Effects of risk factors on longitudinal changes in brain structure and function in the progression of AD.

INTRODUCTION: Past research on Alzheimer's disease (AD) has focused on biomarkers, cognition, and neuroimaging as primary predictors of its progression, albeit additional ones have recently gained attention. When turning to the prediction of the progression from one stage to another, one could benefit from the joint assessment of imaging-based biomarkers and risk/protective factors. METHODS: We included 86 studies that fulfilled our inclusion criteria. RESULTS: Our review summarizes and discusses the results of 30 years of longitudinal research on brain changes assessed with neuroimaging and the risk/protective factors and their effect on AD progression. We group results into four sections: genetic, demographic, cognitive and cardiovascular, and lifestyle factors. DISCUSSION: Given the complex nature of AD, including risk factors could prove invaluable for a better understanding of AD progression. Some of these risk factors are modifiable and could be targeted by potential future treatments.

Cognitive tasks propagate the neural entrainment in response to a visual 40 Hz stimulation in humans.

Introduction: Alzheimer's disease is one of the great challenges in the coming decades, and despite great efforts, a widely effective disease-modifying therapy in humans remains elusive. One particular promising non-pharmacological therapy that has received increased attention in recent years is based on the Gamma ENtrainment Using Sensory stimulation (GENUS), a high-frequency neural response elicited by a visual and/or auditory stimulus at 40 Hz. While this has shown to be effective in animal models, studies on human participants have reported varying success. The current work hypothesizes that the varying success in humans is due to differences in cognitive workload during the GENUS sessions. Methods: We recruited a cohort of 15 participants who underwent a scalp-EEG recording as well as one epilepsy patient who was implanted with 50 subdural surface electrodes over temporo-occipital and temporo-basal cortex and 14 depth contacts that targeted the hippocampus and insula. All participants completed several GENUS sessions, in each of which a different cognitive task was performed. Results: We found that the inclusion of a cognitive task during the GENUS session not only has a positive effect on the strength and extent of the gamma entrainment, but also promotes the propagation of gamma entrainment to additional neural areas including deep ones such as hippocampus which were not recruited when no cognitive task was required from the participants. The latter is of particular interest given that the hippocampal complex is considered to be one of the primary targets for AD therapies. Discussion: This work introduces a possible improvement strategy for GENUS therapy that might contribute to increasing the efficacy of the therapy or shortening the time needed for the positive outcome.

Practical real-time MEG-based neural interfacing with optically pumped magnetometers.

BACKGROUND: Brain-computer interfaces decode intentions directly from the human brain with the aim to restore lost functionality, control external devices or augment daily experiences. To combine optimal performance with wide applicability, high-quality brain signals should be captured non-invasively. Magnetoencephalography (MEG) is a potent candidate but currently requires costly and confining recording hardware. The recently developed optically pumped magnetometers (OPMs) promise to overcome this limitation, but are currently untested in the context of neural interfacing. RESULTS: In this work, we show that OPM-MEG allows robust single-trial analysis which we exploited in a real-time 'mind-spelling' application yielding an average accuracy of 97.7%. CONCLUSIONS: This shows that OPM-MEG can be used to exploit neuro-magnetic brain responses in a practical and flexible manner, and opens up new avenues for a wide range of new neural interface applications in the future.

Electrophysiological Proxy of Cognitive Reserve Index.

Cognitive reserve (CR) postulates that individual differences in task performance can be attributed to differences in the brain's ability to recruit additional networks or adopt alternative cognitive strategies. Variables that are descriptive of lifetime experience such as socioeconomic status, educational attainment, and leisure activity are common proxies of CR. CR is mostly studied using neuroimaging techniques such as functional MRI (fMRI) in which case individuals with a higher CR were observed to activate a smaller brain network compared to individuals with a lower CR, when performing a task equally effectively (higher efficiency), and electroencephalography (EEG) where a particular EEG component (P300) that reflects the attention and working memory load, has been targeted. Despite the contribution of multiple factors such as age, education (formal and informal), working, leisure, and household activities in CR formation, most neuroimaging studies, and those using EEG in particular, focus on formal education level only. The aim of the current EEG study is to investigate how the P300 component, evoked in response to an oddball paradigm, is associated with other components of CR besides education, such as working and leisure activity in older adults. We have used hereto a recently introduced CR index questionnaire (CRIq) that quantifies both professional and leisure activities in terms of their cognitive demand and number of years practiced, as well as a data-driven approach for EEG analysis. We observed complex relationships between CRIq subcomponents and P300 characteristics. These results are especially important given that, unlike previous studies, our measurements (P300 and CRIq) do not require active use of the same executive function and, thus, render our results free of a collinearity bias.

High-gamma oscillations precede visual steady-state responses: A human electrocorticography study.

The robust steady-state cortical activation elicited by flickering visual stimulation has been exploited by a wide range of scientific studies. As the fundamental neural response inherits the spectral properties of the gazed flickering, the paradigm has been used to chart cortical characteristics and their relation to pathologies. However, despite its widespread adoption, the underlying neural mechanisms are not well understood. Here, we show that the fundamental response is preceded by high-gamma (55-125 Hz) oscillations which are also synchronised to the gazed frequency. Using a subdural recording of the primary and associative visual cortices of one human subject, we demonstrate that the latencies of the high-gamma and fundamental components are highly correlated on a single-trial basis albeit that the latter is consistently delayed by approximately 55 ms. These results corroborate previous reports that top-down feedback projections are involved in the generation of the fundamental response, but, in addition, we show that trial-to-trial variability in fundamental latency is paralleled by a highly similar variability in high-gamma latency. Pathology- or paradigm-induced alterations in steady-state responses could thus originate either from deviating visual gamma responses or from aberrations in the neural feedback mechanism. Experiments designed to tease apart the two processes are expected to provide deeper insights into the studied paradigm.

Localization of deep brain activity with scalp and subdural EEG.

To what extent electrocorticography (ECoG) and electroencephalography (scalp EEG) differ in their capability to locate sources of deep brain activity is far from evident. Compared to EEG, the spatial resolution and signal-to-noise ratio of ECoG is superior but its spatial coverage is more restricted, as is arguably the volume of tissue activity effectively measured from. Moreover, scalp EEG studies are providing evidence of locating activity from deep sources such as the hippocampus using high-density setups during quiet wakefulness. To address this question, we recorded a multimodal dataset from 4 patients with refractory epilepsy during quiet wakefulness. This data comprises simultaneous scalp, subdural and depth EEG electrode recordings. The latter was located in the hippocampus or insula and provided us with our "ground truth" for source localization of deep activity. We applied independent component analysis (ICA) for the purpose of separating the independent sources in theta, alpha and beta frequency band activity. In all patients subdural- and scalp EEG components were observed which had a significant zero-lag correlation with one or more contacts of the depth electrodes. Subsequent dipole modeling of the correlating components revealed dipole locations that were significantly closer to the depth electrodes compared to the dipole location of non-correlating components. These findings support the idea that components found in both recording modalities originate from neural activity in close proximity to the depth electrodes. Sources localized with subdural electrodes were ~70% closer to the depth electrode than sources localized with EEG with an absolute improvement of around ~2cm. In our opinion, this is not a considerable improvement in source localization accuracy given that, for clinical purposes, ECoG electrodes were implanted in close proximity to the depth electrodes. Furthermore, the ECoG grid attenuates the scalp EEG, due to the electrically isolating silastic sheets in which the ECoG electrodes are embedded. Our results on dipole modeling show that the deep source localization accuracy of scalp EEG is comparable to that of ECoG. SIGNIFICANCE STATEMENT: Deep and subcortical regions play an important role in brain function. However, as joint recordings at multiple spatial scales to study brain function in humans are still scarce, it is still unresolved to what extent ECoG and EEG differ in their capability to locate sources of deep brain activity. To the best of our knowledge, this is the first study presenting a dataset of simultaneously recorded EEG, ECoG and depth electrodes in the hippocampus or insula, with a focus on non-epileptiform activity (quiet wakefulness). Furthermore, we are the first study to provide experimental findings on the comparison of source localization of deep cortical structures between invasive and non-invasive brain activity measured from the cortical surface.

Overlapping connectivity patterns during semantic processing of abstract and concrete words revealed with multivariate Granger Causality analysis.

. Abstract, unlike concrete, nouns refer to notions beyond our perception. Even though there is no consensus among linguists as to what exactly constitutes a concrete or abstract word, neuroscientists found clear evidence of a "concreteness" effect. This can, for instance, be seen in patients with language impairments due to brain injury or developmental disorder who are capable of perceiving one category better than another. Even though the results are inconclusive, neuroimaging studies on healthy subjects also provide a spatial and temporal account of differences in the processing of abstract versus concrete words. A description of the neural pathways during abstract word reading, the manner in which the connectivity patterns develop over the different stages of lexical and semantic processing compared to that of concrete word processing are still debated. We conducted a high-density EEG study on 24 healthy young volunteers using an implicit categorization task. From this, we obtained high spatio-temporal resolution data and, by means of source reconstruction, reduced the effect of signal mixing observed on scalp level. A multivariate, time-varying and directional method of analyzing connectivity based on the concept of Granger Causality (Partial Directed Coherence) revealed a dynamic network that transfers information from the right superior occipital lobe along the ventral and dorsal streams towards the anterior temporal and orbitofrontal lobes of both hemispheres. Some regions along these pathways appear to be primarily involved in either receiving or sending information. A clear difference in information transfer of abstract and concrete words was observed during the time window of semantic processing, specifically for information transferred towards the left anterior temporal lobe. Further exploratory analysis confirmed a generally stronger connectivity pattern for processing concrete words. We believe our study could guide future research towards a more refined theory of abstract word processing in the brain.

Semantic and perceptual priming activate partially overlapping brain networks as revealed by direct cortical recordings in humans.

Facilitation of object processing in the brain due to a related context (priming) can be influenced by both semantic connections and perceptual similarity. It is thus important to discern these two when evaluating the spatio-temporal dynamics of primed object processing. The repetition-priming paradigm frequently used to study perceptual priming is, however, unable to differentiate between the mentioned priming effects, possibly leading to confounded results. In the current study, we recorded brain signals from the scalp and cerebral convexity of nine patients with refractory epilepsy in response to related and unrelated image-pairs, all of which shared perceptual features while only related ones had a semantic connection. While previous studies employing a repetition-priming paradigm observed largely overlapping networks between semantic and perceptual priming effects, our results suggest that this overlap is only partial (both temporally and spatially). These findings stress the importance of controlling for perceptual features when studying semantic priming.

Decoding Steady-State Visual Evoked Potentials From Electrocorticography.

We report on a unique electrocorticography (ECoG) experiment in which Steady-State Visual Evoked Potentials (SSVEPs) to frequency- and phase-tagged stimuli were recorded from a large subdural grid covering the entire right occipital cortex of a human subject. The paradigm is popular in EEG-based Brain Computer Interfacing where selectable targets are encoded by different frequency- and/or phase-tagged stimuli. We compare the performance of two state-of-the-art SSVEP decoders on both ECoG- and scalp-recorded EEG signals, and show that ECoG-based decoding is more accurate for very short stimulation lengths (i.e., less than 1 s). Furthermore, whereas the accuracy of scalp-EEG decoding benefits from a multi-electrode approach, to address interfering EEG responses and noise, ECoG decoding enjoys only a marginal improvement as even a single electrode, placed over the posterior part of the primary visual cortex, seems to suffice. This study shows, for the first time, that EEG-based SSVEP decoders can in principle be applied to ECoG, and can be expected to yield faster decoding speeds using less electrodes.

Effect of word association on linguistic event-related potentials in moderately to mildly constraining sentences.

The processing of word associations in sentence context depends on several factors. EEG studies have shown that when the expectation of the upcoming word is high (high semantic constraint), the within-sentence word association plays a negligible role, whereas in the opposite case, when there is no expectation (as in pseudo-sentences), the role of word association becomes more pronounced. However, what happens when the expectations are not high (mild to moderate semantic constraint) is not yet clear. By adopting a cross-factorial design, crossing sentence congruity with within-sentence word association, our EEG recordings show that association comes into play during semantic processing of the word only when the sentence is meaningless. We also performed an exploratory source localization analysis of our EEG recordings to chart the brain regions putatively implicated in processing the said factors and showed its complementarity to EEG temporal analysis. This study furthers our knowledge on sentence processing and the brain networks involved in it.

Representation of steady-state visual evoked potentials elicited by luminance flicker in human occipital cortex: An electrocorticography study.

Despite the widespread use of steady-state visual evoked potentials (SSVEPs) elicited by luminance flicker in clinical and research settings, their spatial and temporal representation in the occipital cortex largely remain elusive. We performed intracranial-EEG recordings in response to targets flickering at frequencies from 11 to 15 Hz using a subdural electrode grid covering the entire right occipital cortex of a human subject, and we were able to consistently locate the gazed stimulus frequency at the posterior side of the primary visual cortex (V1). Peripheral flickering, undetectable in scalp-EEG, elicited activations in the interhemispheric fissure at locations consistent with retinotopic maps. Both foveal and peripheral activations spatially coincided with activations in the high gamma band. We detected localized alpha synchronization at the lateral edge of V2 during stimulation and transient post-stimulation theta band activations at the posterior part of the occipital cortex. Scalp-EEG exhibited only a minor occipital post-stimulation theta activation, but a strong transient frontal activation.

Event Related Potential Study of Language Interaction in Bilingual Aphasia Patients.

Half of the global population can be considered bilingual. Nevertheless when faced with patients with aphasia, clinicians and therapists usually ignore the patient's second language (L2) albeit its interference in first language (L1) processing has been shown. The excellent temporal resolution by which each individual linguistic component can be gaged during word-processing, promoted the event-related potential (ERP) technique for studying language processing in healthy bilinguals and monolingual aphasia patients. However, this technique has not yet been applied in the context of bilingual aphasia. In the current study, we report on L2 interference in L1 processing using the ERP technique in bilingual aphasia. We tested four bilingual- and one trilingual patients with aphasia, as well as several young and older (age-matched with patients) healthy subjects as controls. We recorded ERPs when subjects were engaged in a semantic association judgment task on 122 related and 122 unrelated Dutch word-pairs (prime and target words). In 61 related and 61 unrelated word-pairs, an inter-lingual homograph was used as prime. In these word-pairs, when the target was unrelated to the prime in Dutch (L1), it was associated to the English (L2) meaning of the homograph. Results showed a significant effect of homograph use as a prime on early and/or late ERPs in response to word-pairs related in Dutch or English. Each patient presented a unique pattern of L2 interference in L1 processing as reflected by his/her ERP image. These interferences depended on the patient's pre- and post-morbid L2 proficiency. When the proficiency was high, the L2 interference in L1 processing was higher. Furthermore, the mechanism of interference in patients that were pre-morbidly highly proficient in L2 additionally depended on the frequency of pre-morbid L2 exposure. In summary, we showed that the mechanism behind L2 interference in L1 processing in bilingual patients with aphasia depends on a complex interaction between pre- and post-morbid L2 proficiency, pre- and post-morbid L2 exposure, impairment and the presented stimulus (inter-lingual homographs). Our ERP study complements the usually adopted behavioral approach by providing new insights into language interactions on the level of individual linguistic components in bilingual patients with aphasia.

Semantic Features Reveal Different Networks During Word Processing: An EEG Source Localization Study.

The neural principles behind semantic category representation are still under debate. Dominant theories mostly focus on distinguishing concrete from abstract concepts but, in such theories, divisions into categories of concrete concepts are more developed than for their abstract counterparts. An encompassing theory on semantic category representation could be within reach when charting the semantic attributes that are capable of describing both concept types. A good candidate are the three semantic dimensions defined by Osgood (potency, valence, arousal). However, to show to what extent they affect semantic processing, specific neuroimaging tools are required. Electroencephalography (EEG) is on par with the temporal resolution of cognitive behavior and source reconstruction. Using high-density set-ups, it is able to yield a spatial resolution in the scale of millimeters, sufficient to identify anatomical brain parcellations that could differentially contribute to semantic category representation. Cognitive neuroscientists traditionally focus on scalp domain analysis and turn to source reconstruction when an effect in the scalp domain has been detected. Traditional methods will potentially miss out on the fine-grained effects of semantic features as they are possibly obscured by the mixing of source activity due to volume conduction. For this reason, we have developed a mass-univariate analysis in the source domain using a mixed linear effect model. Our analyses reveal distinct networks of sources for different semantic features that are active during different stages of lexico-semantic processing of single words. With our method we identified differences in the spatio-temporal activation patterns of abstract and concrete words, high and low potency words, high and low valence words, and high and low arousal words, and in this way shed light on how word categories are represented in the brain.

A new insight into sentence comprehension: The impact of word associations in sentence processing as shown by invasive EEG recording.

The effect of word association on sentence processing is still a matter of debate. Some studies observe no effect while others found a dependency on sentence congruity or an independent effect. In an attempt to separate the effects of sentence congruity and word association in the spatio-temporal domain, we jointly recorded scalp- and invasive-EEG (iEEG). The latter provides highly localized spatial (unlike scalp-EEG) and high temporal (unlike fMRI) resolutions. We recorded scalp- and iEEG in three patients with refractory epilepsy. The stimuli consisted of 280 sentences with crossed factors of sentence congruity and within sentence word-association. We mapped semantic retrieval processes involved in sentence comprehension onto the left temporal cortex and both hippocampi, and showed for the first time that certain localized regions participate in the processing of word-association in sentence context. Furthermore, simultaneous recording of scalp- and iEEG gave us a direct overview of signal change due to its propagation across the head tissues.

ERP Response Unveils Effect of Second Language Manipulation on First Language Processing.

Lexical access in bilinguals has been considered either selective or non-selective and evidence exists in favor of both hypotheses. We conducted a linguistic experiment to assess whether a bilingual's language mode influences the processing of first language information. We recorded event related potentials during a semantic priming paradigm with a covert manipulation of the second language (L2) using two types of stimulus presentations (short and long). We observed a significant facilitation of word pairs related in L2 in the short version reflected by a decrease in N400 amplitude in response to target words related to the English meaning of an inter-lingual homograph (homograph-unrelated group). This was absent in the long version, as the N400 amplitude for this group was similar to the one for the control-unrelated group. We also interviewed the participants whether they were aware of the importance of L2 in the experiment. We conclude that subjects participating in the long and short versions were in different language modes: closer to monolingual mode for the long and closer to bilingual mode for the short version; and that awareness about covert manipulation of L2 can influence the language mode, which in its turn influences the processing of the first language.

Language processing in bilingual aphasia: a new insight into the problem.

There is increasing evidence that a bilingual person should not be considered as two monolinguals in a single body, a view that has gradually been adopted in the diagnosis and treatment of bilingual aphasia. However, its investigation is complicated due to the large variety in possible language combinations, pre- and postmorbid language proficiencies, and age of second language acquisition. Furthermore, the tests and tasks used to assess linguistic capabilities differ in almost every study, hindering a direct comparison of their outcomes. Behavioral, electrophysiological, and neuroimaging data from healthy population show that the processing of second language domains (semantics, syntax, morphology) depends on factors such as age and method of acquisition, proficiency level and environment in which the second language was acquired. A number of single and multiple case reports that rely on behavioral testing of bilingual aphasics replicate these results. Additionally, they show that the patient's performance depends on the size and location of the lesion, as well as language typology and morphological characteristics. Furthermore, the impairment and recovery patterns and recovery generalization from treated to untreated language depend on the lexical and orthographic distances between the two languages. For healthy bilinguals, language processing is usually studied in comparison to monolinguals. We advocate that a good starting point for identifying patterns specific for bilingual aphasia is to compare patient studies of bilinguals and monolinguals.

Sentence Context Prevails Over Word Association in Aphasia Patients with Spared Comprehension: Evidence from N400 Event-Related Potential.

Behavioral and event-related potential (ERP) studies on aphasia patients showed that lexical information is not lost but rather its integration into the working context is hampered. Studies have been conducted on the processing of sentence-level information (meaningful versus meaningless) and of word-level information (related versus unrelated) in aphasia patients, but we are not aware of any study that assesses the relationship between the two. In healthy subjects the processing of a single word in a sentence context has been studied using the N400 ERP. It was shown that, even when there is only a weak expectation of a final word in a sentence, this expectation will dominate word relatedness. In order to study the effect of semantic relatedness between words in sentence processing in aphasia patients, we conducted a crossed-design ERP study, crossing the factors of word relatedness and sentence congruity. We tested aphasia patients with mild to minimum comprehension deficit and healthy young and older (age-matched with our patients) controls on a semantic anomaly judgment task when simultaneously recording EEG. Our results show that our aphasia patient's N400 amplitudes in response to the sentences of our crossed-design study were similar to those of our age-matched healthy subjects. However, we detected an increase in the N400 ERP latency in those patients, indicating a delay in the integration of the new word into the working context. Additionally, we observed a positive correlation between comprehension level of those patients and N400 effect in response to meaningful sentences without word relatedness contrasted to meaningless sentences without word relatedness.