Rapid Sequential Implication of the Human Medial Temporal Lobe in Memory Encoding and Recognition.

The medial temporal lobe (MTL) is crucial for memory encoding and recognition. The time course of these processes is unknown. The present study juxtaposed encoding and recognition in a single paradigm. Twenty healthy subjects performed a continuous recognition task as brain activity was monitored with a high-density electroencephalography. The task presented New pictures thought to evoke encoding. The stimuli were then repeated up to 4 consecutive times to produce over-familiarity. These repeated stimuli served as "baseline" for comparison with the other stimuli. Stimuli later reappeared after 9-15 intervening items, presumably associated with new encoding and recognition. Encoding-related differences in evoked response potential amplitudes and in spatiotemporal analysis were observed at 145-300 ms, whereby source estimation indicated MTL and orbitofrontal activity from 145 to 205 ms. Recognition-related activity evoked by late repetitions occurred at 405-470 ms, implicating the MTL and neocortical structures. These findings indicate that encoding of information is initiated before it is recognized. The result helps to explain modifications of memories over time, including false memories, confabulation, and consolidation.

Olfactory dysfunction in frontotemporal dementia and psychiatric disorders: A systematic review.

Frontotemporal dementia (FTD) is a progressive neurodegenerative disease. Diagnosis of FTD, especially the behavioural variant, is challenging because of symptomatic overlap with psychiatric disorders (depression, schizophrenia, bipolar disorder). Olfactory dysfunction is common in both FTD and psychiatric disorders, and often appears years before symptom onset. This systematic review analysed 74 studies on olfactory function in FTD, depression, schizophrenia and bipolar disorder to identify differences in olfactory dysfunction profiles, focusing on the most common smell measures: odour identification and discrimination. Results revealed that FTD patients were severely impaired in odour identification but not discrimination; in contrast, patients diagnosed with schizophrenia showed impairments in both measures, while those diagnosed with depression showed no olfactory impairments. Findings in bipolar disorder were mixed. Therefore, testing odour identification and discrimination differentiates FTD from depression and schizophrenia, but not from bipolar disorder. Given the high prevalence of odour identification impairments in FTD, and that smell dysfunction predicts neurodegeneration in other diseases, olfactory testing seems a promising avenue towards improving diagnosis between FTD and psychiatric disorders.

Interactions between decision-making and emotion in behavioral-variant frontotemporal dementia and Alzheimer's disease.

Negative and positive emotions are known to shape decision-making toward more or less impulsive responses, respectively. Decision-making and emotion processing are underpinned by shared brain regions including the ventromedial prefrontal cortex (vmPFC) and the amygdala. How these processes interact at the behavioral and brain levels is still unclear. We used a lesion model to address this question. Study participants included individuals diagnosed with behavioral-variant frontotemporal dementia (bvFTD, n = 18), who typically present deficits in decision-making/emotion processing and atrophy of the vmPFC, individuals with Alzheimer's disease (AD, n = 12) who present with atrophy in limbic structures and age-matched healthy controls (CTRL, n = 15). Prior to each choice on the delay discounting task participants were cued with a positive, negative or neutral picture and asked to vividly imagine witnessing the event. As hypothesized, our findings showed that bvFTD patients were more impulsive than AD patients and CTRL and did not show any emotion-related modulation of delay discounting rate. In contrast, AD patients showed increased impulsivity when primed by negative emotion. This increased impulsivity was associated with reduced integrity of bilateral amygdala in AD but not in bvFTD. Altogether, our results indicate that decision-making and emotion interact at the level of the amygdala supporting findings from animal studies.

Early signal from the hippocampus for memory encoding.

The mediotemporal lobe (MTL), including the hippocampus, is involved in all stages of episodic memory including memory encoding, consolidation, and retrieval. However, the exact timing of the hippocampus' involvement immediately after stimulus encounter remains unclear. In this study, we used high-density 156-channel electroencephalography to study the processing of entirely new stimuli, which had to be encoded, in comparison to highly overlearned stimuli. Sixteen healthy subjects performed a continuous recognition task with meaningful pictures repeated up to four consecutive times. Waveform and topographic cluster analyses of event-related potentials revealed that new items, in comparison to repetitions, were processed significantly differently at 220-300 ms. Source estimation localized activation for processing new stimuli in the right MTL. Our study demonstrates the occurrence of a transient signal from the MTL in response to new information already at 200-300 ms poststimulus onset, which presumably reflects encoding as an initial step toward memory consolidation.

Transcranial direct current stimulation (tDCS) over vmPFC modulates interactions between reward and emotion in delay discounting.

Delay discounting requires computing trade-offs between immediate-small rewards and later-larger rewards. Negative and positive emotions shift decisions towards more or less impulsive responses, respectively. Models have conceptualized this trade-off by describing an interplay between "emotional" and "rational" processes, with the former involved during immediate choices and relying on the ventromedial prefrontal cortex (vmPFC), and the latter involved in long-term choices and relying on the dorsolateral prefrontal cortex (dlPFC). Whether stimulation of the vmPFC modulates emotion-induced delay discounting remains unclear. We applied tDCS over the vmPFC in 20 healthy individuals during a delay discounting task following an emotional (positive, negative) or neutral induction. Our results showed that cathodal tDCS increased impulsivity after positive emotions in high impulsivity trials. For low impulsivity trials, anodal tDCS decreased impulsivity following neutral induction compared with emotional induction. Our findings demonstrate that the vmPFC integrates reward and emotion most prominently in situations of increased impulsivity, whereas when higher cognitive control is required the vmPFC appears to be less engaged, possibly due to recruitment of the dlPFC. Understanding how stimulation and emotion influence decision-making at the behavioural and neural levels holds promise to develop interventions to reduce impulsivity.

Sustained attention failures on a 3-min reaction time task is a sensitive marker of dementia.

The objective of the study is to determine the utility of a simple reaction time task as a marker of general cognitive decline across the frontotemporal lobar degeneration (FTLD) spectrum and in Alzheimer's disease (AD). One hundred and twelve patients presenting with AD or FTLD affecting behaviour (behavioural-variant frontotemporal dementia), language (progressive non fluent aphasia, logopenic progressive aphasia, semantic dementia) or motor function (corticobasal syndrome, progressive supranuclear palsy, frontotemporal dementia-motor neuron disease) and 25 age-matched healthy controls completed the Psychomotor Vigilance Task (PVT), a 3-min reaction time (RT) task. The proportion of lapses (RT > 500 ms) was significantly increased in dementia patients compared to healthy controls, except for semantic dementia, and correlated with all cognitive functions except language. Discrimination of individuals (dementia patients versus healthy controls) based on the proportion of lapses yielded the highest classification performance (Area Under the Curve, AUC, 0.90) compared to standard neuropsychological tests. Only the complete and lengthy neuropsychological battery had a higher predictive value (AUC 0.96). The basic ability to sustain attention is fundamental to perform any cognitive task. Lapses, interpreted as momentary shifts in goal-directed processing, can therefore, be used as a marker of general cognitive decline indicative of possible dementia.

Neural correlates of reality filtering in schizophrenia spectrum disorder.

BACKGROUND: A false sense of reality is a characteristic of schizophrenia spectrum disorders (SSD). Reality confusion may also emanate from posterior orbitofrontal cortex (OFC) lesions, as evident in confabulations that patients act upon and disorientation. This confusion can be measured by repeated runs of a continuous recognition task (CRT): patients increase their false positive rate from the second run on, failing to realize that an item is not a repetition within the current run. Correct handling of these stimuli, a faculty called orbitofrontal reality filtering (ORFi), induces a distinct frontal potential at 200-300 ms, the "ORFi potential". Patients with schizophrenia have been reported to fail in this task, too. Here, we explored the electrophysiology of ORFi in SSD. METHODS: Evoked potentials, source, and connectivity analyses derived from high-density electroencephalograms of 17 patients with SSD and 15 age-matched healthy controls performing two runs of a CRT. RESULTS: Although the patients obtained normal performance, they did not normally express the frontal potential typical of ORFi between 200 and 300 ms. Coherence analysis demonstrated virtually absent functional connectivity in the theta band within the memory network in this period. Source analysis showed increased activity in left medial temporal and prefrontal regions in patients. CONCLUSIONS: SSD patients appear to invoke compensatory resources to handle the challenges of reality filtering. An abnormal ORFi potential may be an early biomarker of SSD.

Absence of an early hippocampal encoding signal after medial temporal lesions: No consequence for the spacing effect.

Immediately repeated meaningful pictures in a continuous recognition task induce a positive frontal potential at about 200-300 ms, which appears to emanate from the medial temporal lobe (MTL) centered on the hippocampus, as concluded from inverse solutions, coherence measurements, and depth electrode recordings in humans. In this study, we tested patients with unilateral MTL lesions due to stroke to verify the provenance of this signal and its association with the spacing effect (SE)-the improved learning of material encountered in spaced rather than massed presentation. We found that unilateral left or right MTL lesions abolished the early frontal MTL-mediated signal but not the spacing effect. We conclude that the SE does not depend on MTL integrity. We suggest that the early frontal signal at 200-300 ms after immediate picture repetition may serve as a direct biomarker of MTL integrity that may be useful in the early stages of diseases like Alzheimer's.

Consolidation of a Learned Skill Correlates with Dopamine SPECT Uptake in Early Parkinson's Disease.

BACKGROUND AND PURPOSE: Basal ganglia play a pivotal role in procedural memory. However, the correlation between skill learning and striatal ¹²³I-ioflupane uptake in Parkinson's disease (PD) has not been reported previously. Our objective was to determine whether visuomotor skill learning is associated with striatal ¹²³I-ioflupane uptake in early PD. METHODS: We designed a case-control study to assess learning and consolidation of a visuomotor learning task (mirrored drawing of star-shaped figures) performed on two consecutive days by early-PD patients (disease duration <2 years) and age-matched healthy subjects. Outcomes were the error rate and time per trial, as well as performance indices to assess the relative improvement on the first day (learning) and the retention on the second day (consolidation). For PD patients, we evaluated the correlation of skill learning with semiquantitative ¹²³I-ioflupane uptake. RESULTS: We included 9 PD patients and 10 control subjects with the same baseline characteristics (age, male/female ratio, educational level, Mini Mental State Examination score, and Hospital Anxiety and Depression Scale score, all p>0.18) other than the score on part III of the Movement Disorders Society Unified Parkinson's Disease Rating Scale, which was higher in the PD patients (mean±SD: 15.0±10.4 vs. 1.3±1.1, p<0.001). The learning indices were the same in the two groups (p>0.5), whereas PD patients showed a lower consolidation index for the time per trial (p=0.009). Moreover, this performance was correlated with uptake in the right caudate nucleus (Spearman's rho=0.82, p=0.007) and the right striatum (Spearman's rho=0.67, p=0.049), including when multiple linear regression adjusting for the levodopa equivalent daily dose was performed (p=0.005 for the caudate nucleus and p=0.024 for the striatum). CONCLUSIONS: This study provides evidence of a correlation between procedural memory impairment and striatal dopaminergic dysfunction in early PD.

Resting-state connectivity after visuo-motor skill learning is inversely associated with offline consolidation in Parkinson's disease and healthy controls.

Procedural memory refers to skills acquired through practice and depends on cortico-striatal and cortico-cerebellar circuits. These circuits are typically affected in Parkinson's disease (PD), leading to impaired skill learning, including defective offline consolidation, early in the course of the disease. Evidence points to a role of slow oscillations (<4 Hz) during sleep for offline consolidation. However recent studies showed consolidation over the course of the day, suggesting that consolidation may arise during wakefulness, too. Here we investigate whether functional connectivity (FC) at rest after visuo-motor skill learning is associated with the extent of offline improvements in healthy controls and PD patients. Nineteen participants (9 PD, 10 healthy controls) performed a mirror-drawing task. High-density 156-channel resting state EEG was recorded before and immediately after training. Performance on the task was measured again 24 h later to test for offline consolidation. Delta-band (1-3.5 Hz) FC centered on the left parietal cortex after training predicted offline consolidation. Weak FC was observed in most healthy controls and associated with marked overnight improvement, while strong FC was observed in most PD patients and associated with weak offline consolidation or loss of the skill. These findings indicate that offline consolidation starts immediately after visuo-motor skill learning in brain regions and frequencies typically involved in sleep-related consolidation.

Resting-state connectivity predicts visuo-motor skill learning.

Spontaneous brain activity at rest is highly organized even when the brain is not explicitly engaged in a task. Functional connectivity (FC) in the alpha frequency band (α, 8-12 Hz) during rest is associated with improved performance on various cognitive and motor tasks. In this study we explored how FC is associated with visuo-motor skill learning and offline consolidation. We tested two hypotheses by which resting-state FC might achieve its impact on behavior: preparing the brain for an upcoming task or consolidating training gains. Twenty-four healthy participants were assigned to one of two groups: The experimental group (n = 12) performed a computerized mirror-drawing task. The control group (n = 12) performed a similar task but with concordant cursor direction. High-density 156-channel resting-state EEG was recorded before and after learning. Subjects were tested for offline consolidation 24h later. The Experimental group improved during training and showed offline consolidation. Increased α-FC between the left superior parietal cortex and the rest of the brain before training and decreased α-FC in the same region after training predicted learning. Resting-state FC following training did not predict offline consolidation and none of these effects were present in controls. These findings indicate that resting-state alpha-band FC is primarily implicated in providing optimal neural resources for upcoming tasks.

Simultaneous Reality Filtering and Encoding of Thoughts: The Substrate for Distinguishing between Memories of Real Events and Imaginations?

Any thought, whether it refers to the present moment or reflects an imagination, is again encoded as a new memory trace. Orbitofrontal reality filtering (ORFi) denotes an on-line mechanism which verifies whether upcoming thoughts relate to ongoing reality or not. Its failure induces reality confusion with confabulations and disorientation. If the result of this process were simultaneously encoded, it would easily explain later distinction between memories relating to a past reality and memories relating to imagination, a faculty called reality monitoring. How the brain makes this distinction is unknown but much research suggests that it depends on processes active when information is encoded. Here we explored the precise timing between ORFi and encoding as well as interactions between the involved brain structures. We used high-density evoked potentials and two runs of a continuous recognition task (CRT) combining the challenges of ORFi and encoding. ORFi was measured by the ability to realize that stimuli appearing in the second run had not appeared in this run yet. Encoding was measured with immediately repeated stimuli, which has been previously shown to induce a signal emanating from the medial temporal lobe (MTL), which has a protective effect on the memory trace. We found that encoding, as measured with this task, sets in at about 210 ms after stimulus presentation, 35 ms before ORFi. Both processes end at about 330 ms. Both were characterized by increased coherence in the theta band in the MTL during encoding and in the orbitofrontal cortex (OFC) during ORFi. The study suggests a complex interaction between OFC and MTL allowing for thoughts to be re-encoded while they undergo ORFi. The combined influence of these two processes at 200-300 ms may leave a memory trace that allows for later effortless reality monitoring in most everyday situations.

[Formula: see text]Children's sense of reality: The development of orbitofrontal reality filtering.

Orbitofrontal reality filtering denotes a memory control mechanism necessary to keep thought and behavior in phase with reality. In adults, it is mediated by the orbitofrontal cortex and subcortical connections and its failure induces reality confusion, confabulations, and disorientation. Here we investigated for the first time the development of this mechanism in 83 children from ages 7 to 11 years and 20 adults. We used an adapted version of a continuous recognition task composed of two runs with the same picture set but arranged in different order. The first run measures storage and recognition capacity (item memory), the second run measures reality filtering. We found that accuracy and reaction times in response to all stimulus types of the task improved in parallel across ages. Importantly, at no age was there a notable performance drop in the second run. This means that reality filtering was already efficacious at age 7 and then steadily improved as item memory became stronger. At the age of 11 years, reality filtering dissociated from item memory, similar to the pattern observed in adults. However, performance in 11-year-olds was still inferior as compared to adults. The study shows that reality filtering develops early in childhood and becomes more efficacious as memory capacity increases. For the time being, it remains unresolved, however, whether this function already depends on the orbitofrontal cortex, as it does in adults, or on different brain structures in the developing brains of children.

No Influence of Positive Emotion on Orbitofrontal Reality Filtering: Relevance for Confabulation.

Orbitofrontal reality filtering (ORFi) is a mechanism that allows us to keep thought and behavior in phase with reality. Its failure induces reality confusion with confabulation and disorientation. Confabulations have been claimed to have a positive emotional bias, suggesting that they emanate from a tendency to embellish the situation of a handicap. Here we tested the influence of positive emotion on ORFi in healthy subjects using a paradigm validated in reality confusing patients and with a known electrophysiological signature, a frontal positivity at 200-300 ms after memory evocation. Subjects made two continuous recognition tasks ("two runs"), composed of the same set of neutral and positive pictures, but arranged in different order. In both runs, participants had to indicate picture repetitions within, and only within, the ongoing run. The first run measures learning and recognition. The second run, where all items are familiar, requires ORFi to avoid false positive responses. High-density evoked potentials were recorded from 19 healthy subjects during completion of the task. Performance was more accurate and faster on neutral than positive pictures in both runs and for all conditions. Evoked potential correlates of emotion and reality filtering occurred at 260-350 ms but dissociated in terms of amplitude and topography. In both runs, positive stimuli evoked a more negative frontal potential than neutral ones. In the second run, the frontal positivity characteristic of reality filtering was separately, and to the same degree, expressed for positive and neutral stimuli. We conclude that ORFi, the ability to place oneself correctly in time and space, is not influenced by emotional positivity of the processed material.

Effect of prefrontal and parietal tDCS on learning and recognition of verbal and non-verbal material.

OBJECTIVE: Information learned in a spaced way is usually better recognized than information learned in a massed way. The brain mechanisms underlying this spacing effect remain unclear. METHODS: We applied anodal transcranial direct current stimulation (tDCS) to the left and right prefrontal (PFC) or posterior parietal (PPC) cortices to study how stimulation influences learning and retrieval of information, as evidenced by item recognition and the spacing effect, and whether the effects are lateralized according to stimulus material and site of stimulation. We devised a continuous recognition task with verbal and non-verbal stimuli repeated either immediately or after a delay. Stimulus recognition was tested 30min later. RESULTS: There was a spacing effect for both materials, which, however, was not modulated by tDCS. Nonetheless, tDCS differentially impacted memory retrieval regardless of repetition mode during learning: tDCS over the PPC during learning enhanced recognition of non-verbal material regardless of side of stimulation, while tDCS over the left PFC decreased recognition regardless of material. CONCLUSIONS: The PPC seems to be involved specifically in the mnesic treatment of non-verbal material whereas the left PFC specifically influences learning irrespective of stimulus material. SIGNIFICANCE: Prefrontal and posterior parietal cortices follow different lateralization rules in recognition memory.

Partly segregated cortico-subcortical pathways support phonologic and semantic verbal fluency: A lesion study.

Verbal fluency refers to the ability to generate as many words as possible in a limited time interval, without repetition and according to either a phonologic (each word begins with a given letter) or a semantic rule (each word belongs to a given semantic category). While current literature suggests the involvement of left fronto-temporal structures in fluency tasks, whether the same or distinct brain areas are necessary for each type of fluency remains unclear. We tested the hypothesis for an involvement of partly segregated cortico-subcortical structures between phonologic and semantic fluency by examining with a voxel-based lesion symptom mapping approach the effects of brain lesions on fluency scores corrected for age and education level in a group of 191 unselected brain-damaged patients with a first left or right hemispheric lesion. There was a positive correlation between the scores to the two types of fluency, suggesting that common mechanisms underlie the word generation independent of the production rule. The lesion-symptom mapping revealed that lesions to left basal ganglia impaired both types of fluency and that left superior temporal, supramarginal and rolandic operculum lesions selectively impaired phonologic fluency and left middle temporal lesions impaired semantic fluency. Our results corroborate current neurocognitive models of word retrieval and production, and refine the role of cortical-subcortical interaction in lexical search by highlighting the common executive role of basal ganglia in both types of verbal fluency and the preferential involvement of the ventral and dorsal language pathway in semantic and phonologic fluency, respectively.

Prefrontal transcranial direct current stimulation facilitates affective flexibility.

Performance on paradigms involving switching between emotional and non-emotional task-sets (affective flexibility) predicts emotion regulation abilities and is impaired in patients with different emotional disorders. A better understanding of how neurostimulation techniques such as transcranial direct current stimulation (tDCS) influence affective switching may provide support for the improvement of rehabilitation programs. In the current study healthy volunteers received anodal tDCS over the right dorsolateral prefrontal cortex (DLPFC), the left DLPFC or sham stimulation while performing an affective-switching task. Participants had to repeat or switch between facial judgments of emotional expressions (emotional task-set) or gender (non-emotional task-set). Right tDCS resulted in faster responses in the gender task only when it followed a judgment of emotion. These effects were not observed following left tDCS. Further, switching away from emotion was easier for the right compared to left tDCS group (reduced switch costs for gender), while switching away from gender toward emotion was easier for the left compared to the right group (reduced switch-costs for emotion). In sum, tDCS over the DLPFC may modulate affective flexibility and right stimulation may be particularly helpful to facilitate disengagement from emotional task-sets. The usefulness of tDCS-trained affective switching may be further investigated on larger therapeutic protocols targeting emotional disorders.

Differential processing of immediately repeated verbal and non-verbal stimuli: an evoked-potential study.

Stimuli are better retained in memory if they are repeated after a delay than if they are immediately repeated. This effect is called the spacing effect (SE). Recent electroencephalographic (EEG) studies showed that delayed repetition of meaningful designs in a continuous recognition task induces an evoked response very similar to new presentations. In contrast, immediately repeated designs induced circumscribed, stronger activation of the left medio-temporal lobe (MTL) at 200-300 ms. In amnesic subjects, this signal was missing, indicating that it has a memory-protective effect. Here, high-density EEG was used in humans to explore whether meaningless verbal (non-words) and non-verbal (geometric designs) stimuli also have a SE associated with such lateralized, temporally limited activation of the left MTL upon immediate repetition. The results revealed a SE for both materials. Timing and localization of brain activity differed as a function of stimulus material. Specific responses to immediate repetitions occurred at 200-285 ms for non-verbal stimuli and at 285-380 ms for verbal material. Source estimations revealed increased activity in right inferior frontal areas for immediate non-verbal repetitions and in left fronto-parietal areas for immediate verbal repetition in comparison to new presentations. These findings show that, while the SE is a ubiquitous phenomenon, the neural processes underlying it vary according to stimulus material.

Task relevance effects in electrophysiological brain activity: early, but not first.

A current controversy surrounds the question whether high-level features of a stimulus such as its relevance to the current task may affect early attentional processes. According to one view abruptly appearing stimuli gain priority during an initial feedforward processing stage and therefore capture attention even if they are irrelevant to the task. Alternatively, only stimuli that share a relevant property with the target may capture attention of the observer. Here, we used high-density EEG to test whether task relevance may modulate early feedforward brain activity, or whether it only becomes effective once the physical characteristics of the stimulus have been processed. We manipulated task relevance and visual saliency of distracters presented left or right of an upcoming central target. We found that only the relevance of distracters had an effect on manual reaction times to the target. However, the analysis of electrocortical activity revealed three discrete processing stages during which pure effects of distracter saliency (~80-160 ms), followed by an interaction between saliency and relevance (~130-240 ms) and finally pure effects of relevance (~230-370 ms) were observed. Electrical sources of early saliency effects and later relevance effects were localized in the posterior parietal cortex, predominantly over the right hemisphere. These findings support the view that during the initial feedforward stage only physical (bottom-up) factors determine cortical responses to visual stimuli, while top-down effects interfere at later processing stages.

Training-induced behavioral and brain plasticity in inhibitory control.

Deficits in inhibitory control, the ability to suppress ongoing or planned motor or cognitive processes, contribute to many psychiatric and neurological disorders. The rehabilitation of inhibition-related disorders may therefore benefit from neuroplasticity-based training protocols aiming at normalizing inhibitory control proficiency and the underlying brain networks. Current literature on training-induced behavioral and brain plasticity in inhibitory control suggests that improvements may follow either from the development of automatic forms of inhibition or from the strengthening of top-down, controlled inhibition. Automatic inhibition develops in conditions of consistent and repeated associations between inhibition-triggering stimuli and stopping goals. Once established, the stop signals directly elicit inhibition, thereby bypassing slow, top-down executive control and accelerating stopping processes. In contrast, training regimens involving varying stimulus-response associations or frequent inhibition failures prevent the development of automatic inhibition and thus strengthen top-down inhibitory processes rather than bottom-up ones. We discuss these findings in terms of developing optimal inhibitory control training regimens for rehabilitation purposes.