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.

Electrical and synaptic integration of glioma into neural circuits.

High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.

Electrophysiological markers of memory consolidation in the human brain when memories are reactivated during sleep.

Human accomplishments depend on learning, and effective learning depends on consolidation. Consolidation is the process whereby new memories are gradually stored in an enduring way in the brain so that they can be available when needed. For factual or event knowledge, consolidation is thought to progress during sleep as well as during waking states and to be mediated by interactions between hippocampal and neocortical networks. However, consolidation is difficult to observe directly but rather is inferred through behavioral observations. Here, we investigated overnight memory change by measuring electrical activity in and near the hippocampus. Electroencephalographic (EEG) recordings were made in five patients from electrodes implanted to determine whether a surgical treatment could relieve their seizure disorders. One night, while each patient slept in a hospital monitoring room, we recorded electrophysiological responses to 10 to 20 specific sounds that were presented very quietly, to avoid arousal. Half of the sounds had been associated with objects and their precise spatial locations that patients learned before sleep. After sleep, we found systematic improvements in spatial recall, replicating prior results. We assume that when the sounds were presented during sleep, they reactivated and strengthened corresponding spatial memories. Notably, the sounds also elicited oscillatory intracranial EEG activity, including increases in theta, sigma, and gamma EEG bands. Gamma responses, in particular, were consistently associated with the degree of improvement in spatial memory exhibited after sleep. We thus conclude that this electrophysiological activity in the hippocampus and adjacent medial temporal cortex reflects sleep-based enhancement of memory storage.

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.

Vision perceptually restores auditory spectral dynamics in speech.

Visual speech facilitates auditory speech perception, but the visual cues responsible for these benefits and the information they provide remain unclear. Low-level models emphasize basic temporal cues provided by mouth movements, but these impoverished signals may not fully account for the richness of auditory information provided by visual speech. High-level models posit interactions among abstract categorical (i.e., phonemes/visemes) or amodal (e.g., articulatory) speech representations, but require lossy remapping of speech signals onto abstracted representations. Because visible articulators shape the spectral content of speech, we hypothesized that the perceptual system might exploit natural correlations between midlevel visual (oral deformations) and auditory speech features (frequency modulations) to extract detailed spectrotemporal information from visual speech without employing high-level abstractions. Consistent with this hypothesis, we found that the time-frequency dynamics of oral resonances (formants) could be predicted with unexpectedly high precision from the changing shape of the mouth during speech. When isolated from other speech cues, speech-based shape deformations improved perceptual sensitivity for corresponding frequency modulations, suggesting that listeners could exploit this cross-modal correspondence to facilitate perception. To test whether this type of correspondence could improve speech comprehension, we selectively degraded the spectral or temporal dimensions of auditory sentence spectrograms to assess how well visual speech facilitated comprehension under each degradation condition. Visual speech produced drastically larger enhancements during spectral degradation, suggesting a condition-specific facilitation effect driven by cross-modal recovery of auditory speech spectra. The perceptual system may therefore use audiovisual correlations rooted in oral acoustics to extract detailed spectrotemporal information from visual speech.

Visual cortex responds to sound onset and offset during passive listening.

Sounds enhance our ability to detect, localize, and respond to co-occurring visual targets. Research suggests that sounds improve visual processing by resetting the phase of ongoing oscillations in visual cortex. However, it remains unclear what information is relayed from the auditory system to visual areas and if sounds modulate visual activity even in the absence of visual stimuli (e.g., during passive listening). Using intracranial electroencephalography (iEEG) in humans, we examined the sensitivity of visual cortex to three forms of auditory information during a passive listening task: auditory onset responses, auditory offset responses, and rhythmic entrainment to sounds. Because some auditory neurons respond to both sound onsets and offsets, visual timing and duration processing may benefit from each. In addition, if auditory entrainment information is relayed to visual cortex, it could support the processing of complex stimulus dynamics that are aligned between auditory and visual stimuli. Results demonstrate that in visual cortex, amplitude-modulated sounds elicited transient onset and offset responses in multiple areas, but no entrainment to sound modulation frequencies. These findings suggest that activity in visual cortex (as measured with iEEG in response to auditory stimuli) may not be affected by temporally fine-grained auditory stimulus dynamics during passive listening (though it remains possible that this signal may be observable with simultaneous auditory-visual stimuli). Moreover, auditory responses were maximal in low-level visual cortex, potentially implicating a direct pathway for rapid interactions between auditory and visual cortices. This mechanism may facilitate perception by time-locking visual computations to environmental events marked by auditory discontinuities.NEW & NOTEWORTHY Using intracranial electroencephalography (iEEG) in humans during a passive listening task, we demonstrate that sounds modulate activity in visual cortex at both the onset and offset of sounds, which likely supports visual timing and duration processing. However, more complex auditory rate information did not affect visual activity. These findings are based on one of the largest multisensory iEEG studies to date and reveal the type of information transmitted between auditory and visual regions.

Visual speech differentially modulates beta, theta, and high gamma bands in auditory cortex.

Speech perception is a central component of social communication. Although principally an auditory process, accurate speech perception in everyday settings is supported by meaningful information extracted from visual cues. Visual speech modulates activity in cortical areas subserving auditory speech perception including the superior temporal gyrus (STG). However, it is unknown whether visual modulation of auditory processing is a unitary phenomenon or, rather, consists of multiple functionally distinct processes. To explore this question, we examined neural responses to audiovisual speech measured from intracranially implanted electrodes in 21 patients with epilepsy. We found that visual speech modulated auditory processes in the STG in multiple ways, eliciting temporally and spatially distinct patterns of activity that differed across frequency bands. In the theta band, visual speech suppressed the auditory response from before auditory speech onset to after auditory speech onset (-93 to 500 ms) most strongly in the posterior STG. In the beta band, suppression was seen in the anterior STG from -311 to -195 ms before auditory speech onset and in the middle STG from -195 to 235 ms after speech onset. In high gamma, visual speech enhanced the auditory response from -45 to 24 ms only in the posterior STG. We interpret the visual-induced changes prior to speech onset as reflecting crossmodal prediction of speech signals. In contrast, modulations after sound onset may reflect a decrease in sustained feedforward auditory activity. These results are consistent with models that posit multiple distinct mechanisms supporting audiovisual speech perception.

Defining the latent period of epileptogenesis and epileptogenic zone in a focal cortical dysplasia type II (FCDII) rat model.

OBJECTIVES: Focal cortical dysplasia type II (FCDII) is one of the most common underlying pathologies in patients with drug-resistant epilepsy. However, mechanistic understanding of FCDII fails to keep pace with genetic discoveries, primarily due to the significant challenge in developing a clinically relevant animal model. Conceptually and clinically important questions, such as the unknown latent period of epileptogenesis and the controversial epileptogenic zone, remain unknown in all experimental FCDII animal models, making it even more challenging to investigate the underlying epileptogenic mechanisms. METHODS: In this study, we used continuous video-electroencephalography (EEG) monitoring to detect the earliest interictal and ictal events in a clustered regularly interspaced short palindromic repeats (CRISPR)-in utero electroporation (IUE) FCDII rat model that shares genetic, pathological, and electroclinical signatures with those observed in humans. We then took advantage of in vivo local field potential (LFP) recordings to localize the epileptogenic zone in these animals. RESULTS: To the best of our knowledge, we showed for the first time that epileptiform discharges emerged during the third postnatal week, and that the first seizure occurred as early as during the fourth postnatal week. We also showed that both interictal and ictal discharges are localized within the dysplastic cortex, concordant with human clinical data. SIGNIFICANCE: Together, our work identified the temporal and spatial frame of epileptogenesis in a highly clinically relevant FCDII animal model, paving the way for mechanistic studies at molecular, cellular, and circuitry levels.

Joint Encoding of Auditory Timing and Location in Visual Cortex.

Co-occurring sounds can facilitate perception of spatially and temporally correspondent visual events. Separate lines of research have identified two putatively distinct neural mechanisms underlying two types of crossmodal facilitations: Whereas crossmodal phase resetting is thought to underlie enhancements based on temporal correspondences, lateralized occipital evoked potentials (ERPs) are thought to reflect enhancements based on spatial correspondences. Here, we sought to clarify the relationship between these two effects to assess whether they reflect two distinct mechanisms or, rather, two facets of the same underlying process. To identify the neural generators of each effect, we examined crossmodal responses to lateralized sounds in visually responsive cortex of 22 patients using electrocorticographic recordings. Auditory-driven phase reset and ERP responses in visual cortex displayed similar topography, revealing significant activity in pericalcarine, inferior occipital-temporal, and posterior parietal cortex, with maximal activity in lateral occipitotemporal cortex (potentially V5/hMT+). Laterality effects showed similar but less widespread topography. To test whether lateralized and nonlateralized components of crossmodal ERPs emerged from common or distinct neural generators, we compared responses throughout visual cortex. Visual electrodes responded to both contralateral and ipsilateral sounds with a contralateral bias, suggesting that previously observed laterality effects do not emerge from a distinct neural generator but rather reflect laterality-biased responses in the same neural populations that produce phase-resetting responses. These results suggest that crossmodal phase reset and ERP responses previously found to reflect spatial and temporal facilitation in visual cortex may reflect the same underlying mechanism. We propose a new unified model to account for these and previous results.

Inducing synesthesia in non-synesthetes: Short-term visual deprivation facilitates auditory-evoked visual percepts.

Sounds can modulate activity in visual cortex, facilitating the detection of visual targets. However, these sound-driven modulations are not thought to evoke conscious visual percepts in the general population. In individuals with synesthesia, however, multisensory interactions do lead to qualitatively different experiences such as sounds evoking flashes of light. Why, if multisensory interactions are present in all individuals, do only synesthetes experience abnormal qualia? Competing models differ in the time required for synesthetic experiences to emerge. The cross-activation model suggests synesthesia arises over months or years from the development of abnormal neural connections. Here we demonstrate that after ∼5 min of visual deprivation, sounds can evoke synesthesia-like percepts (vivid colors and Klüver form-constants) in ∼50% of non-synesthetes. These results challenge aspects of the cross-activation model and suggest that synesthesia exists as a latent feature in all individuals, manifesting when the balance of activity across the senses has been altered.

Altered White Matter and Sensory Response to Bodily Sensation in Female-to-Male Transgender Individuals.

While most people take identification with their body for granted, conditions such as phantom limb pain, alien hand syndrome, and xenomelia suggest that the feeling of bodily congruence is constructed and susceptible to alteration. Individuals with xenomelia typically experience one of their limbs as over-present and aversive, leading to a desire to amputate the limb. Similarly, many transgender individuals describe their untreated sexed body parts as incongruent and aversive, and many experience phantom body parts of the sex they identify with (Ramachandran, 2008). This experience may relate to differences in brain representation of the sexed body part, as suggested in xenomelia (McGeoch et al., 2011). We utilized magnetoencephalography imaging to record brain activity during somatosensory stimulation of the breast-a body part that feels incongruent to most presurgical female-to-male (FtM)-identified transgender individuals-and the hand, a body part that feels congruent. We measured the sensory evoked response in right hemisphere somatosensory and body-related brain areas and found significantly reduced activation in the supramarginal gyrus and secondary somatosensory cortex, but increased activation at the temporal pole for chest sensation in the FtM group (N = 8) relative to non-transgender females (N = 8). In addition, we found increased white matter coherence in the supramarginal gyrus and temporal pole and decreased white matter diffusivity in the anterior insula and temporal pole in the FtM group. These findings suggest that dysphoria related to gender-incongruent body parts in FtM individuals may be tied to differences in neural representation of the body and altered white matter connectivity.

Peripheral sounds rapidly activate visual cortex: evidence from electrocorticography.

Neurophysiological studies with animals suggest that sounds modulate activity in primary visual cortex in the presence of concurrent visual stimulation. Noninvasive neuroimaging studies in humans have similarly shown that sounds modulate activity in visual areas even in the absence of visual stimuli or visual task demands. However, the spatial and temporal limitations of these noninvasive methods prevent the determination of how rapidly sounds activate early visual cortex and what information about the sounds is relayed there. Using spatially and temporally precise measures of local synaptic activity acquired from depth electrodes in humans, we demonstrate that peripherally presented sounds evoke activity in the anterior portion of the contralateral, but not ipsilateral, calcarine sulcus within 28 ms of sound onset. These results suggest that auditory stimuli rapidly evoke spatially specific activity in visual cortex even in the absence of concurrent visual stimulation or visual task demands. This rapid auditory-evoked activation of primary visual cortex is likely to be mediated by subcortical pathways or direct cortical projections from auditory to visual areas.

Primary somatosensory cortex hand representation dynamically modulated by motor output.

The brain's primary motor and primary somatosensory cortices are generally viewed as functionally distinct entities. Here we show by means of magnetoencephalography with a phantom-limb patient, that movement of the phantom hand leads to a change in the response of the primary somatosensory cortex to tactile stimulation. This change correlates with the described conscious perception and suggests a greater degree of functional unification between the primary motor and somatosensory cortices than is currently realized. We suggest that this may reflect the evolution of this part of the human brain, which is thought to have occurred from an undifferentiated sensorimotor cortex.

Survival of the synesthesia gene: why do people hear colors and taste words?

Synesthesia is a perceptual experience in which stimuli presented through one modality will spontaneously evoke sensations in an unrelated modality. The condition occurs from increased communication between sensory regions and is involuntary, automatic, and stable over time. While synesthesia can occur in response to drugs, sensory deprivation, or brain damage, research has largely focused on heritable variants comprising roughly 4% of the general population. Genetic research on synesthesia suggests the phenomenon is heterogeneous and polygenetic, yet it remains unclear whether synesthesia ever provided a selective advantage or is merely a byproduct of some other useful selected trait. Progress in uncovering the genetic basis of synesthesia will help us understand why synesthesia has been conserved in the population.

Parietal connectivity mediates multisensory facilitation.

Our senses interact in daily life through multisensory integration, facilitating perceptual processes and behavioral responses. The neural mechanisms proposed to underlie this multisensory facilitation include anatomical connections directly linking early sensory areas, indirect connections to higher-order multisensory regions, as well as thalamic connections. Here we examine the relationship between white matter connectivity, as assessed with diffusion tensor imaging, and individual differences in multisensory facilitation and provide the first demonstration of a relationship between anatomical connectivity and multisensory processing in typically developed individuals. Using a whole-brain analysis and contrasting anatomical models of multisensory processing we found that increased connectivity between parietal regions and early sensory areas was associated with the facilitation of reaction times to multisensory (auditory-visual) stimuli. Furthermore, building on prior animal work suggesting the involvement of the superior colliculus in this process, using probabilistic tractography we determined that the strongest cortical projection area connected with the superior colliculus includes the region of connectivity implicated in our independent whole-brain analysis.

Enhanced mental rotation ability in time-space synesthesia.

Time-space synesthesia is a variant of sequence-space synesthesia and involves the involuntary association of months of the year with 2D and 3D spatial forms, such as arcs, circles, and ellipses. Previous studies have revealed conflicting results regarding the association between time-space synesthesia and enhanced spatial processing ability. Here, we tested 15 time-space synesthetes, and 15 non-synesthetic controls matched for age, education, and gender on standard tests of mental rotation ability, spatial working memory, and verbal working memory. Synesthetes performed better than controls on our test of mental rotation, but similarly to controls on tests of spatial and verbal working memory. Results support a dissociation between visuo-spatial imagery and spatial working memory capacity, and suggest time-space synesthesia is associated only with enhanced visuo-spatial imagery. These data are consistent with the time-space connectivity thesis that time-space synesthesia results from enhanced connectivity in the parietal lobe between regions supporting the representation of temporal sequences and those underlying visuo-spatial imagery.

Evidence for a Causal Dissociation of the McGurk Effect and Congruent Audiovisual Speech Perception via TMS.

Congruent visual speech improves speech perception accuracy, particularly in noisy environments. Conversely, mismatched visual speech can alter what is heard, leading to an illusory percept known as the McGurk effect. This illusion has been widely used to study audiovisual speech integration, illustrating that auditory and visual cues are combined in the brain to generate a single coherent percept. While prior transcranial magnetic stimulation (TMS) and neuroimaging studies have identified the left posterior superior temporal sulcus (pSTS) as a causal region involved in the generation of the McGurk effect, it remains unclear whether this region is critical only for this illusion or also for the more general benefits of congruent visual speech (e.g., increased accuracy and faster reaction times). Indeed, recent correlative research suggests that the benefits of congruent visual speech and the McGurk effect reflect largely independent mechanisms. To better understand how these different features of audiovisual integration are causally generated by the left pSTS, we used single-pulse TMS to temporarily impair processing while subjects were presented with either incongruent (McGurk) or congruent audiovisual combinations. Consistent with past research, we observed that TMS to the left pSTS significantly reduced the strength of the McGurk effect. Importantly, however, left pSTS stimulation did not affect the positive benefits of congruent audiovisual speech (increased accuracy and faster reaction times), demonstrating a causal dissociation between the two processes. Our results are consistent with models proposing that the pSTS is but one of multiple critical areas supporting audiovisual speech interactions. Moreover, these data add to a growing body of evidence suggesting that the McGurk effect is an imperfect surrogate measure for more general and ecologically valid audiovisual speech behaviors.

Colored halos around faces and emotion-evoked colors: a new form of synesthesia.

The claim that some individuals see colored halos or auras around faces has long been part of popular folklore. Here we report on a 23-year-old man (subject TK) diagnosed with Asperger's disorder, who began to consistently experience colors around individuals at the age of 10. TK's colors are based on the individual's identity and emotional connotation. We interpret these experiences as a form of synesthesia, and confirm their authenticity through a target detection paradigm. Additionally, we investigate TK's claim that emotions evoke highly specific colors, allowing him, despite his Asperger's, to introspect on emotions and recognize them in others.

Neuro-Oncology Patients as Human Research Subjects: Ethical Considerations for Cognitive and Behavioral Testing for Research Purposes.

Language, cognition, and behavioral testing have become a fundamental component of standard clinical care for brain cancer patients. Many existing publications have identified and addressed potential ethical issues that are present in the biomedical setting mostly centering around the enrollment of vulnerable populations for therapeutic clinical trials. Well-established guides and publications have served as useful tools for clinicians; however, little has been published for researchers who share the same stage but administer tests and collect valuable data solely for non-therapeutic investigational purposes derived from voluntary patient participation. Obtaining informed consent and administering language, cognition, and behavioral tasks for the sole purpose of research involving cancer patients that exhibit motor speech difficulties and cognitive impairments has its own hardships. Researchers may encounter patients who experience emotional responses during tasks that challenge their existing impairments. Patients may have difficulty differentiating between clinical testing and research testing due to similarity of task design and their physician's dual role as a principal investigator in the study. It is important for researchers to practice the proposed methods emphasized in this article to maintain the overall well-being of patients while simultaneously fulfilling the purpose of the study in a research setting.