The HUSH complex controls brain architecture and protocadherin fidelity

Fine-tuning of neural connectivity is important for cerebral functions and brain evolution. Protocadherins provide barcodes for neuronal identity as well as synapse formation and expansion of protocadherin cluster genes has been linked to advanced cognitive functions. The tightly controlled stochastic and combinatorial expression of the different protocadherin isoforms in individual neurons provides the molecular basis for neuronal diversity, neuronal network complexity and function of the vertebrate brain. How protocadherins are epigenetically controlled has not yet been fully elucidated. Here we show that the HUSH (human silencing hub) complex containing H3K9me3 binding protein M-phase phosphoprotein 8 (MPP8) and Microrchidia CW-type zinc finger protein 2 (MORC2), critically controls the fidelity of protocadherin expression. MPP8 and MORC2A are highly expressed in the murine brain and exclusively found in neurons. Genetic inactivation of Mphosph8 (coding for MPP8) or Morc2a in the nervous system of mice leads to increased brain size, altered brain architecture, and behavioral changes. Mechanistically, MPP8 and MORC2A precisely and selectively suppress the repetitive-like protocadherin gene cluster on mouse chromosome 18 in a H3K9me3-dependent manner, thereby affecting synapse formation. Moreover, we demonstrate that individual MPHOSPH8- or MORC2-deficient neurons in human cerebral organoids express increased numbers of clustered protocadherin isoforms. Our data identify the HUSH complex, previously linked to silencing of repetitive transposable elements, as a key epigenetic regulator of protocadherin expression in the nervous system and thereby brain development and neuronal individuality in mice and humans.

Theta-burst stimulation entrains frequency-specific oscillatory responses

Background: Brain stimulation has emerged as a powerful tool in human neuroscience, becoming integral to next-generation psychiatric and neurologic therapeutics. Theta-burst stimulation (TBS), in which electrical pulses are delivered in rhythmic bouts of 3-8 Hz, seeks to recapitulate neural activity seen endogenously during cognitive tasks. A growing literature suggests that TBS can be used to alter or enhance cognitive processes, but little is known about how these stimulation events influence underlying neural activity.Objective/Hypothesis: The goal of our study was to investigate the effect of direct electrical TBS on mesoscale neural activity in humans by asking (1) whether TBS evokes persistent theta oscillations in cortical areas, (2) whether these oscillations occur at the stimulated frequency, and (3) whether stimulation events propagate in a manner consistent with underlying functional and structural brain architecture.Methods: We recruited 20 neurosurgical epilepsy patients with indwelling electrodes and delivered direct cortical TBS at varying locations and frequencies. Simultaneous iEEG was recorded from non-stimulated electrodes and analyzed to understand how TBS influences mesoscale neural activity. Results: We found that TBS rapidly evoked theta rhythms in widespread brain regions, preferentially at the stimulation frequency, and that these oscillations persisted for hundreds of milliseconds post stimulation offset. Furthermore, the functional connectivity between recording and stimulation sites predicted the strength of theta response, suggesting that underlying brain architecture guides the flow of stimulation through the brain.Conclusions: By demonstrating that direct TBS induces frequency-specific oscillatory responses, our results suggest this technology can be used to directly and predictably influence the activity of cognitively-relevant brain networks.

The evolution of hierarchical structure building capacity for language and music: a bottom-up perspective

A central property of human language is its hierarchical structure. Humans can flexibly combine elements to build a hierarchical structure expressing rich semantics. A hierarchical structure is also considered as playing a key role in many other human cognitive domains. In music, auditory-motor events are combined into hierarchical pitch and/or rhythm structure expressing affect. How did such a hierarchical structure building capacity evolve? This paper investigates this question from a bottom-up perspective based on a set of action-related components as a shared basis underlying cognitive capacities of nonhuman primates and humans. Especially, I argue that the evolution of hierarchical structure building capacity for language and music is tractable for comparative evolutionary study once we focus on the gradual elaboration of shared brain architecture: the cortico-basal ganglia-thalamocortical circuits for hierarchical control of goal-directed action and the dorsal pathways for hierarchical internal models. I suggest that this gradual elaboration of the action-related brain architecture in the context of vocal control and tool-making went hand in hand with amplification of working memory, and made the brain ready for hierarchical structure building in language and music.

Theta-burst stimulation entrains frequency-specific oscillatory responses

Brain stimulation has emerged as a powerful tool in human neuroscience, becoming integral to next-generation psychiatric and neurologic therapeutics. Theta-burst stimulation (TBS), in which electrical pulses are delivered in rhythmic bouts of 3–8 Hz, seeks to recapitulate neural activity seen endogenously during cognitive tasks. A growing literature suggests that TBS can be used to alter or enhance cognitive processes, but little is known about how these stimulation events influence underlying neural activity. In particular, it is not understood whether TBS evokes persistent theta oscillations, whether these oscillations occur at the stimulated frequency, and whether stimulation events propagate in a manner consistent with underlying functional and structural brain architecture. To answer these questions, we recruited 20 neurosurgical patients with indwelling electrodes and delivered direct cortical TBS at varying locations and frequencies. We find that TBS rapidly evokes theta rhythms in widespread brain regions, preferentially at the stimulation frequency, and that these oscillations persist for hundreds of milliseconds post stimulation offset. Furthermore, the functional connectivity between recording and stimulation sites predicts the strength of theta response, suggesting that underlying brain architecture guides the flow of stimulation through the brain. These results show that TBS can be used to directly and predictably influence the activity of cognitively-relevant brain networks.

MRI network progression in mesial temporal lobe epilepsy related to healthy brain architecture

We measured MRI network progression in mesial temporal lobe epilepsy (mTLE) patients as a function of healthy brain architecture. Resting-state functional MRI and diffusion-weighted MRI were acquired in 40 unilateral mTLE patients and 70 healthy controls. Data were used to construct region-to-region functional connectivity, structural connectivity, and streamline length connectomes per subject. Three models of distance from the presumed seizure focus in the anterior hippocampus in the healthy brain were computed using the average connectome across controls. A fourth model was defined using regions of transmodal (higher cognitive function) to unimodal (perceptual) networks across a published functional gradient in the healthy brain. These models were used to test whether network progression in patients increased when distance from the anterior hippocampus or along a functional gradient in the healthy brain decreases. Results showed that alterations of structural and functional networks in mTLE occur in greater magnitude in regions of the brain closer to the seizure focus based on healthy brain topology, and decrease as distance from the focus increases over duration of disease. Overall, this work provides evidence that changes across the brain in focal epilepsy occur along healthy brain architecture.

Brain-Environment Alignment during Movie Watching Predicts Cognitive-Affective Function in Adulthood

BOLD fMRI studies have provided compelling evidence that the human brain demonstrates substantial moment-to-moment fluctuations in both activity and functional connectivity patterns. While the role of brain signal variability in fostering cognitive adaptation to ongoing environmental demands is well-documented, the relevance of moment-to-moment changes in functional brain architecture is still debated. To probe the role of architectural variability in naturalistic information processing, we used neuroimaging and behavioural data collected during movie watching by the Cambridge Centre for Ageing and Neuroscience (N = 642, 326 women) and the Human Connectome Project (N = 176, 106 women). Both moment-to-moment and contextual change-evoked architectural variability increased from young to older adulthood. However, coupling between moment-to-moment changes in functional brain architecture and concrete environmental features was stronger at younger ages. Architectural variability (both momentary and context-evoked) was associated with age-distinct profiles of network communication, specifically, greater functional integration of the default mode network in older adulthood, but greater informational flow across neural networks implicated in environmentally driven attention and control (cingulo-opercular, salience, ventral attention) in younger adulthood. Whole-brain communication pathways anchored in default mode regions relevant to episodic and semantic context creation (i.e., angular and middle temporal gyri) contributed to greater brain reconfiguration in response to narrative context changes, as well as stronger coupling between moment-to-moment changes in functional brain architecture and changes in concrete environmental features. Cognitive adaptation was directly linked to levels of brain-environment alignment, but only indirectly associated with levels of architectural variability. Specifically, stronger coupling between moment-to-moment variability in brain architecture and concrete environmental features predicted poorer cognitive adaptation (i.e., fluid IQ) and greater affectively driven environmental vigilance. Complementarily, across the adult lifespan, higher fluid (but not crystallized) IQ was related to stronger expression of the network communication profile underlying momentary and context-based architectural variability during youth. Our results indicate that the adaptiveness of dynamic brain reconfiguration during naturalistic information processing changes across the lifespan due to the associated network communication profiles. Moreover, our findings on brain-environment alignment complement the existing literature on the beneficial consequences of modulating brain signal variability in response to environmental complexity. Specifically, they imply that coupling between moment-to-moment variability in functional brain architecture and concrete environmental features may index a bias towards perceptually-bound, rather than conceptual processing, which hinders affective functioning and strategic engagement with the external environment.