Asynchronous, online spaced-repetition training alleviates word-finding difficulties in aphasia.

Word-finding difficulties for naming everyday objects are often prevalent in aphasia. Traditionally, treating these difficulties has involved repeated drilling of troublesome items with a therapist. Spaced repetition schedules can improve the efficiency of such training. However, spaced repetition in a therapy environment can be both difficult to implement and time-consuming. The current study evaluated the potential utility of automated, asynchronous, online spaced repetition training for the treatment of word-finding difficulties in individuals with aphasia. Twenty-one participants completed a two-week training study, completing approximately 60 minutes per day of asynchronous online drilling. The training items were identified using a pretest, and word-finding difficulties were evaluated both at the end of training (i.e., a post-test) and four weeks later (i.e., a retention test). The trained items were separated into three different spaced-repetition schedules: (1) Short-spacing; (2) Long-spacing; and (3) Adaptive-spacing. At the retention-test, all trained items outperformed non-trained items in terms of accuracy and reaction time. Further, preliminary evidence suggested a potential reaction time advantage for the adaptive-spacing condition. Overall, online, asynchronous spaced repetition training appears to be effective in treating word-finding difficulties in aphasia. Further research will be required to determine if different spaced repetition schedules can be leveraged to enhance this effect.

Electrophysiological abnormalities as indicators of early-stage pathology in Primary Progressive Aphasia (PPA): A case study in semantic variant PPA.

Language induced and spontaneous oscillatory activity was measured using MEG in a patient with the semantic variant of Primary Progressive Aphasia (svPPA) and 15 healthy controls.The patient showed oscillatory slowing in the left anterior temporal lobe (ATL) that extended into non-atrophied brain tissue in left and right frontal areas. The white matter connections were reduced to the left and right ATL and left frontal regions, exhibiting electrophysiological abnormalities. Altered diffusion metrics in all four language tracts, indicted compromised white matter integrity. Task-related and spontaneous oscillatory abnormalities can indicate early neurodegeneration in svPPA, providing promising targets for intervention.

Sensitivity of amplitude and phase based MEG measures of interhemispheric connectivity during unilateral finger movements.

Interactions between different brain regions can be revealed by dependencies between their neuronal oscillations. We examined the sensitivity of different oscillatory connectivity measures in revealing interhemispheric interactions between primary motor cortices (M1s) during unilateral finger movements. Based on frequency, amplitude, and phase of the oscillations, a number of metrics have been developed to measure connectivity between brain regions, and each metric has its own strengths, weaknesses, and pitfalls. Taking advantage of the well-known movement-related modulations of oscillatory amplitude in M1s, this study compared and contrasted a number of leading connectivity metrics during distinct phases of oscillatory power changes. Between M1s during unilateral movements, we found that phase-based metrics were effective at revealing connectivity during the beta (15-35 Hz) rebound period linked to movement termination, but not during the early period of beta desynchronization occurring during the movement itself. Amplitude correlation metrics revealed robust connectivity during both periods. Techniques for estimating the direction of connectivity had limited success. Granger Causality was not well suited to studying these connections because it was strongly confounded by differences in signal-to-noise ratio linked to modulation of beta amplitude occurring during the task. Phase slope index was suggestive but not conclusive of a unidirectional influence between motor cortices during the beta rebound. Our findings suggest that a combination of amplitude and phase-based metrics is likely required to fully characterize connectivity during task protocols that involve modulation of oscillatory power, and that amplitude-based metrics appear to be more sensitive despite the lack of directional information.

Contralesional Cathodal Transcranial Direct Current Stimulation Does Not Enhance Upper Limb Function in Subacute Stroke: A Pilot Randomized Clinical Trial.

Transcranial direct current stimulation (tDCS) has the potential to improve upper limb motor outcomes after stroke. According to the assumption of interhemispheric inhibition, excessive inhibition from the motor cortex of the unaffected hemisphere to the motor cortex of the affected hemisphere may worsen upper limb motor recovery after stroke. We evaluated the effects of active cathodal tDCS of the primary motor cortex of the unaffected hemisphere (ctDCSM1UH) compared to sham, in subjects within 72 hours to 6 weeks post ischemic stroke. Cathodal tDCS was intended to inhibit the motor cortex of the unaffected hemisphere and hence decrease the inhibition from the unaffected to the affected hemisphere and enhance motor recovery. We hypothesized that motor recovery would be greater in the active than in the sham group. In addition, greater motor recovery in the active group might be associated with bigger improvements in measures in activity and participation in the active than in the sham group. We also explored, for the first time, changes in cognition and sleep after ctDCSM1UH. Thirty subjects were randomized to six sessions of either active or sham ctDCSM1UH as add-on interventions to rehabilitation. The NIH Stroke Scale (NIHSS), Fugl-Meyer Assessment of Motor Recovery after Stroke (FMA), Barthel Index (BI), Stroke Impact Scale (SIS), and Montreal Cognitive Assessment (MoCA) were assessed before, after treatment, and three months later. In the intent-to-treat (ITT) analysis, there were significant GROUP∗TIME interactions reflecting stronger gains in the sham group for scores in NIHSS, FMA, BI, MoCA, and four SIS domains. At three months post intervention, the sham group improved significantly compared to posttreatment in FMA, NIHSS, BI, and three SIS domains while no significant changes occurred in the active group. Also at three months, NIHSS improved significantly in the sham group and worsened significantly in the active group. FMA scores at baseline were higher in the active than in the sham group. After adjustment of analysis according to baseline scores, the between-group differences in FMA changes were no longer statistically significant. Finally, none of the between-group differences in changes in outcomes after treatment were considered clinically relevant. In conclusion, active CtDCSM1UH did not have beneficial effects, compared to sham. These results were consistent with other studies that applied comparable tDCS intensities/current densities or treated subjects with severe upper limb motor impairments during the first weeks post stroke. Dose-finding studies early after stroke are necessary before planning larger clinical trials.

Interhemispheric connectivity during lateralized lexical decision.

The well-established right visual field (RVF-lh) advantage in word recognition is commonly attributed to the typical left hemisphere dominance in language; words presented to the LVF-rh are processed less efficiently due to the need for transcallosal transfer from the right to left hemisphere. The exact stage for this hemispheric transfer is currently unsettled. Some studies suggest that transfer occurs at very early stages between primary visual regions, whereas other studies suggest that transfer occurs between the left visual word form area and its right hemisphere homolog. This study explores these conflicting accounts and finds evidence for both. Participants conducted a lateralized lexical decision task with both unilateral and bilateral display conditions. Connectivity analyses were conducted from magnetoencephalography signals that were localized to the left middle occipital gyrus (LMOG), right middle occipital gyrus (RMOG), left visual word form area (LVWFA), and right visual word form area (RVWA). Results from unilateral trials showed asymmetrical interhemispheric connectivity from the RMOG to LMOG and symmetrical interhemispheric connectivity between the LVWFA and RVWFA. Furthermore, bilateral presentations led to reduced interhemispheric connectivity between both homologous region of interest pairs. Together, these results suggest that lateralized word recognition involves multiple stages of interhemispheric interactions and that these interactions are reduced with bilateral displays.

Electrophysiological signatures of phonological and semantic maintenance in sentence repetition.

Verbal short-term memory comprises resources for phonological rehearsal, which have been characterized anatomically, and for maintenance of semantic information, which are less understood. Sentence repetition tasks tap both processes interactively. To distinguish brain activity involved in phonological vs. semantic maintenance, we recorded magnetoencephalography during a sentence repetition task, incorporating three manipulations emphasizing one mechanism over the other. Participants heard sentences or word lists and attempted to repeat them verbatim after a 5-second delay. After MEG, participants completed a cued recall task testing how much they remembered of each sentence. Greater semantic engagement relative to phonological rehearsal was hypothesized for 1) sentences vs. word lists, 2) concrete vs. abstract sentences, and 3) well recalled vs. poorly recalled sentences. During auditory perception and the memory delay period, we found highly left-lateralized activation in the form of 8-30 Hz event-related desynchronization. Compared to abstract sentences, concrete sentences recruited posterior temporal cortex bilaterally, demonstrating a neural signature for the engagement of visual imagery in sentence maintenance. Maintenance of arbitrary word lists recruited right hemisphere dorsal regions, reflecting increased demands on phonological rehearsal. Sentences that were ultimately poorly recalled in the post-test also elicited extra right hemisphere activation when they were held in short-term memory, suggesting increased demands on phonological resources. Frontal midline theta oscillations also reflected phonological rather than semantic demand, being increased for word lists and poorly recalled sentences. These findings highlight distinct neural resources for phonological and semantic maintenance, with phonological maintenance associated with stronger oscillatory modulations.

The organisation of spatial and temporal relations in memory.

Episodic memories are comprised of details of "where" and "when"; spatial and temporal relations, respectively. However, evidence from behavioural, neuropsychological, and neuroimaging studies has provided mixed interpretations about how memories for spatial and temporal relations are organised-they may be hierarchical, fully interactive, or independent. In the current study, we examined the interaction of memory for spatial and temporal relations. Using explicit reports and eye-tracking, we assessed younger and older adults' memory for spatial and temporal relations of objects that were presented singly across time in unique spatial locations. Explicit change detection of spatial relations was affected by a change in temporal relations, but explicit change detection of temporal relations was not affected by a change in spatial relations. Younger and older adults showed eye movement evidence of incidental memory for temporal relations, but only younger adults showed eye movement evidence of incidental memory for spatial relations. Together, these findings point towards a hierarchical organisation of relational memory. The implications of these findings are discussed in the context of the neural mechanisms that may support such a hierarchical organisation of memory.

Functional reorganization of language networks for semantics and syntax in chronic stroke: Evidence from MEG.

Using magnetoencephalography, we investigated the potential of perilesional and contralesional activity to support language recovery in patients with poststroke aphasia. In healthy young controls, left-lateralized ventral frontotemporal regions responded to semantic anomalies during sentence comprehension and bilateral dorsal frontoparietal regions responded to syntactic anomalies. Older adults showed more extensive bilateral responses to the syntactic anomalies and less lateralized responses to the semantic anomalies, with decreased activation in the left occipital and parietal regions for both semantic and syntactic anomalies. In aphasic participants, we observed compensatory recruitment in the right hemisphere (RH), which varied depending on the type of linguistic information that was processed. For semantic anomalies, aphasic patients activated some preserved left hemisphere regions adjacent to the lesion, as well as homologous parietal and temporal RH areas. Patients also recruited right inferior and dorsolateral frontal cortex that was not activated in the healthy participants. Responses for syntactic anomalies did not reach significance in patients. Correlation analyses indicated that recruitment of homologous temporoparietal RH areas is associated with better semantic performance, whereas higher accuracy on the syntactic task was related to bilateral superior temporoparietal and right frontal activity. The results suggest that better recovery of semantic processing is associated with a shift to ventral brain regions in the RH. In contrast, preservation of syntactic processing is mediated by dorsal areas, bilaterally, although recovery of syntactic processing tends to be poorer than semantic. Hum Brain Mapp 37:2869-2893, 2016. © 2016 Wiley Periodicals, Inc.

Age-related changes to oscillatory dynamics in hippocampal and neocortical networks.

Recent models of hippocampal function have emphasized its role in relational binding - the ability to form lasting representations regarding the relations among distinct elements or items which can support memory performance, even over brief delays (e.g., several seconds). The present study examined the extent to which aging is associated with changes in the recruitment of oscillatory activity within hippocampal and neocortical regions to support relational binding performance on a short delay visuospatial memory task. Structural magnetic resonance imaging and MEG were used to characterize potential age-related changes in hippocampal volume, oscillatory activity, and subsequent memory performance, and the relationships among them. Participants were required to bind the relative visuospatial positions of objects that were presented singly across time. Subsequently, the objects were re-presented simultaneously, and participants were required to indicate whether the relative spatial positions among the objects had been maintained. Older and younger adults demonstrated similar task accuracy, and older adults had preserved hippocampal volumes relative to younger adults. Age-group differences were found in pre-stimulus theta (∼5Hz) and beta (∼20Hz) oscillations, and this pre-stimulus activity was related to hippocampal volumes in younger adults. Age-group differences were also found in the recruitment of oscillatory activity from the pre-stimulus period to the task. Only younger adults showed a task-related change in theta power that was predictive of memory performance. In contrast, older adults demonstrated task-related alpha (∼10Hz) oscillatory power changes that were not observed in younger adults. These findings provide novel evidence for the role of the hippocampus and functionally connected regions in relational binding that is disrupted in aging. The present findings are discussed in the context of current models regarding the cognitive neuroscience of aging.

Semantic and phonological contributions to short-term repetition and long-term cued sentence recall.

The function of verbal short-term memory is supported not only by the phonological loop, but also by semantic resources that may operate on both short and long time scales. Elucidation of the neural underpinnings of these mechanisms requires effective behavioral manipulations that can selectively engage them. We developed a novel cued sentence recall paradigm to assess the effects of two factors on sentence recall accuracy at short-term and long-term stages. Participants initially repeated auditory sentences immediately following a 14-s retention period. After this task was complete, long-term memory for each sentence was probed by a two-word recall cue. The sentences were either concrete (high imageability) or abstract (low imageability), and the initial 14-s retention period was filled with either an undemanding finger-tapping task or a more engaging articulatory suppression task (Exp. 1, counting backward by threes; Exp. 2, repeating a four-syllable nonword). Recall was always better for the concrete sentences. Articulatory suppression reduced accuracy in short-term recall, especially for abstract sentences, but the sentences initially recalled following articulatory suppression were retained better at the subsequent cued-recall test, suggesting that the engagement of semantic mechanisms for short-term retention promoted encoding of the sentence meaning into long-term memory. These results provide a basis for using sentence imageability and subsequent memory performance as probes of semantic engagement in short-term memory for sentences.

Localization of electrophysiological responses to semantic and syntactic anomalies in language comprehension with MEG.

Syntactically and semantically anomalous words encountered during sentence comprehension are known to elicit dissociable electrophysiological responses, which are thought to reflect distinct aspects of language processing. However, the sources of these responses have not been well characterized. We used beamforming analysis of magnetoencephalography (MEG) data to map generators of electrophysiological responses to linguistic anomalies. Anomalous words occurred in the context of a sentence acceptability judgement task conducted in both visual and auditory modalities. Time-frequency analysis revealed that both kinds of violations elicited event-related synchronization (ERS) in the delta-theta frequency range (1-5 Hz), and desynchronization (ERD) in the alpha-beta range (8-30 Hz). In addition, these responses were differentially modulated by violation type and presentation modality. 1-5 Hz responses were consistently localized within medial prefrontal cortex and did not vary significantly across violation types, but were stronger for visual presentation. In contrast, 8-30 Hz ERD occurred in different regions for different violation types. For semantic violations the distribution was predominantly in the bilateral occipital cortex and left temporal and inferior frontal regions, and these effects did not differ for visual and auditory presentation. In contrast, syntactic responses were strongly affected by presentation modality. Under visual presentation, syntactic violations elicited bilateral 8-30 Hz ERD extending into dorsal parietal and frontal regions, whereas effects were much weaker and mostly statistically insignificant in the auditory modality. These results suggest that delta-theta ERS reflects generalized increases in working memory demands related to linguistic anomaly detection, while alpha-beta ERD reflects specific activation of cortical regions involved in distinct aspects of linguistic processing, such as semantic vs. phonological short-term memory. Beamforming analysis of time-domain average signals (ERFs) revealed an N400m effect for semantic anomalies in both modalities, localized to left superior temporal and posterior frontal regions, and a later P600-like effect for syntactic anomalies in both modalities, widespread over bilateral frontal, posterior temporal, and parietal regions. These results indicate that time-domain averaged responses and induced oscillatory responses have distinct properties, including localization and modality dependence, and likely reflect dissociable and complementary aspects of neural activity related to language comprehension and additional task-related processes.

Oscillatory responses to semantic and syntactic violations.

EEG studies employing time-frequency analysis have revealed changes in theta and alpha power in a variety of language and memory tasks. Semantic and syntactic violations embedded in sentences evoke well-known ERPs, but little is known about the oscillatory responses to these violations. We investigated oscillatory responses to both kinds of violations, while monolingual and bilingual participants performed an acceptability judgment task. Both violations elicited power decreases (event-related desynchronization, ERD) in the 8-30 Hz frequency range, but with different scalp topographies. In addition, semantic anomalies elicited power increases (event-related synchronization, ERS) in the 1-5 Hz frequency band. The 1-5 Hz ERS was strongly phase-locked to stimulus onset and highly correlated with time domain averages, whereas the 8-30 Hz ERD response varied independently of these. In addition, the results showed that language expertise modulated 8-30 Hz ERD for syntactic violations as a function of the executive demands of the task. When the executive function demands were increased using a grammaticality judgment task, bilinguals but not monolinguals demonstrated reduced 8-30 Hz ERD for syntactic violations. These findings suggest a putative role of the 8-30 Hz ERD response as a marker of linguistic processing that likely represents a separate neural process from those underlying ERPs.

Enhanced mind-matter interactions following rTMS induced frontal lobe inhibition.

A major barrier to acceptance of psi is that effects are small and hard to replicate. To address this issue, we developed a novel neurobiological model to study this controversial phenomenon based upon the concept that the brain may act as a psi-inhibitory filter. Our previous research in individuals with frontal lobe damage suggests that this filter includes the left medial middle frontal region. We report our findings in healthy participants with rTMS induced reversible brain lesions. In support of our a priori hypothesis, we found a significant psi effect following rTMS inhibition of the left medial middle frontal lobe. This significant effect was found using a post hoc weighting procedure aligned with our overarching hypothesis. This suggests that the brain may inhibit psi and that individuals with neurological or reversible rTMS induced frontal lesions may comprise an enriched sample for detection and replication of this controversial phenomenon. Our findings are potentially transformative for the way we view interactions between the brain and seemingly random events.

Cognitive components of aging-related increase in word-finding difficulty.

Word-finding difficulty (WFD) is a common cognitive complaint in aging, manifesting both in natural speech and in controlled laboratory tests. Various theories of cognitive aging have addressed WFD, and understanding its underlying mechanisms can help to clarify whether it has diagnostic value for neurodegenerative disease. Two influential "information-universal" theories attribute it to rather broad changes in cognition. The processing speed theory posits a general slowdown of all cognitive processes, while the inhibitory deficit hypothesis (IDH) predicts a specific problem in suppressing irrelevant information. One "information specific" theory of language production, the transmission deficit hypothesis (TDH), posits a breakdown in retrieval of phonological word forms from a corresponding lemma. To adjudicate between these accounts, we administered an online gamified covert naming task featuring picture-word interference (PWI), previously validated to elicit similar semantic interference and phonological facilitation effects as overt naming tasks. 125 healthy adults aged 18 to 85 completed the task, along with a battery of executive function tasks and a naturalistic speech sample to quantify WFD in connected speech. PWI effects provided strong support for the TDH but limited support for IDH, in that semantic interference increased and phonological facilitation decreased across the lifespan. However, neither of these effects on single-word retrieval associated with WFD measured in connected speech. Rather, overall reaction time for word retrieval (controlling for psychomotor slowing) was the best predictor of spontaneous WFD and executive function decline, suggesting processing speed as the key factor, and that verbal reaction time may be an important clinical measure.

Contrasting MEG effects of anodal and cathodal high-definition TDCS on sensorimotor activity during voluntary finger movements.

Introduction: Protocols for noninvasive brain stimulation (NIBS) are generally categorized as "excitatory" or "inhibitory" based on their ability to produce short-term modulation of motor-evoked potentials (MEPs) in peripheral muscles, when applied to motor cortex. Anodal and cathodal stimulation are widely considered excitatory and inhibitory, respectively, on this basis. However, it is poorly understood whether such polarity-dependent changes apply for neural signals generated during task performance, at rest, or in response to sensory stimulation. Methods: To characterize such changes, we measured spontaneous and movement-related neural activity with magnetoencephalography (MEG) before and after high-definition transcranial direct-current stimulation (HD-TDCS) of the left motor cortex (M1), while participants performed simple finger movements with the left and right hands. Results: Anodal HD-TDCS (excitatory) decreased the movement-related cortical fields (MRCF) localized to left M1 during contralateral right finger movements while cathodal HD-TDCS (inhibitory), increased them. In contrast, oscillatory signatures of voluntary motor output were not differentially affected by the two stimulation protocols, and tended to decrease in magnitude over the course of the experiment regardless. Spontaneous resting state oscillations were not affected either. Discussion: MRCFs are thought to reflect reafferent proprioceptive input to motor cortex following movements. Thus, these results suggest that processing of incoming sensory information may be affected by TDCS in a polarity-dependent manner that is opposite that seen for MEPs-increases in cortical excitability as defined by MEPs may correspond to reduced responses to afferent input, and vice-versa.

P600-like positivity and Left Anterior Negativity responses are elicited by semantic reversibility in nonanomalous sentences.

ERPs are commonly elicited by semantic and syntactic violations in sentences, leading to proposals that they reflect neural activity underlying ordinary language comprehension. We examined ERPs in an auditory sentence-picture-matching task, using nonanomalous sentences that were either semantically reversible, (boy pushes girl) or irreversible, (boy eats apple). Timelocked to the end of the critical clause, which occurred in the middle of a longer sentence, we observed an enhanced central-posterior positivity in response to the reversible sentences. The topography of this response is consistent with the P600 potential reported in studies of syntactic anomalies and other manipulations related to sentence structure. Following the end of the sentence, during a memory delay period prior to picture onset, reversible sentences also evoked a protracted anterior negativity, predominantly on the left. This negativity was stronger for sentences containing relative clauses compared to simple active sentences, but did not differ between object-embedded and the less complex subject-embedded clauses. The observation of a P600 occurring selectively in reversible sentences supports the interpretation of that potential as reflecting the syntactic processing of thematic relationships, as irreversible sentences contained alternative cues for thematic roles. The left anterior negativity likely reflects later processes of rehearsal and reanalysis of sentence content in working memory.

Spectral slowing in chronic stroke reflects abnormalities in both periodic and aperiodic neural dynamics.

Decades of electrophysiological work have demonstrated the presence of "spectral slowing" in stroke patients - a prominent shift in the power spectrum towards lower frequencies, most evident in the vicinity of the lesion itself. Despite the reliability of this slowing as a marker of dysfunctional tissue across patient groups as well as animal models, it has yet to be explained in terms of the pathophysiological processes of stroke. To do so requires clear understanding of the neural dynamics that these differences represent, acknowledging the often overlooked fact that spectral power reflects more than just the amplitude of neural oscillations. To accomplish this, we used a combination of frequency domain and time domain measures to disambiguate and quantify periodic (oscillatory) and aperiodic (non-oscillatory) neural dynamics in resting state magnetoencephalography (MEG) recordings from chronic stroke patients. We found that abnormally elevated low frequency power in these patients was best explained by a steepening of the aperiodic component of the power spectrum, rather than an enhancement of low frequency oscillations, as is often assumed. However, genuine oscillatory activity at higher frequencies was also found to be abnormal, with patients showing alpha slowing and diminished oscillatory activity in the beta band. These aperiodic and periodic abnormalities were found to covary, and could be detected even in the un-lesioned hemisphere, however they were most prominent in perilesional tissue, where their magnitude was predictive of cognitive impairment. This work redefines spectral slowing as a pattern of changes involving both aperiodic and periodic neural dynamics and narrows the gap in understanding between non-invasive markers of dysfunctional tissue and disease processes responsible for altered neural dynamics.

Improvement in executive function for older adults through smartphone apps: a randomized clinical trial comparing language learning and brain training.

Bilingualism has been linked to improved executive function and delayed onset of dementia, but it is unknown whether similar benefits can be obtained later in life through deliberate intervention. Given the logistical hurdles of second language acquisition in a randomized trial for older adults, few interventional studies have been done thus far. However, recently developed smartphone apps offer a convenient means to acquire skills in a second language and can be compared with brain training apps specifically designed to improve executive function. In a randomized clinical trial, 76 adults aged 65-75 were assigned to either 16 weeks of Spanish learning using the app Duolingo 30 minutes a day, an equivalent amount of brain training using the app BrainHQ, or a waitlist control condition. Executive function was assessed before and after the intervention with preregistered (NCT03638882) tests previously linked to better performance in bilinguals. For two of the primary measures: incongruent Stroop color naming and 2-back accuracy, Duolingo provided equivalent benefits as BrainHQ compared to a control group. On reaction time for N-back and Simon tests, the BrainHQ group alone experienced strong gains over the other two groups. Duolingo was rated as more enjoyable. These results suggest that app-based language learning may provide some similar benefits as brain training in improving executive function in seniors but has less impact on processing speed. However, future advancements in app design may optimize not only the acquisition of the target language but also the side benefits of the language learning experience.