Aberrant Neuronal Dynamics during Working Memory Operations in the Aging HIV-Infected Brain

Impairments in working memory are among the most prevalent features of HIV-associated neurocognitive disorders (HAND), yet their origins are unknown, with some studies arguing that encoding operations are disturbed and others supporting deficits in memory maintenance. The current investigation directly addresses this issue by using a dynamic mapping approach to identify when and where processing in working memory circuits degrades. HIV-infected older adults and a demographically-matched group of uninfected controls performed a verbal working memory task during magnetoencephalography (MEG). Significant oscillatory neural responses were imaged using a beamforming approach to illuminate the spatiotemporal dynamics of neuronal activity. HIV-infected patients were significantly less accurate on the working memory task and their neuronal dynamics indicated that encoding operations were preserved, while memory maintenance processes were abnormal. Specifically, no group differences were detected during the encoding period, yet dysfunction in occipital, fronto-temporal, hippocampal, and cerebellar cortices emerged during memory maintenance. In addition, task performance in the controls covaried with occipital alpha synchronization and activity in right prefrontal cortices. In conclusion, working memory impairments are common and significantly impact the daily functioning and independence of HIV-infected patients. These impairments likely reflect deficits in the maintenance of memory representations, not failures to adequately encode stimuli

Sensorimotor Modulations by Cognitive Processes During Accurate Speech Discrimination: An EEG Investigation of Dorsal Stream Processing

Internal models mediate the transmission of information between anterior and posterior regions of the dorsal stream in support of speech perception, though it remains unclear how this mechanism responds to cognitive processes in service of task demands. The purpose of the current study was to identify the influences of attention and working memory on sensorimotor activity across the dorsal stream during speech discrimination, with set size and signal clarity employed to modulate stimulus predictability and the time course of increased task demands, respectively. Independent Component Analysis of 64–channel EEG data identified bilateral sensorimotor mu and auditory alpha components from a cohort of 42 participants, indexing activity from anterior (mu) and posterior (auditory) aspects of the dorsal stream. Time frequency (ERSP) analysis evaluated task-related changes in focal activation patterns with phase coherence measures employed to track patterns of information flow across the dorsal stream. ERSP decomposition of mu clusters revealed event-related desynchronization (ERD) in beta and alpha bands, which were interpreted as evidence of forward (beta) and inverse (alpha) internal modeling across the time course of perception events. Stronger pre-stimulus mu alpha ERD in small set discrimination tasks was interpreted as more efficient attentional allocation due to the reduced sensory search space enabled by predictable stimuli. Mu-alpha and mu-beta ERD in peri- and post-stimulus periods were interpreted within the framework of Analysis by Synthesis as evidence of working memory activity for stimulus processing and maintenance, with weaker activity in degraded conditions suggesting that covert rehearsal mechanisms are sensitive to the quality of the stimulus being retained in working memory. Similar ERSP patterns across conditions despite the differences in stimulus predictability and clarity, suggest that subjects may have adapted to tasks. In light of this, future studies of sensorimotor processing should consider the ecological validity of the tasks employed, as well as the larger cognitive environment in which tasks are performed. The absence of interpretable patterns of mu-auditory coherence modulation across the time course of speech discrimination highlights the need for more sensitive analyses to probe dorsal stream connectivity

EEG, MEG and neuromodulatory approaches to explore cognition: Current status and future directions

Neural oscillations and their association with brain states and cognitive functions have been object of extensive investigation over the last decades. Several electroencephalography (EEG) and magnetoencephalography (MEG) analysis approaches have been explored and oscillatory properties have been identified, in parallel with the technical and computational advancement. This review provides an up-to-date account of how EEG/MEG oscillations have contributed to the understanding of cognition. Methodological challenges, recent developments and translational potential, along with future research avenues, are discussed. Keywords: Cognition; Electrophysiology; Event-related-potentials; Neural oscillations; Neural synchronisation; Neuromodulatio

Brain Rhythms and Working Memory in Healthy Ageing

Working memory (WM), the ability to maintain and manipulate information to guide immediate cognitive processing, is vulnerable to age-related decline. Compared with younger adults, older adults demonstrate smaller WM capacities, a decrease in the ability to manipulate items held in WM, and a greater susceptibility to interference from distracting information. However, the neural underpinnings of WM decline in normal ageing are unclear. One technique that can be used to investigate the neurophysiological processes underlying cognition is electroencephalography (EEG), which non-invasively records activity from the awake human brain. The research described in this thesis uses EEG to investigate the neurophysiology of WM in healthy younger and older adults, with a particular focus on neural oscillatory activity in the alpha frequency range (8-12 Hz). As such, Chapter 1 consists of a review of the literature relevant to use of EEG to investigate the neurophysiology of WM performance in younger and older adults. WM performance deficits in older adults are particularly salient under increasing WM loads. Alpha oscillations have been shown to support verbal WM performance under high loads in younger adults, so the aim of Chapter 2 was to investigate the load-dependent modulation of alpha oscillatory power and frequency in younger and older adults during verbal WM. No age differences in verbal WM performance were found, and alpha power and alpha peak frequency were modulated in a similar task- and load-dependent manner in both younger and older adults. Another factor influencing WM performance in older adults is a decline in selective attention. Older adults perform worse on and are less able to modulate alpha power than younger adults in tasks involving cues about ‘where’ or ‘when’ a memory set will appear. The study described in Chapter 3 investigated whether providing cues towards memory set presentation time led to enhanced selective attention before the onset of the memory set, as indexed by alpha oscillatory activity. Predictive cues led to improved WM performance in both age groups, but alpha power in preparation of the memory set did not influence task performance. In Chapter 3, there were no age differences in WM performance when manipulating memory set presentation time. However, processing speed may not only limit the speed at which items are encoded into WM, but also the speed at which stimuli are transformed into a stable memory representation (i.e., WM consolidation). Therefore, the study contained in Chapter 4 investigated age differences in the ability to consolidate items into visual WM. In this study, older adults demonstrated poorer WM performance and slower consolidation at low WM loads, providing evidence for altered visual WM consolidation with age. Finally, visual WM is severely limited in capacity, highlighting the importance of encoding task-relevant information while ignoring distractors. The modulation of alpha oscillatory power has been implicated in the inhibition of distractors during WM in younger adults, but it is unclear if alpha power modulation also supports distractor inhibition in older adults. The study described in Chapter 5 investigated age differences in alpha oscillatory power before the onset of distractors during the visual WM retention period. Although there were no age differences in WM performance, younger adults demonstrated functionally relevant increases in alpha power before distractors, while older adults showed decreases in alpha power. Therefore, younger and older adults likely use different neural strategies to inhibit distractors during WM performance. Taken together, the results of the studies contained in this thesis provide further evidence for age-related changes to neural oscillatory activity, particularly in the alpha frequency band, even when age differences in WM performance are not present. These findings may have important implications for providing novel targets for detecting or preventing age-related cognitive decline.Thesis (Ph.D.) -- University of Adelaide, School of Biomedicine, 202

THE ROLE OF GAMMA OSCILLATIONS AND CORTICAL INHIBITION IN THE DEVELOPMENT OF WORKING MEMORY IN ADOLESCENCE

Adolescence is a dynamic period of social, cognitive, and biological changes. In particular, working memory, the ability to actively encode and maintain information over a short period of time, develops early in childhood and gradually increases in capacity and stability during adolescence. The precise neurophysiological mechanism by which working memory capacity increases during adolescence is unclear. The objective of this investigation was to evaluate the role of cortical gamma-band (\u3e 30 Hz) oscillations—which are associated with working memory in adults—for the development of working memory capacity in adolescents, and to identify the extent to which the temporal profile of gamma-aminobutyric acid (GABA)-mediated cortical inhibition underlies these changes. I hypothesized that cortical gamma-band rhythms would become faster during adolescence in a manner that supports improved working memory capacity, and that the kinetics of cortical inhibition would also become faster to support these faster rhythms. To this end, I recruited two cohorts of typically developing children (10 – 12 years) and adolescents (15 – 17 years) for a combined electrophysiology (EEG) and transcranial magnetic stimulation (TMS) study. First, I investigated the endogenous rhythmic activity generated by children and adolescence when performing a serially presented working memory task of varying set size. I found evidence of maturation in the generation of gamma-band rhythms which differed in power between groups, but identified no effects of a change in the central frequency of gamma-band activity. Next, I used TMS to exogenously evoke oscillatory activity in the left prefrontal cortex to identify the cortical natural (i.e., resonant) frequency. Using this measure, I found that adolescents exhibit higher median natural frequencies (MdCHILD = 16 Hz; MdADO = 24 Hz, Z = 2.35, p = 0.009), but that sex may play a mediating role when this change emerges. While this measure positively correlated with working memory capacity (rs = 0.47, p = 0.007), this effect disappeared when controlling for age and sex (rs = 0.29, p = 0.128). Finally, I investigated the role of inhibitory timing as a potential mechanism for improved cognition and increased natural frequency using classic paired pulse TMS techniques. Six inter-pulse intervals (IPI) in the range of short- and long-intracortical inhibition (SICI, LICI) were tested to assess the temporal characteristics of GABA type-A and type-B receptor-mediated inhibition (GABAAR, GABABR, respectively). For SICI, I found alpha-band (9-14 Hz) facilitation in children and suppression in adolescents. For LICI, adolescents demonstrated greater suppression of gamma-band power compared to children, and equal suppression to children in the beta-band (15-30 Hz). I found no evidence for a change in timing of SICI- or LICI-induced modulations though LICI suppression of gamma- and beta-band power correlated with working memory capacity. The overall hypothesis that the prefrontal cortex can produce faster rhythms during adolescent development was supported, but the hypothesized relationships between those rhythms, working memory capacity, and the timing of GABA-mediated inhibition were not. Rather, I observed several developmental differences in oscillatory power that suggest excitation-inhibition balance underlies the developmental increases in working memory capacity and gamma-band synchrony

The Effects of Neurocognitive Aging on Sentence Processing

Across the lifespan, successful language comprehension is crucial for continued participation in everyday life. The success of language comprehension relies on the intact functioning of both language-specific processes as well as domain-general cognitive processes that support language comprehension in general. This two-sided nature of successful language comprehension may contribute to the two diverging observations in healthy aging: the preservation and the decline of language comprehension on both the cognitive and the neural level. To date, our understanding of these two competing facets is incomplete and unclear. While greater language experience comes with increasing age, most domain-general cognitive functions, like verbal working memory, decline in healthy aging. The here presented thesis shows that when the electrophysiological network relevant for verbal working memory is already compromised at rest, language comprehension declines in older adults. Moreover, it could be shown that, as verbal working memory capacity declines with age, resources may be- come insufficient to successfully encode language-specific information into memory, yielding language comprehension difficulties in old age. Age differences in the electrophysiological dynamics underlying sentence encoding indicate that the encoding of detailed information may increasingly be inhibited throughout the lifespan, possibly to avoid overloading the verbal working memory. However, limitations in verbal working memory could be attenuated by the use of language-specific constraints. That is, semantic and syntactic constraints can be used to establish relations between words which reduces the memory load from individual word information to information about word group. Here, it was found that older adults do not benefit from the use of syntactic constraints as much as younger adults while the benefit of using semantic constraints was comparable across age. Overall, the here presented thesis suggests that previous findings on language comprehension in healthy aging are not contradictory but rather converge on a simultaneous combination of selective preservation and decline of various language-specific processes, burdened by domain-general neurocognitive aging

The oscillatory mechanisms of working memory maintenance

Working memory (WM) is a cognitive process which allows for maintenance of information that is no longer perceived. Although theoretical models have recognized that working memory involves interactions across cell assemblies in multiple brain areas, the exact neural mechanisms which support this process remain unknown. In this thesis I investigate the neural dynamics in the human hippocampus, the ventral, dorsal and frontal cortex as well as the long-range network connectivity across these brain areas to understand how such a distributed network allows for maintenance of various information pieces in WM. The results described here support a model in which working memory relies on dynamic interactions across frequencies (the cross-frequency coupling, CFC) in a distributed network of cortical areas coordinated by the prefrontal cortex. In particular, maintenance of information during a delay period selectively involves the hippocampus, dorsal and ventral visual stream as well as the prefrontal cortex each of which represents different features. The hippocampus contributes to this large network specifically by representing multiple items in working memory. In two independent experiments I observed that the low-frequency activity (a marker of neural inhibition) was linearly reduced across memory loads. Importantly, the hippocampus showed very prominent low-frequency power during maintenance of a single item suggesting that during this condition the neural processing was strongly inhibited. In turn, the broadband gamma activity was linearly increasing as a function of memory load. This pattern of results may be interpreted as reflecting an increased involvement of the hippocampus in representing longer sequences. Importantly, the low-frequency decrease was not static but fluctuated periodically between two different modes. One of the modes was characterized by the load-dependent power decreases and reduced cross-frequency coupling (memory activation mode) whereas the other mode was reflected by the load-independent high levels of power and increased coupling strength (load-independent mode). Crucially, these modes were temporally organized by the phase of an endogenous delta rhythm forming a “hierarchy of oscillations”. This periodicity was essential for the successful performance. Finally, during the memory activation mode the WM capacity limit was inter-individually correlated with the peak frequency change as predicted by the multiplexing model of WM. All these effects were subsequently replicated in an independent dataset. These results suggest that the hippocampus is involved in WM maintenance showing periodic fluctuations between two different oscillatory modes. Parameters of the hippocampal iEEG signal correlate with individual WM capacity, specifically during the memory activation mode. The ventral and dorsal visual stream each contributes to the distributed WM network by representing configuration and spatial information, respectively. Specifically, the alpha power in the ventral visual stream was decreased during maintenance of face identities. In turn, the alpha power was desynchronized in the dorsal visual stream while participants were maintaining face orientations. This shows that the alpha power double dissociates between the feature specific networks in the ventral and dorsal visual stream. These effects are further interpreted as reflecting selective involvement of the dorsal and ventral visual pathway depending on the maintained features. Importantly, each of the visual streams was selectively synchronized with the prefrontal cortex depending on the memory condition and the alpha power. This corroborates a central prediction from the gating by inhibition model which assumes that the increased alpha power serves as the mechanism for gating of information by inhibiting task redundant pathways. Moreover, during maintenance of information the phase of alpha modulated the amplitude of high-frequency activity both in the dorsal and ventral visual stream. Additionally,the low-frequency phase in the prefrontal cortex modulated high-frequency activity both in the dorsal and ventral visual stream. These results suggest that both the dorsal and ventral visual streams are selectively involved during maintenance of distinct features (i.e. face orientation and identity, respectively). They also indicate that the prefrontal cortex selectively gets synchronized with the visual regions depending on the alpha power in that region and the maintained feature. Finally, the activity in the prefrontal cortex influences processing across long distance as evident from changes in the phase synchrony with the visual cortical areas and by modulating gamma power in the visual cortical regions. It is also noted that the ventrolateral prefrontal cortex (vlPFC) contains information regarding abstract rules (i.e. response mapping). In particular, using a multivariate decoding approach I found that the local field potentials recorded from the vlPFC dissociate between different types of responses. At the same time I observed no evidence for the load-dependent or stimulus-specific changes in that brain region. The null effect should be treated with caution. Nevertheless, the current results suggest that the vlPFC may contribute to working memory by processing of abstract rules such as a mapping between the stimulus and the response. Furthermore, I found that the alpha power dependent duty cycle in the vlPFC constrains the duration of the gamma burst which has been suggested as a mechanism for neural inhibition. This finding is important because such a property of the alpha activity has never been observed in a brain region other than the primary sensory cortex. Together, the results presented in this thesis support a model according to which the working memory is a complex and highly dynamic process engaging hierarchies of oscillations across multiple cortical regions. In particular, the hippocampus is important for the multi-item WM. The dorsal and ventral visual streams are relevant for distinct visual features. Finally, the prefrontal cortex represents abstract rules and influences processing in other cortical regions likely providing a top down control over these regions

“Too Many betas do not Spoil the Broth”: The Role of Beta Brain Oscillations in Language Processing

Over the past 20 years, brain oscillations have proven to be a gateway to the understanding of cognitive processes. It has been shown that different neurocognitive aspects of language processing are associated with brain oscillations at various frequencies. Frequencies in the beta range (13–30 Hz) turned out to be particularly important with respect to cognitive and linguistic manipulations during language processing. Beta activity has been involved in higher-order linguistic functions such as the discrimination of word categories and the retrieval of action semantics as well as semantic memory, and syntactic binding processes, which support meaning construction during sentence processing. From a neurophysiological point of view, the important role of the beta frequencies for such a complex cognitive task as language processing seems reasonable. Experimental evidence suggests that frequencies in the beta range are ideal for maintaining and preserving the activity of neuronal assemblies over time. In particular, recent computational and experimental evidence suggest that beta frequencies are important for linking past and present input and the detection of novelty of stimuli, which are essential processes for language perception as well as production. In addition, the beta frequency’s role in the formation of cell assemblies underlying short-term memory seems indispensable for language analysis. Probably the most important point is the well-known relation of beta oscillations with motor processes. It can be speculated that beta activities reflect the close relationship between language comprehension and motor functions, which is one of the core claims of current theories on embodied cognition. In this article, the importance of beta oscillations for language processing is reviewed based both on findings in psychophysiological and neurophysiological literature