Neural oscillations and a nascent corticohippocampal theory of reference

The ability to use words to refer to the world is vital to the communicative power of human language. In particular, the anaphoric use of words to refer to previously mentioned concepts (antecedents) allows dialogue to be coherent and meaningful. Psycholinguistic theory posits that anaphor comprehension involves reactivating a memory representation of the antecedent. Whereas this implies the involvement of recognition memory, or the mnemonic sub-routines by which people distinguish old from new, the neural processes for reference resolution are largely unknown. Here, we report time-frequency analysis of four EEG experiments to reveal the increased coupling of functional neural systems associated with referentially coherent expressions compared to referentially problematic expressions. Despite varying in modality, language, and type of referential expression, all experiments showed larger gamma-band power for referentially coherent expressions compared to referentially problematic expressions. Beamformer analysis in high-density Experiment 4 localised the gamma-band increase to posterior parietal cortex around 400-600 ms after anaphor-onset and to frontaltemporal cortex around 500-1000 ms. We argue that the observed gamma-band power increases reflect successful referential binding and resolution, which links incoming information to antecedents through an interaction between the brain’s recognition memory networks and frontal-temporal language network. We integrate these findings with previous results from patient and neuroimaging studies, and we outline a nascent cortico-hippocampal theory of reference

An electrophysiological investigation of co-referential processes in visual narrative comprehension

Visual narratives make use of various means to convey referential and co-referential meaning, so comprehenders must recognize that different depictions across sequential images represent the same character(s). In this study, we investigated how the order in which different types of panels in visual sequences are presented affects how the unfolding narrative is comprehended. Participants viewed short comic strips while their electroencephalo- gram (EEG) was recorded. We analyzed evoked and induced EEG activity elicited by both full panels (showing a full character) and refiner panels (showing only a zoom of that full panel), and took into account whether they preceded or followed the panel to which they were co-referentially related (i.e., were cataphoric or anaphoric). We found that full panels elicited both larger N300 amplitude and increased gamma-band power compared to refiner panels. Anaphoric panels elicited a sustained negativity compared to cataphoric panels, which appeared to be sensitive to the referential status of the anaphoric panel. In the time-frequency domain, anaphoric panels elicited reduced 8–12 Hz alpha power and increased 45–65 Hz gamma-band power compared to cataphoric panels. These findings are consistent with models in which the processes involved in visual narrative compre- hension partially overlap with those in language comprehension

Comprehending Events on the Fly: Inhibition and Selection during Sentence Processing

In our everyday conversations we talk about how things or people change. Instantiations of objects in their different states need to be maintained during language comprehension for future selection of the relevant state, as in The chef will chop the onion. And then/but first, she will weigh the onion. Previous fMRI studies (Solomon et al, 2015) demonstrated that selecting between multiple competing representations of the same object token, such as the intact and the chopped onion, elicits increased activation in the brain area associated with conflict resolution -- left pVLPFC. When there is no cue to the earlier introduced object, as in The chef will chop/smell the onion. And then, she will weigh another onion, no retrieval cost is observed because none of the states is relevant. However, due to the poor temporal resolution of fMRI, it is difficult to make assumptions about the dynamics of this effect and where exactly in the sentence it occurs. To track this competition effect over time, dEEG was recorded as participants (N=23) read sentences presented to them word by word. Critical sentences were organized in a two-by-two design with degree of change and token reference being the two factors. A time-frequency analysis of EEG, synchronized from the onset of the final determiner phrase in the second sentence, revealed a significant increase in alpha (8-12 Hz) in sentences describing state change and referring back to the same token. This finding is consistent with literature relating alpha oscillations to cortical inhibitory processing and selection mechanisms

The Role of Gamma Oscillations During Integration of Metaphoric Gestures and Abstract Speech

Metaphoric (MP) co-speech gestures are commonly used during daily communication. They communicate about abstract information by referring to gestures that are clearly concrete (e.g., raising a hand for “the level of the football game is high”). To understand MP co-speech gestures, a multisensory integration at semantic level is necessary between abstract speech and concrete gestures. While semantic gesture-speech integration has been extensively investigated using functional magnetic resonance imaging, evidence from electroencephalography (EEG) is rare. In the current study, we set out an EEG experiment, investigating the processing of MP vs. iconic (IC) co-speech gestures in different contexts, to reveal the oscillatory signature of MP gesture integration. German participants (n = 20) viewed video clips with an actor performing both types of gestures, accompanied by either comprehensible German or incomprehensible Russian (R) speech, or speaking German sentences without any gestures. Time-frequency analysis of the EEG data showed that, when gestures were accompanied by comprehensible German speech, MP gestures elicited decreased gamma band power (50–70 Hz) between 500 and 700 ms in the parietal electrodes when compared to IC gestures, and the source of this effect was localized to the right middle temporal gyrus. This difference is likely to reflect integration processes, as it was reduced in the R language and no-gesture conditions. Our findings provide the first empirical evidence suggesting the functional relationship between gamma band oscillations and higher-level semantic processes in a multisensory setting

Tracing the interplay between syntactic and lexical features: fMRI evidence from agreement comprehension

Available online 29 March 2018The current fMRI study was designed to investigate whether the processing of different gender-related cues embedded in nouns affects the computation of agreement dependencies and, if so, where this possible interaction is mapped in the brain. We used the Spanish gender agreement system, which makes it possible to manipulate two different factors: the agreement between different sentence constituents (i.e., by contrasting congruent versus incongruent determiner-noun pairs) and the formal (i.e., orthographical/morphological) and/or lexical information embedded in the noun –i.e., by contrasting transparent (e.g., libromasc. [book]; lunafem. [moon]) and opaque nouns (e.g., l apizmasc. [pencil]; vejezfem. [old age]). Crucially, these data illustrated, for the first time, how the network underlying agreement is sensitive to different gender-to-ending cues: different sources of gender information associated with nouns affect the neural circuits involved in the computation of local agreement dependencies. When the gender marking is informative (as in the case of transparent nouns), both formal and lexical information is used to establish grammatical relations. In contrast, when no formal cues are available (as in the case of opaque nouns), gender information is retrieved from the lexicon. We demonstrated the involvement of the posterior MTG/STG, pars triangularis within the IFG, and parietal regions during gender agreement computation. Critically, in order to integrate the different available information sources, the dynamics of this fronto-temporal loop change and additional regions, such as the hippocampus, the angular and the supramarginal gyri are recruited. These results underpin previous neuroanatomical models proposed in the context of both gender processing and sentence comprehension. But, more importantly, they provide valuable information regarding how and where the brain's language system dynamically integrates all the available form-based and lexical cues during comprehension.This research was partially supported by Severo Ochoa program grant SEV-2015-049; grant ERC-2011-ADG-295362 from the European Research Council, and grants PSI2015-67353-R and PSI2015-65694-P from the MINECO

Closed-Loop Brain-Computer Interfaces for Memory Restoration Using Deep Brain Stimulation

The past two decades have witnessed the rapid growth of therapeutic brain-computer interfaces (BCI) targeting a diversity of brain dysfunctions. Among many neurosurgical procedures, deep brain stimulation (DBS) with neuromodulation technique has emerged as a fruitful treatment for neurodegenerative disorders such as epilepsy, Parkinson\u27s disease, post-traumatic amnesia, and Alzheimer\u27s disease, as well as neuropsychiatric disorders such as depression, obsessive-compulsive disorder, and schizophrenia. In parallel to the open-loop neuromodulation strategies for neuromotor disorders, recent investigations have demonstrated the superior performance of closed-loop neuromodulation systems for memory-relevant disorders due to the more sophisticated underlying brain circuitry during cognitive processes. Our efforts are focused on discovering unique neurophysiological patterns associated with episodic memories then applying control theoretical principles to achieve closed-loop neuromodulation of such memory-relevant oscillatory activity, especially, theta and gamma oscillations. First, we use a unique dataset with intracranial electrodes inserted simultaneously into the hippocampus and seven cortical regions across 40 human subjects to test for the presence of a pattern that the phase of hippocampal theta oscillation modulates gamma oscillations in the cortex, termed cross-regional phase-amplitude coupling (xPAC), representing a key neurophysiological mechanism that promotes the temporal organization of interregional oscillatory activities, which has not previously been observed in human subjects. We then establish that the magnitude of xPAC predicts memory encoding success along with other properties of xPAC. We find that strong functional xPAC occurs principally between the hippocampus and other mesial temporal structures, namely entorhinal and parahippocampal cortices, and that xPAC is overall stronger for posterior hippocampal connections. Next, we focus on hippocampal gamma power as a `biomarker\u27 and use a novel dataset in which open-loop DBS was applied to the posterior cingulate cortex (PCC) during the encoding of episodic memories. We evaluate the feasibility of modulating hippocampal power by a precise control of stimulation via a linear quadratic integral (LQI) controller based on autoregressive with exogenous input (ARX) modeling for in-vivo use. In the simulation framework, we demonstrate proposed BCI system achieves effective control of hippocampal gamma power in 15 out of 17 human subjects and we show our DBS pattern is physiologically safe with realistic time scales. Last, we further develop the PCC-applied binary-noise (BN) DBS paradigm targeting the neuromodulation of both hippocampal theta and gamma oscillatory power in 12 human subjects. We utilize a novel nonlinear autoregressive with exogenous input neural network (NARXNN) as the plant paired with a proportional–integral–derivative (PID) controller (NARXNN-PID) for delivering a precise stimulation pattern to achieve desired oscillatory power level. Compared to a benchmark consisted of a linear state-space model (LSSM) with a PID controller, we not only demonstrate that the superior performance of our NARXNN plant model but also show the greater capacity of NARXNN-PID architecture in controlling both hippocampal theta and gamma power. We outline further experimentation to test our BCI system and compare our findings to emerging closed-loop neuromodulation strategies

Functional segregation of hippocampal subdivisions in learning and memory

The hippocampus is well known for its function in declarative memories, especially in episodic memories and spatial navigation. Considering strikingly different features along its longitudinal axis from dorsal to ventral hippocampus, it has been proposed that hippocampal subdivisions might have distinct functional roles. Among several hypotheses, a particular prominent one is that dorsal hippocampus is required for cognitive functions, while ventral hippocampus is involved in emotional learning and stress responses, but their precise roles in learning and memory have remained controversial. In this thesis, I further explore the idea of a functional segregation, focusing on the roles of dorsal and ventral hippocampus in different types of declarative memories. Therefore, I use chemogenetic silencing to locally interfere with subdivision function in reinforced and incidental learning at various time points after memory acquisition and at memory retrieval. First, I compare the functions of dorsal and ventral hippocampus in single-trial learning. Then, I am addressing their roles in the formation of associations to previously acquired memories. Moreover, applying chemogenetic silencing and powerful recently developed techniques to genetically target learning-related neuronal populations, I study the localization of single-trial and association memories within the hippocampus. I show how in all hippocampus-dependent tasks both dorsal and ventral hippocampus is required, but with distinct contributions and irrespective of emotional relevance. Specifically, ventral hippocampus is involved in forming and recalling primary associations, whereas dorsal hippocampus is particularly important during a window of 5h post new learning. During this window dorsal hippocampus recalls memories and forms secondary associations learned on top of previously acquired memories. Thereby, the subdivisions provide a mechanism to recall previously acquired memories and to form associations to them without interference of memories, but instead with the possibility to independently use the distinct memory components. In a supplementary part, I have started to investigate the function of the transversal hippocampal axis, in particular the dentate gyrus in association learning. This study allows a first insight into a possible mechanism that might shape memory assemblies to form associations

Hippocampal Interneuron Dynamics Supporting Memory Encoding and Consolidation

Neural circuits within the hippocampus, a mammalian brain structure critical for both the encoding and consolidation of episodic memories, are composed of intimately connected excitatory pyramidal cells and inhibitory interneurons. While decades of research have focused on how the in vivo physiological properties of pyramidal cells may support these cognitive processes, and the anatomical and physiological properties of interneurons have been extensively studied in vitro, relatively little is known about how the in vivo activity patterns of interneurons support memory encoding and consolidation. Here, I have utilized Acousto-Optic Deflection (AOD)-based two-photon calcium imaging and post-hoc immunohistochemistry to perform large-scale recordings of molecularly-defined interneuron subtypes, within both CA1 and CA3, during various behavioral tasks and states. I conclude that the subtype-specific dynamics of inhibitory circuits within the hippocampus are critical in supporting its role in memory encoding and consolidation

Cholinergic Mechanisms Regulating Cognitive Function and RNA Metabolism

Acetylcholine (ACh) is one of the main neuromodulators in the mammalian central nervous system (CNS). This chemical messenger has been implicated in the underlying physiology of many distinct cognitive functions. However, the exact role that ACh plays in regulating information processing in the brain is still not fully understood. The vesicular acetylcholine transporter (VAChT) is required for the storage of ACh into synaptic vesicles, and therefore it presents a means to modulate release. Diminished VAChT levels cause a decrease in cholinergic tone, whereas increased VAChT expression has been shown to augment ACh release. Previously published data have shown that elimination of VAChT in the basal forebrain in genetically-modified mice impairs learning and memory. For our studies we have used different mouse lines in which the expression of the VAChT gene is changed, both increased and decreased. We are therefore able to study the consequences of altered cholinergic tone in vivo. Our hypothesis is that changes in cholinergic tone produce specific molecular signatures in target brain areas that underlie alterations in cognitive function. Our studies aimed to elucidate the behavioural and molecular consequences of cholinergic dysfunction. Behavioral testing included classical learning and memory tests as well as sophisticated tasks using novel touch screens chambers to measure attention, learning and memory as well as cognitive flexibility. At the molecular level, the goal was to examine how long-term changes in cholinergic tone impact mechanisms regulating synaptic plasticity and neuronal health. Finally, by aging mouse models of cholinergic dysfunction we were able to elucidate the role that cholinergic tone plays in the classical pathological hallmarks of neurodegenerative disorders. Ultimately, by establishing the molecular signature of increased and decreased cholinergic tone in targeted brain regions (cortex and hippocampus) it may become possible to find novel targets for therapeutic interventions to improve cognitive deficits due to altered cholinergic tone