated cortex can meaningfully participate in neural computations. For example, gliomas may result in a local disorganization of activity that impedes the transient synchronization of neural oscillations. Alternatively, glioma-infiltrated cortex may retain the ability to engage in synchronized activity in a manner similar to normal-appearing cortex but exhibit other altered spatiotemporal patterns of activity with subsequent impact on cognitive processing. Here, we use subdural electrocorticography to sample both normal-appearing and glioma-infiltrated cortex during speech. We find that glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex but recruits a diffuse spatial network. On a temporal scale, we show that signals from glioma-infiltrated cortex have decreased entropy, which may affect its ability to encode information during nuanced tasks such as production of monosyllabic versus polysyllabic words. Furthermore, we show that temporal decoding strategies for distinguishing monosyllabic from polysyllabic words were feasible for signals arising from normal-appearing cortex but not from glioma-infiltrated cortex. These findings inform our understanding of cognitive processing in chronic disease states and have implications for neuromodulation and prosthetics in patients with malignant gliomas.

Preserved functional organization of auditory cortex in two individuals missing one temporal lobe from infancy.

Human cortical responses to natural sounds, measured with fMRI, can be approximated as the weighted sum of a small number of canonical response patterns (components), each having interpretable functional and anatomical properties. Here, we asked whether this organization is preserved in cases where only one temporal lobe is available due to early brain damage by investigating a unique family: one sibling missing their left temporal lobe from infancy, another missing the right temporal lobe from infancy, and a third anatomically neurotypical. None of the siblings manifested behavioral deficits. We analyzed fMRI responses to diverse natural sounds within the intact hemispheres of these individuals and compared them to 12 neurotypical participants. All siblings manifested typical-like auditory responses in their intact hemispheres. These results suggest that the development of the auditory cortex in each hemisphere does not depend on the existence of the other hemisphere, highlighting the redundancy and equipotentiality of the bilateral auditory system.

Precision fMRI reveals that the language network exhibits adult-like left-hemispheric lateralization by 4 years of age.

Left hemisphere damage in adulthood often leads to linguistic deficits, but many cases of early damage leave linguistic processing preserved, and a functional language system can develop in the right hemisphere. To explain this early apparent equipotentiality of the two hemispheres for language, some have proposed that the language system is bilateral during early development and only becomes left-lateralized with age. We examined language lateralization using functional magnetic resonance imaging with two large pediatric cohorts (total n=273 children ages 4-16; n=107 adults). Strong, adult-level left-hemispheric lateralization (in activation volume and response magnitude) was evident by age 4. Thus, although the right hemisphere can take over language function in some cases of early brain damage, and although some features of the language system do show protracted development (magnitude of language response and strength of inter-regional correlations in the language network), the left-hemisphere bias for language is robustly present by 4 years of age. These results call for alternative accounts of early equipotentiality of the two hemispheres for language.

Preserved functional organization of human auditory cortex in individuals missing one temporal lobe from infancy.

Human cortical responses to natural sounds, measured with fMRI, can be approximated as the weighted sum of a small number of canonical response patterns (components), each having interpretable functional and anatomical properties. Here, we asked whether this organization is preserved in cases where only one temporal lobe is available due to early brain damage by investigating a unique family: one sibling born without a left temporal lobe, another without a right temporal lobe, and a third anatomically neurotypical. We analyzed fMRI responses to diverse natural sounds within the intact hemispheres of these individuals and compared them to 12 neurotypical participants. All siblings manifested the neurotypical auditory responses in their intact hemispheres. These results suggest that the development of the auditory cortex in each hemisphere does not depend on the existence of the other hemisphere, highlighting the redundancy and equipotentiality of the bilateral auditory system.

Functional identification of language-responsive channels in individual participants in MEG investigations.

Making meaningful inferences about the functional architecture of the language system requires the ability to refer to the same neural units across individuals and studies. Traditional brain imaging approaches align and average brains together in a common space. However, lateral frontal and temporal cortex, where the language system resides, is characterized by high structural and functional inter-individual variability. This variability reduces the sensitivity and functional resolution of group-averaging analyses. This problem is compounded by the fact that language areas often lay in close proximity to regions of other large-scale networks with different functional profiles. A solution inspired by other fields of cognitive neuroscience (e.g., vision) is to identify language areas functionally in each individual brain using a 'localizer' task (e.g., a language comprehension task). This approach has proven productive in fMRI, yielding a number of discoveries about the language system, and has been successfully extended to intracranial recording investigations. Here, we apply this approach to MEG. Across two experiments (one in Dutch speakers, n=19; one in English speakers, n=23), we examined neural responses to the processing of sentences and a control condition (nonword sequences). We demonstrated that the neural response to language is spatially consistent at the individual level. The language-responsive sensors of interest were, as expected, less responsive to the nonwords condition. Clear inter-individual differences were present in the topography of the neural response to language, leading to greater sensitivity when the data were analyzed at the individual level compared to the group level. Thus, as in fMRI, functional localization yields benefits in MEG and thus opens the door to probing fine-grained distinctions in space and time in future MEG investigations of language processing.

Probabilistic atlas for the language network based on precision fMRI data from >800 individuals.

Two analytic traditions characterize fMRI language research. One relies on averaging activations across individuals. This approach has limitations: because of inter-individual variability in the locations of language areas, any given voxel/vertex in a common brain space is part of the language network in some individuals but in others, may belong to a distinct network. An alternative approach relies on identifying language areas in each individual using a functional 'localizer'. Because of its greater sensitivity, functional resolution, and interpretability, functional localization is gaining popularity, but it is not always feasible, and cannot be applied retroactively to past studies. To bridge these disjoint approaches, we created a probabilistic functional atlas using fMRI data for an extensively validated language localizer in 806 individuals. This atlas enables estimating the probability that any given location in a common space belongs to the language network, and thus can help interpret group-level activation peaks and lesion locations, or select voxels/electrodes for analysis. More meaningful comparisons of findings across studies should increase robustness and replicability in language research.

The Domain-General Multiple Demand Network Is More Active in Early Balanced Bilinguals Than Monolinguals During Executive Processing.

The bilingual experience may place special cognitive demands on speakers and has been argued to lead to improvements in domain-general executive abilities, like cognitive control and working memory. Such improvements have been argued for based on both behavioral and brain imaging evidence. However, the empirical landscape is complex and ridden with controversy. Here we attempt to shed light on this question through an fMRI investigation of relatively large, relatively homogeneous, and carefully matched samples of early balanced bilinguals (n = 55) and monolinguals (n = 54), using robust, previously validated individual-level markers of neural activity in the domain-general multiple demand (MD) network, which supports executive functions. We find that the bilinguals, compared to the monolinguals, show significantly stronger neural responses to an executive (spatial working memory) task, and a larger difference between a harder and an easier condition of the task, across the MD network. These stronger neural responses are accompanied by better behavioral performance on the working memory task. We further show that the bilingual-vs.-monolingual difference in neural responses is not ubiquitous across the brain as no group difference in magnitude is observed in primary visual areas, which also respond to the task. Although the neural group difference in the MD network appears robust, it remains difficult to causally link it to bilingual experience specifically.