Is auditory processing measured by the N100 an endophenotype for psychosis? A family study and a meta-analysis.

BACKGROUND: The N100, an early auditory event-related potential, has been found to be altered in patients with psychosis. However, it is unclear if the N100 is a psychosis endophenotype that is also altered in the relatives of patients. METHODS: We conducted a family study using the auditory oddball paradigm to compare the N100 amplitude and latency across 243 patients with psychosis, 86 unaffected relatives, and 194 controls. We then conducted a systematic review and a random-effects meta-analysis pooling our results and 14 previously published family studies. We compared data from a total of 999 patients, 1192 relatives, and 1253 controls in order to investigate the evidence and degree of N100 differences. RESULTS: In our family study, patients showed reduced N100 amplitudes and prolonged N100 latencies compared to controls, but no significant differences were found between unaffected relatives and controls. The meta-analysis revealed a significant reduction of the N100 amplitude and delay of the N100 latency in both patients with psychosis (standardized mean difference [s.m.d.] = -0.48 for N100 amplitude and s.m.d. = 0.43 for N100 latency) and their relatives (s.m.d. = - 0.19 for N100 amplitude and s.m.d. = 0.33 for N100 latency). However, only the N100 latency changes in relatives remained significant when excluding studies with affected relatives. CONCLUSIONS: N100 changes, especially prolonged N100 latencies, are present in both patients with psychosis and their relatives, making the N100 a promising endophenotype for psychosis. Such changes in the N100 may reflect changes in early auditory processing underlying the etiology of psychosis.

Brain state before a memory probe and associative retrieval in older adults.

Older individuals' difficulty in remembering events from a particular time and place may be explained by changes in retrieval-related control processes. We investigated how aging affects neural activity leading up to a retrieval probe and how such activity relates to later performance. Electrical brain activity was recorded while healthy younger and older humans memorized visual word pairs consisting of an object word (e.g., doll) preceded by a location word (e.g., garden). Only object words were presented during the memory test, the task being to decide whether an object had been presented earlier and, if so, what location had been paired with it. A warning signal before each test probe alerted to an upcoming object. A sustained negative-going event-related potential deflection preceded objects whose associated location could be remembered, especially in older individuals. The poorer an older individual's associative memory, the bigger was this deflection. Aging thus seems accompanied by changes in anticipatory brain states that relate to recollection. Such states may serve to mobilize control processes that aid the recovery of contextual details.

The ERP response to the amount of information conveyed by words in sentences.

Reading times on words in a sentence depend on the amount of information the words convey, which can be estimated by probabilistic language models. We investigate whether event-related potentials (ERPs), too, are predicted by information measures. Three types of language models estimated four different information measures on each word of a sample of English sentences. Six different ERP deflections were extracted from the EEG signal of participants reading the same sentences. A comparison between the information measures and ERPs revealed a reliable correlation between N400 amplitude and word surprisal. Language models that make no use of syntactic structure fitted the data better than did a phrase-structure grammar, which did not account for unique variance in N400 amplitude. These findings suggest that different information measures quantify cognitively different processes and that readers do not make use of a sentence's hierarchical structure for generating expectations about the upcoming word.

Emotion regulation modulates anticipatory brain activity that predicts emotional memory encoding in women.

It has been shown that the effectiveness with which unpleasant events are encoded into memory is related to brain activity set in train before the events. Here, we assessed whether encoding-related activity before an aversive event can be modulated by emotion regulation. Electrical brain activity was recorded from the scalps of healthy women while they performed an incidental encoding task on randomly intermixed unpleasant and neutral visual scenes. A cue presented 1.5 s before each picture indicated the upcoming valence. In half of the blocks of trials, the instructions emphasized to let emotions arise in a natural way. In the other half, participants were asked to decrease their emotional response by adopting the perspective of a detached observer. Memory for the scenes was probed 1 day later with a recognition memory test. Brain activity before unpleasant scenes predicted later memory of the scenes, but only when participants felt their emotions and did not detach from them. The findings indicate that emotion regulation can eliminate the influence of anticipatory brain activity on memory encoding. This may be relevant for the understanding and treatment of psychiatric diseases with a memory component.

Concreteness in word processing: ERP and behavioral effects in a lexical decision task.

Relative to abstract words, concrete words typically elicit faster response times and larger N400 and N700 event-related potential (ERP) brain responses. These effects have been interpreted as reflecting the denser links to associated semantic information of concrete words and their recruitment of visual imagery processes. Here, we examined whether there are ERP differences between concrete and abstract stimuli controlled for a large number of factors including context availability (i.e., richness of semantic associations) and imageability. We found that abstract words elicited faster behavioral responses but that concrete words still elicited larger N400 and N700 responses. We propose that once all other factors, including imageability and context availability are controlled, abstract words may trigger a larger number of superficial linguistic associations that can be quickly used for response decisions. The ERP differences, however, would index the greater semantic processing (integration of multimodal information) for concrete than abstract words during meaning activation.

Expected reward modulates encoding-related theta activity before an event.

Oscillatory brain activity in the theta frequency range (4-8 Hz) before the onset of an event has been shown to affect the likelihood of successfully encoding the event into memory. Recent work has also indicated that frontal theta activity might be modulated by reward, but it is not clear how reward expectancy, anticipatory theta activity, and memory formation might be related. Here, we used scalp electroencephalography (EEG) to assess the relationship between these factors. EEG was recorded from healthy adults while they memorized a series of words. Each word was preceded by a cue that indicated whether a high or low monetary reward would be earned if the word was successfully remembered in a later recognition test. Frontal theta power between the presentation of the reward cue and the onset of a word was predictive of later memory for the word, but only in the high reward condition. No theta differences were observed before word onset following low reward cues. The magnitude of prestimulus encoding-related theta activity in the high reward condition was correlated with the number of high reward words that were later confidently recognized. These findings provide strong evidence for a link between reward expectancy, theta activity, and memory encoding. Theta activity before event onset seems to be especially important for the encoding of motivationally significant stimuli. One possibility is that dopaminergic activity during reward anticipation mediates frontal theta activity related to memory.

Available processing resources influence encoding-related brain activity before an event.

Effective cognitive functioning not only relies on brain activity elicited by an event, but also on activity that precedes it. This has been demonstrated in a number of cognitive domains, including memory. Here, we show that brain activity that precedes the effective encoding of a word into long-term memory depends on the availability of sufficient processing resources. We recorded electrical brain activity from the scalps of healthy adult men and women while they memorized intermixed visual and auditory words for later recall. Each word was preceded by a cue that indicated the modality of the upcoming word. The degree to which processing resources were available before word onset was manipulated by asking participants to make an easy or difficult perceptual discrimination on the cue. Brain activity before word onset predicted later recall of the word, but only in the easy discrimination condition. These findings indicate that anticipatory influences on long-term memory are limited in capacity and sensitive to the degree to which attention is divided between tasks. Prestimulus activity that affects later encoding can only be engaged when the necessary cognitive resources can be allocated to the encoding process.

Prestimulus brain activity predicts primacy in list learning.

Brain activity immediately before an event can predict whether the event will later be remembered. This indicates that memory formation is influenced by anticipatory mechanisms engaged ahead of stimulus presentation. Here, we asked whether anticipatory processes affect the learning of short word lists, and whether such activity varies as a function of serial position. Participants memorized lists of intermixed visual and auditory words with either an elaborative or rote rehearsal strategy. At the end of each list, a distraction task was performed followed by free recall. Recall performance was better for words in initial list positions and following elaborative rehearsal. Electrical brain activity before auditory words predicted later recall in the elaborative rehearsal condition. Crucially, anticipatory activity only affected recall when words occurred in initial list positions. This indicates that anticipatory processes, possibly related to general semantic preparation, contribute to primacy effects.

Study-test congruency affects encoding-related brain activity for some but not all stimulus materials.

Memory improves when encoding and retrieval processes overlap. Here, we investigated how the neural bases of long-term memory encoding vary as a function of the degree to which functional processes engaged at study are engaged again at test. In an incidental learning paradigm, electrical brain activity was recorded from the scalps of healthy adults while they made size judgments on intermixed series of pictures and words. After a 1-hr delay, memory for the items was tested with a recognition task incorporating remember/know judgments. In different groups of participants, studied items were either probed in the same mode of presentation (word-word; picture-picture) or in the alternative mode of presentation (word-picture; picture-word). Activity over anterior scalp sites predicted later memory of words, irrespective of type of test probe. Encoding-related activity for pictures, by contrast, differed qualitatively depending on how an item was cued at test. When a picture was probed with a picture, activity over anterior scalp sites predicted encoding success. When a picture was probed with a word, encoding-related activity was instead maximal over posterior sites. Activity differed according to study-test congruency from around 100 msec after picture onset. These findings indicate that electrophysiological correlates of encoding are sensitive to the similarity between processes engaged at study and test. The time course supports a direct and not merely consequential role of encoding-retrieval overlap in encoding. However, because congruency only affected one type of stimulus material, encoding-retrieval overlap may not be a universal organizing principle of neural correlates of memory.

Sex differences in the use of anticipatory brain activity to encode emotional events.

Women and men differ in the way they experience emotional events. Previous work has indicated that the impact of an emotional event depends on how it is anticipated. Separately, it has been shown that anticipation affects memory formation. Here, we assessed whether anticipatory brain activity influences the encoding of emotional events into long-term memory and, in addition, how biological sex affects the use of such activity. Electrical brain activity was recorded from the scalps of healthy men and women while they performed an incidental encoding task (indoor/outdoor judgments) on pleasant, unpleasant, and neutral pictures. Pictures were preceded by a cue that indicated the valence of the upcoming item. Memory was tested after a 20 min delay with a recognition task incorporating the remember/know procedure. Brain activity before picture onset predicted later memory of an event. Crucially, the role of anticipatory activity depended entirely on the valence of a picture and the sex of an individual. Right-lateralized anticipatory activity selectively influenced the encoding of unpleasant pictures in women, but not in men. These findings indicate that anticipatory processes influence the way in which women encode negative events into memory. The selective use of such activity may indicate that anticipatory activity is one mechanism by which individuals regulate their emotions.

Material-specific neural correlates of recollection: objects, words, and faces.

It is unclear how neural correlates of episodic memory retrieval differ depending on the type of material that is retrieved. Here, we used a source memory task to compare electrical brain activity for the recollection of three types of stimulus material. At study, healthy adults judged how well visually presented objects, words, and faces fitted with paired auditorily presented names of locations. At test, only visual stimuli were presented. The task was to decide whether an item had been presented earlier and, if so, what location had been paired with the item. Stimulus types were intermixed across trials in Experiment 1 and presented in separate study-test lists in Experiment 2. A graded pattern of memory performance was observed across objects, words, and faces in both experiments. Between 300 and 500 msec, event-related potentials for recollected objects and faces showed a more frontal scalp distribution compared to words in both experiments. Later in the recording epoch, all three stimulus materials elicited recollection effects over left posterior scalp sites. However, these effects extended more anteriorly for objects and faces when stimulus categories were blocked. These findings demonstrate that the neural correlates of recollection are material specific, the crucial difference being between pictorial and verbal material. Faces do not appear to have a special status. The sensitivity of recollection effects to the kind of experimental design suggests that, in addition to type of stimulus material, higher-level control processes affect the cognitive and neural mechanisms underlying episodic retrieval.

Voluntary control over prestimulus activity related to encoding.

A new development in our understanding of human long-term memory is that effective memory formation relies on neural activity just before an event. It is unknown whether such prestimulus activity is under voluntary control or a reflection of random fluctuations over time. In the present study, we addressed two issues: (1) whether prestimulus activity is influenced by an individual's motivation to encode, and (2) at what point in time encoding-related activity emerges. Electrical brain activity was recorded while healthy male and female adults memorized series of words. Each word was preceded by a cue, which indicated the monetary reward that would be received if the following word was later remembered. Memory was tested after a short delay with a five-way recognition task to separate different sources of recognition. Electrical activity elicited by the reward cue predicted later memory of a word. Crucially, however, this was only observed when the incentive to memorize a word was high. Encoding-related activity preceded high-reward words that were later recollected. This activity started shortly after cue onset and persisted until word onset. Prestimulus activity thus not only signals cue-related processing but also an ensuing preparatory state. In contrast, reward-related activity was limited to the time period immediately after the reward cue. These findings indicate that engaging neural activity that benefits the encoding of an upcoming event is under voluntary control, reflecting a strategic preparatory state in anticipation of processing an event.

Event-related potentials to event-related words: grammatical class and semantic attributes in the representation of knowledge.

A number of recent studies have provided contradictory evidence on the question of whether grammatical class plays a role in the neural representation of lexical knowledge. Most of the previous studies comparing the processing of nouns and verbs, however, confounded word meaning and grammatical class by comparing verbs referring to actions with nouns referring to objects. Here, we recorded electrical brain activity from native Italian speakers reading single words all referring to events (e.g., corsa [the run]; correre [to run]), thus avoiding confounding nouns and verbs with objects and actions. We manipulated grammatical class (noun versus verb) as well as semantic attributes (motor versus sensory events). Activity between 300 and 450ms was more negative for nouns than verbs, and for sensory than motor words, over posterior scalp sites. These grammatical class and semantic effects were not dissociable in terms of latency, duration, or scalp distribution. In a later time window (450-110ms) and at frontal regions, grammatical class and semantic effects interacted; motor verbs were more positive than the other three word categories. We suggest that the lack of a temporal and topographical dissociation between grammatical class and semantic effects in the time range of the N400 component is compatible with an account in which both effects reflect the same underlying process related to meaning retrieval, and we link the later effect with working memory operations associated to the experimental task.

The time course of ventrolateral prefrontal cortex involvement in memory formation.

Human neuroimaging studies have implicated a number of brain regions in long-term memory formation. Foremost among these is ventrolateral prefrontal cortex. Here, we used double-pulse transcranial magnetic stimulation (TMS) to assess whether the contribution of this part of cortex is crucial for laying down new memories and, if so, to examine the time course of this process. Healthy adult volunteers performed an incidental encoding task (living/nonliving judgments) on sequences of words. In separate series, the task was performed either on its own or while TMS was applied to one of two sites of experimental interest (left/right anterior inferior frontal gyrus) or a control site (vertex). TMS pulses were delivered at 350, 750, or 1,150 ms following word onset. After a delay of 15 min, memory for the items was probed with a recognition memory test including confidence judgments. TMS to all three sites nonspecifically affected the speed and accuracy with which judgments were made during the encoding task. However, only TMS to prefrontal cortex affected later memory performance. Stimulation of left or right inferior frontal gyrus at all three time points reduced the likelihood that a word would later be recognized by a small, but significant, amount (approximately 4%). These findings indicate that bilateral ventrolateral prefrontal cortex plays an essential role in memory formation, exerting its influence between > or = 350 and 1,150 ms after an event is encountered.

Neural correlates of task and source switching: similar or different?

Controlling everyday behaviour relies on the ability to configure appropriate task sets and guide attention towards information relevant to the current context and goals. Here, we ask whether these two aspects of cognitive control have different neural bases. Electrical brain activity was recorded while sixteen adults performed two discrimination tasks. The tasks were performed on either a visual input (letter on the screen) or self-generated information (letter generated internally by continuing the alphabetical sequence). In different blocks, volunteers either switched between (i) the two tasks, (ii) the two sources of information, or (iii) tasks and source of information. Event-related potentials differed significantly between switch and no-switch trials from an early point in time, encompassing at least three distinct effects. Crucially, although these effects showed quantitative differences across switch types, no qualitative differences were observed. Thus, at least under the current circumstances, switching between different tasks and between perceptually derived or self-generated sources of information rely on similar neural correlates until at least 900 ms after the onset of a switch event.

Prestimulus subsequent memory effects for auditory and visual events.

It has been assumed that the effective encoding of information into memory primarily depends on neural activity elicited when an event is initially encountered. Recently, it has been shown that memory formation also relies on neural activity just before an event. The precise role of such activity in memory is currently unknown. Here, we address whether prestimulus activity affects the encoding of auditory and visual events, is set up on a trial-by-trial basis, and varies as a function of the type of recognition judgment an item later receives. Electrical brain activity was recorded from the scalps of 24 healthy young adults while they made semantic judgments on randomly intermixed series of visual and auditory words. Each word was preceded by a cue signaling the modality of the upcoming word. Auditory words were preceded by auditory cues and visual words by visual cues. A recognition memory test with remember/know judgments followed after a delay of about 45 min. As observed previously, a negative-going, frontally distributed modulation just before visual word onset predicted later recollection of the word. Crucially, the same effect was found for auditory words and observed on stay as well as switch trials. These findings emphasize the flexibility and general role of prestimulus activity in memory formation, and support a functional interpretation of the activity in terms of semantic preparation. At least with an unpredictable trial sequence, the activity is set up anew on each trial.

Seeing sounds and hearing colors: an event-related potential study of auditory-visual synesthesia.

In auditory-visual synesthesia, sounds automatically elicit conscious and reliable visual experiences. It is presently unknown whether this reflects early or late processes in the brain. It is also unknown whether adult audiovisual synesthesia resembles auditory-induced visual illusions that can sometimes occur in the general population or whether it resembles the electrophysiological deflection over occipital sites that has been noted in infancy and has been likened to synesthesia. Electrical brain activity was recorded from adult synesthetes and control participants who were played brief tones and required to monitor for an infrequent auditory target. The synesthetes were instructed to attend either to the auditory or to the visual (i.e., synesthetic) dimension of the tone, whereas the controls attended to the auditory dimension alone. There were clear differences between synesthetes and controls that emerged early (100 msec after tone onset). These differences tended to lie in deflections of the auditory-evoked potential (e.g., the auditory N1, P2, and N2) rather than the presence of an additional posterior deflection. The differences occurred irrespective of what the synesthetes attended to (although attention had a late effect). The results suggest that differences between synesthetes and others occur early in time, and that synesthesia is qualitatively different from similar effects found in infants and certain auditory-induced visual illusions in adults. In addition, we report two novel cases of synesthesia in which colors elicit sounds, and vice versa.

Distinct patterns of neural activity during memory formation of nonwords versus words.

Research into the neural underpinnings of memory formation has focused on the encoding of familiar verbal information. Here, we address how the brain supports the encoding of novel information that does not have meaning. Electrical brain activity was recorded from the scalps of healthy young adults while they performed an incidental encoding task (syllable judgments) on separate series of words and "nonwords" (nonsense letter strings that are orthographically legal and pronounceable). Memory for the items was then probed with a recognition memory test. For words as well as nonwords, event-related potentials differed depending on whether an item would subsequently be remembered or forgotten. However, the polarity and timing of the effect varied across item type. For words, subsequently remembered items showed the usually observed positive-going, frontally distributed modulation from around 600 msec after word onset. For nonwords, by contrast, a negative-going, spatially widespread modulation predicted encoding success from 1000 msec onward. Nonwords also showed a modulation shortly after item onset. These findings imply that the brain supports the encoding of familiar and unfamiliar letter strings in qualitatively different ways, including the engagement of distinct neural activity at different points in time. The processing of semantic attributes plays an important role in the encoding of words and the associated positive frontal modulation.

Fragments of a larger whole: retrieval cues constrain observed neural correlates of memory encoding.

Laying down a new memory involves activity in a number of brain regions. Here, it is shown that the particular regions associated with successful encoding depend on the way in which memory is probed. Event-related functional magnetic resonance imaging signals were acquired while subjects performed an incidental encoding task on a series of visually presented words denoting objects. A recognition memory test using the Remember/Know procedure to separate responses based on recollection and familiarity followed 1 day later. Critically, half of the studied objects were cued with a corresponding spoken word, and half with a corresponding picture. Regardless of cue, activity in prefrontal and hippocampal regions predicted subsequent recollection of a word. Type of retrieval cue modulated activity in prefrontal, temporal, and parietal cortices. Words subsequently recognized on the basis of a sense of familiarity were at study also associated with differential activity in a number of brain regions, some of which were probe dependent. Thus, observed neural correlates of successful encoding are constrained by type of retrieval cue, and are only fragments of all encoding-related neural activity. Regions exhibiting cue-specific effects may be sites that support memory through the degree of overlap between the processes engaged during encoding and those engaged during retrieval.

Episodic encoding is more than the sum of its parts: an fMRI investigation of multifeatural contextual encoding.

Episodic memories are characterized by their contextual richness, yet little is known about how the various features comprising an episode are brought together in memory. Here we employed fMRI and a multidimensional source memory procedure to investigate processes supporting the mnemonic binding of item and contextual information. Volunteers were scanned while encoding items for which the contextual features (color and location) varied independently, allowing activity elicited at the time of study to be segregated according to whether both, one, or neither feature was successfully retrieved on a later memory test. Activity uniquely associated with successful encoding of both features was identified in the intra-parietal sulcus, a region strongly implicated in the support of attentionally mediated perceptual binding. The findings suggest that the encoding of disparate features of an episode into a common memory representation requires that the features be conjoined in a common perceptual representation when the episode is initially experienced.