Jed A. Meltzer

Effects of Working Memory Load on Oscillatory Power in Human Intracranial EEG

Studies of working memory load effects on human EEG power have indicated divergent effects in different frequency bands. Although gamma power typically increases with load, the load dependency of the lower frequency theta and alpha bands is uncertain. We obtained intracranial electroencephalography measurements from 1453 electrode sites in 14 epilepsy patients performing a Sternberg task, in order to characterize the anatomical distribution of load-related changes across the frequency spectrum. Gamma power increases occurred throughout the brain, but were most common in the occipital lobe. In the theta and alpha bands, both increases and decreases were observed, but with different anatomical distributions. Increases in theta and alpha power were most prevalent in frontal midline cortex. Decreases were most commonly observed in occipital cortex, colocalized with increases in the gamma range, but were also detected in lateral frontal and parietal regions. Spatial overlap with group functional magnetic resonance imaging results was minimal except in the precentral gyrus. These findings suggest that power in any given frequency band is not a unitary phenomenon; rather, reactivity in the same frequency band varies in different brain regions, and may relate to the engagement or inhibition of a given area in a cognitive task.

Activation of human hippocampal formation reflects success in both encoding and cued recall of paired associates.

Contemporary theories of hippocampal function suggest that both encoding and retrieval of episodic memories may be accomplished by neural circuitry embedded within the same anatomical structures, but neuroimaging support for this hypothesis has been ambiguous. Recent studies suggest that the best available indicators of hippocampal encoding and retrieval operations are selective activations due to novelty, encoding success, and recall success in a paired associate learning paradigm. In the current study, both encoding and cued recall of paired associate words were conducted during a single session of fMRI scanning. Bilateral activation in the medial temporal lobe was detected for encoding word pairs vs. a fixation baseline and for encoding novel word pairs vs. repeated word pairs. These activations were stronger in subjects who successfully memorized more word pairs. In cued recall, greater responses were seen in higher performing subjects. In lower performing subjects, responses were greater to cue words whose paired associate was correctly recalled than to cue words whose correct associate had been forgotten (or not encoded). The difference between correct and incorrect trials was more pronounced on repeated presentations of the same cue words, but not apparent on their first presentation alone. Overlap of encoding and retrieval effects was maximal in the middle of the longitudinal extent of the right hippocampus, with one additional locus of overlap outside the MTL, in left occipitotemporal cortex. The conjunction of these effects suggests that it is correct to view both encoding and recall of associative memories as functions of an integrated hippocampal system.

Biphasic Hemodynamic Responses Influence Deactivation and May Mask Activation in Block-Design fMRI Paradigms

A previous block‐design fMRI study revealed deactivation in the hippocampus in the transverse patterning task, specifically designed, on the basis of lesion literature, to engage hippocampal information processing. In the current study, a mixed block/event‐related design was used to determine the temporal nature of the signal change leading to the seemingly paradoxical deactivation. All positive activations in the hippocampal‐dependent condition, relative to a closely matched control task, were seen to result from positive BOLD transients in the typical 4–7 s poststimulus time range. However, most deactivations, including in the hippocampus and in other “default mode” regions commonly deactivated in cognitive tasks, were attributable to enhanced negative transient signals in a later time range, 10–12 s. This late hemodynamic transient was most pronounced in medial prefrontal cortex. In some regions, the hippocampal‐dependent condition enhanced both the early positive and late negative transients to approximately the same degree, resulting in no significant signal change when block analysis is used, despite very different event‐related responses. These results imply that delayed negative transients can play a role in determining the presence and sign of brain activation in block‐design studies, in which case an event‐related analysis can be more sensitive than a block analysis, even if the different conditions occur within blocks. In this case, default mode deactivations are timelocked to stimulus presentation as much as positive activations are, but in a later time range, suggesting a specific role of negative transient signals in task performance. Hum Brain Mapp, 2008.

A Functional Magnetic Resonance Imaging Study of the Long-term Influences of Early Indomethacin Exposure on Language Processing in the Brains of Prematurely Born Children

BACKGROUND. Previous studies have demonstrated that indomethacin lowers the incidence and decreases the severity of intraventricular hemorrhage, as well as improves the cognitive outcome, in prematurely born male infants. OBJECTIVE. The purpose of this work was to use functional magnetic resonance imaging to test the hypothesis that neonatal indomethacin treatment would differentially affect brain activation across genders in school-aged, prematurely born children during performance of a language task. METHODS. Forty-seven prematurely born children (600–1250-g birth weight) and 24 matched term control subjects were evaluated using a functional magnetic resonance imaging passive language task and neurodevelopmental assessments that included the Wechsler Intelligence Scale for Children-III and the Peabody Picture Vocabulary Test-Revised. Neural activity was assessed during both phonologic and semantic processing in the functional magnetic resonance imaging protocol. RESULTS. Neurodevelopmental assessments demonstrated significant differences in full-scale, verbal, and performance intelligence quotient, as well as Peabody Picture Vocabulary Test scores, between the preterm and term control subjects. Rates of perinatal complications did not differ significantly across preterm treatment groups, but male preterm subjects randomly assigned to saline tended to have lower Peabody Picture Vocabulary Test-Revised scores than did all of the other preterm groups. During phonological processing, a significant treatment-by-gender effect was demonstrated in 3 brain regions: the left inferior parietal lobule, the left inferior frontal gyrus (Brocas area), and the right dorsolateral prefrontal cortex. CONCLUSIONS. These data demonstrate a differential effect of indomethacin administration early in postnatal life on the subsequent development of neural systems that subserve language functioning in these male and female preterm infants.

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.

Temperature dependence of non-linear capacitance in human embryonic kidney cells transfected with prestin, the outer hair cell motor protein

The transmembrane motor protein prestin is thought to underlie outer hair cell (OHC) motility. Prestin expressed in non-auditory cells confers OHC-like electrical characteristics to the cell membrane, including the generation of gating-like currents (or non-linear capacitance), whose voltage dependence is susceptible to membrane tension and initial voltage conditions. Here we report that prestins voltage sensitivity is, like that of the native motor, markedly temperature dependent. Prestin-transfected HEK cells were whole-cell voltage clamped while temperature was varied from 10-35 degrees C. V(pkcm), the voltage at peak capacitance, reversibly and linearly shifted to depolarized levels with increasing temperatures, while peak capacitance also increased, but with significant hysteresis upon recooling. Mathematical modeling suggests that this increase may be due to a charged voltage sensor having a wider range of movement through or larger unit charge within the plasma membrane at higher temperatures.

Transverse patterning dissociates human EEG theta power and hippocampal BOLD activation

Theta oscillations (4-8 Hz) are often modulated in human electroencephalogram (EEG) studies of memory, whereas overlapping frequencies dominate rodent hippocampal EEG. An emerging parallelism between theta reactivity and hippocampal functional magnetic resonance imaging activation has suggested a homology between theta activity in humans and rodents, representing a process of cortico-hippocampal interaction involved in memory. In the present study, we investigated EEG reactivity during performance of a relational memory task that induces a negative hippocampal blood oxygenation level dependent (BOLD) signal change, compared to a nonrelational control condition. Relational trials induced theta increases and alpha decreases. Low Resolution Electromagnetic Brain Tomography estimates localized theta and alpha modulation to frontal midline and parietal midline cortices, respectively, both of which exhibit negative BOLD responses in this task. Thus, theta and alpha dynamics are dissociable from positive BOLD activation, and may, in fact, colocalize with negative BOLD responses.

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.

Hippocampal and neocortical oscillatory contributions to visuospatial binding and comparison.

Over 50 years of research has revealed a critical role for the hippocampus in the formation of long-term declarative memories. More recent evidence has specified the functions of the hippocampus as the binding and comparison of memory representations that may be used under shorter, as well as longer, delays (Olsen, Moses, Riggs, & Ryan, 2012). Hippocampal neural oscillations (e.g., theta rhythm) have been studied extensively in animals; however, the oscillations that underlie binding, comparison, and their relationship to memory performance remain to be fully explored in humans. Here magnetoencephalography was used to examine theta oscillations within the hippocampus and cortex to address this critical gap in the literature. The task consisted of (a) an encoding phase in which participants had to integrate the relative spatial positions among 3 sequentially presented objects, (b) a delay phase, and (c) a test phase in which all study objects were presented simultaneously in novel locations, and participants had to indicate whether the relative positions had changed. Theta power in the hippocampus and medial prefrontal cortex (PFC) increased across encoding and delay periods during which binding and maintenance processes dominate, while comparison of spatial relations at test was associated with greater theta power in right lateral PFC and intraparietal sulcus for manipulated versus intact trials. Critically, relational memory was positively related to hippocampal theta power increases across the encoding period. These findings provide novel evidence for the role of hippocampal theta in the incremental formation and retention of relations across space and time.

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.