Ventromedial prefrontal cortex activation and neurofeedback modulation during episodic future thinking for individuals with suicidal thoughts and behaviors.

Individuals experiencing suicidal thoughts and behaviors (STBs) show less specificity and positivity during episodic future thinking (EFT). Here, we present findings from two studies aiming to (1) further our understanding of how STBs may relate to neural responsivity during EFT and (2) examine the feasibility of modulating EFT-related activation using real-time fMRI neurofeedback (rtfMRI-nf). Study 1 involved 30 individuals with major depressive disorder (MDD; half with STBs) who performed an EFT task during fMRI, for which they imagined personally-relevant future positive, negative, or neutral events. Positive EFT elicited greater ventromedial prefrontal cortex (vmPFC) activation compared to negative EFT. Importantly, the MDD + STB group exhibited reduced vmPFC activation across all EFT conditions compared to MDD-STB; although EFT fluency and subjective experience remained consistent across groups. Study 2 included rtfMRI-nf focused on vmPFC modulation during positive EFT for six participants with MDD + STBs. Results support the feasibility and acceptability of the rtfMRI-nf protocol and quantitative and qualitative observations are provided to help inform future, larger studies aiming to examine similar neurofeedback protocols. Results implicate vmPFC blunting as a promising treatment target for MDD + STBs and suggest rtfMRI-nf as one potential technique to explore for enhancing vmPFC engagement.

An fMRI investigation of the relationship between future imagination and cognitive flexibility.

While future imagination is largely considered to be a cognitive process grounded in default mode network activity, studies have shown that future imagination recruits regions in both default mode and frontoparietal control networks. In addition, it has recently been shown that the ability to imagine the future is associated with cognitive flexibility, and that tasks requiring cognitive flexibility result in increased coupling of the default mode network with frontoparietal control and salience networks. In the current study, we investigated the neural correlates underlying the association between cognitive flexibility and future imagination in two ways. First, we experimentally varied the degree of cognitive flexibility required during future imagination by manipulating the disparateness of episodic details contributing to imagined events. To this end, participants generated episodic details (persons, locations, objects) within three social spheres; during fMRI scanning they were presented with sets of three episodic details all taken from the same social sphere (Congruent condition) or different social spheres (Incongruent condition) and required to imagine a future event involving the three details. We predicted that, relative to the Congruent condition, future simulation in the Incongruent condition would be associated with increased activity in regions of the default mode, frontoparietal and salience networks. Second, we hypothesized that individual differences in cognitive flexibility, as measured by performance on the Alternate Uses Task, would correspond to individual differences in the brain regions recruited during future imagination. A task partial least squares (PLS) analysis showed that the Incongruent condition resulted in an increase in activity in regions in salience networks (e.g. the insula) but, contrary to our prediction, reduced activity in many regions of the default mode network (including the hippocampus). A subsequent functional connectivity (within-subject seed PLS) analysis showed that the insula exhibited increased coupling with default mode regions during the Incongruent condition. Finally, a behavioral PLS analysis showed that individual differences in cognitive flexibility were associated with differences in activity in a number of regions from frontoparietal, salience and default-mode networks during both future imagination conditions, further highlighting that the cognitive flexibility underlying future imagination is grounded in the complex interaction of regions in these networks.

Remembering what could have happened: neural correlates of episodic counterfactual thinking.

Recent evidence suggests that our capacities to remember the past and to imagine what might happen in the future largely depend on the same core brain network that includes the middle temporal lobe, the posterior cingulate/retrosplenial cortex, the inferior parietal lobe, the medial prefrontal cortex, and the lateral temporal cortex. However, the extent to which regions of this core brain network are also responsible for our capacity to think about what could have happened in our past, yet did not occur (i.e., episodic counterfactual thinking), is still unknown. The present study examined this issue. Using a variation of the experimental recombination paradigm (Addis, Pan, Vu, Laiser, & Schacter, 2009. Neuropsychologia. 47: 2222-2238), participants were asked both to remember personal past events and to envision alternative outcomes to such events while undergoing functional magnetic resonance imaging. Three sets of analyses were performed on the imaging data in order to investigate two related issues. First, a mean-centered spatiotemporal partial least square (PLS) analysis identified a pattern of brain activity across regions of the core network that was common to episodic memory and episodic counterfactual thinking. Second, a non-rotated PLS analysis identified two different patterns of brain activity for likely and unlikely episodic counterfactual thoughts, with the former showing significant overlap with the set of regions engaged during episodic recollection. Finally, a parametric modulation was conducted to explore the differential engagement of brain regions during counterfactual thinking, revealing that areas such as the parahippocampal gyrus and the right hippocampus were modulated by the subjective likelihood of counterfactual simulations. These results suggest that episodic counterfactual thinking engages regions that form the core brain network, and also that the subjective likelihood of our counterfactual thoughts modulates the engagement of different areas within this set of regions.

Prefrontal-hippocampal-fusiform activity during encoding predicts intraindividual differences in free recall ability: an event-related functional-anatomic MRI study.

The ability to spontaneously recall recently learned information is a fundamental mnemonic activity of daily life, but has received little study using functional neuroimaging. We developed a functional MRI (fMRI) paradigm to study regional brain activity during encoding that predicts free recall. In this event-related fMRI study, ten lists of fourteen pictures of common objects were shown to healthy young individuals and regional brain activity during encoding was analyzed based on subsequent free recall performance. Free recall of items was predicted by activity during encoding in hippocampal, fusiform, and inferior prefrontal cortical regions. Within-subject variance in free recall performance for the ten lists was predicted by a linear combination of condition-specific inferior prefrontal, hippocampal, and fusiform activity. Recall performance was better for lists in which prefrontal activity was greater for all items of the list and hippocampal and fusiform activity were greater specifically for items that were recalled from the list. Thus, the activity of medial temporal, fusiform, and prefrontal brain regions during the learning of new information is important for the subsequent free recall of this information. These fronto-temporal brain regions act together as a large-scale memory-related network, the components of which make distinct yet interacting contributions during encoding that predict subsequent successful free recall performance.

Top-down facilitation of visual recognition.

Cortical analysis related to visual object recognition is traditionally thought to propagate serially along a bottom-up hierarchy of ventral areas. Recent proposals gradually promote the role of top-down processing in recognition, but how such facilitation is triggered remains a puzzle. We tested a specific model, proposing that low spatial frequencies facilitate visual object recognition by initiating top-down processes projected from orbitofrontal to visual cortex. The present study combined magnetoencephalography, which has superior temporal resolution, functional magnetic resonance imaging, and a behavioral task that yields successful recognition with stimulus repetitions. Object recognition elicited differential activity that developed in the left orbitofrontal cortex 50 ms earlier than it did in recognition-related areas in the temporal cortex. This early orbitofrontal activity was directly modulated by the presence of low spatial frequencies in the image. Taken together, the dynamics we revealed provide strong support for the proposal of how top-down facilitation of object recognition is initiated, and our observations are used to derive predictions for future research.

fMRI studies of associative encoding in young and elderly controls and mild Alzheimer's disease.

OBJECTIVE: To examine alterations in patterns of brain activation seen in normal aging and in mild Alzheimer's disease by functional magnetic resonance imaging (fMRI) during an associative encoding task. METHODS: 10 young controls, 10 elderly controls, and seven patients with mild Alzheimer's disease were studied using fMRI during a face-name association encoding task. The fMRI paradigm used a block design with three conditions: novel face-name pairs, repeated face-name pairs, and visual fixation. RESULTS: The young and elderly controls differed primarily in the pattern of activation seen in prefrontal and parietal cortices: elderly controls showed significantly less activation in both superior and inferior prefrontal cortices but greater activation in parietal regions than younger controls during the encoding of novel face-name pairs. Compared with elderly controls, the Alzheimer patients showed significantly less activation in the hippocampal formation but greater activation in the medial parietal and posterior cingulate regions. CONCLUSIONS: The pattern of fMRI activation during the encoding of novel associations is differentially altered in the early stages of Alzheimer's disease compared with normal aging.

Suppression of false recognition in Alzheimer's disease and in patients with frontal lobe lesions.

Previous research has shown that patients with Alzheimer's disease show increasing levels of false recognition across five repeated study-test trials of semantic associates. The present study tested the hypotheses that (i) the increasing false recognition was partly due to the frontal lobe dysfunction of patients with Alzheimer's disease, and (ii) a failure of source monitoring was the central mechanism by which frontal lobe dysfunction led to increasing false recognition across trials. In Experiment 1, patients with frontal lobe lesions and controls were examined in the same repeated trials paradigm as that used previously in patients with Alzheimer's disease. Although controls were able to reduce their false recognition across trials, the patients with frontal lobe lesions were not, and instead showed a constant level of elevated false recognition across the study-test trials. In Experiment 2, two groups of patients with Alzheimer's disease and healthy older adult controls were studied: the first group was given a single study session followed by a recognition test, the second group was given five study sessions followed by a single recognition test. Older adults who were exposed to five study lists demonstrated lower levels of false relative to true recognition, whereas patients with Alzheimer's disease in this condition exhibited levels of false recognition elevated to that of their true recognition, even with the source memory confusion of intervening tests eliminated. The authors suggest that impairment in aspects of frontal lobe function, such as verification-inhibition mechanisms, probably contributes to the inability of patients with Alzheimer's disease to suppress their false recognition across repeated trials. Lastly, it is speculated that one way in which the frontal lobes enable normal episodic memory function is by facilitating the suppression of false recognition and other distortions of memory.

Prefrontal contributions to executive control: fMRI evidence for functional distinctions within lateral Prefrontal cortex.

The prefrontal cortex (PFC) plays a fundamental role in internally guided behavior. Although it is generally accepted that PFC subserves working memory and executive control operations, it remains unclear whether the subregions within lateral PFC support distinct executive control processes. An event-related fMRI study was implemented to test the hypothesis that ventrolateral and dorsolateral PFC are functionally distinct, as well as to assess whether functional specialization exists within ventrolateral PFC. Participants performed two executive control tasks that differed in the types of control processes required. During rote rehearsal, participants covertly rehearsed three words in the order presented, thus requiring phonological access and maintenance. During elaborative rehearsal, participants made semantic comparisons between three words held in working memory, reordering them from least to most desirable. Thus, in addition to maintenance, elaborative rehearsal required goal-relevant coding of items in working memory ("monitoring") and selection from among the items to implement their reordering. Results revealed that left posterior ventrolateral PFC was active during performance of both tasks, whereas right dorsolateral PFC was differentially engaged during elaborative rehearsal. The temporal characteristics of the hemodynamic responses further suggested that dorsolateral activation lagged ventrolateral activation. Finally, differential activation patterns were observed within left ventrolateral PFC, distinguishing between posterior and anterior regions. These data suggest that anatomically separable subregions within lateral PFC may be functionally distinct and are consistent with models that posit a hierarchical relationship between dorsolateral and ventrolateral regions such that the former monitors and selects goal-relevant representations being maintained by the latter.

Misattribution, false recognition and the sins of memory.

Memory is sometimes a troublemaker. Schacter has classified memory's transgressions into seven fundamental 'sins': transience, absent-mindedness, blocking, misattribution, suggestibility, bias and persistence. This paper focuses on one memory sin, misattribution, that is implicated in false or illusory recognition of episodes that never occurred. We present data from cognitive, neuropsychological and neuroimaging studies that illuminate aspects of misattribution and false recognition. We first discuss cognitive research examining possible mechanisms of misattribution associated with false recognition. We also consider ways in which false recognition can be reduced or avoided, focusing in particular on the role of distinctive information. We next turn to neuropsychological research concerning patients with amnesia and Alzheimer's disease that reveals conditions under which such patients are less susceptible to false recognition than are healthy controls, thus providing clues about the brain mechanisms that drive false recognition. We then consider neuroimaging studies concerned with the neural correlates of true and false recognition, examining when the two forms of recognition can and cannot be distinguished on the basis of brain activity. Finally, we argue that even though misattribution and other memory sins are annoying and even dangerous, they can also be viewed as by-products of adaptive features of memory.

On the tip of the tongue: an event-related fMRI study of semantic retrieval failure and cognitive conflict.

The tip of the tongue (TOT) state refers to a temporary inaccessibility of information that one is sure exists in long-term memory and is on the verge of recovering. Using event-related fMRI, we assessed the neural correlates of this semantic retrieval failure to determine whether the anterior cingulate-lateral prefrontal neural circuit posited to mediate conflict resolution is engaged during metacognitive conflicts that arise during the TOT. Results revealed that, relative to successful retrieval or unsuccessful retrieval not accompanied by a TOT, retrieval failures accompanied by TOTs elicited a selective response in anterior cingulate-prefrontal cortices. During a TOT, cognitive control mechanisms may be recruited in attempts to resolve the conflict and retrieval failure that characterize this state.

Encoding novel face-name associations: a functional MRI study.

The process of forming new associations between previously unrelated items of information, such as a name and a face, likely requires the integration of activity within multiple brain regions. The hippocampus and related structures in the medial temporal lobe are thought to be particularly critical in binding together items of information. We studied eight healthy young subjects with functional magnetic resonance imaging (fMRI) during the encoding of novel face-name associations compared to viewing repeated face-name pairs. A consistent pattern of activation was observed in the hippocampus, pulvinar nucleus of the thalamus, fusiform and dorsolateral prefrontal cortices across individual subjects. The location of the activation within the hippocampus was more anterior than previously reported in studies using similar novel vs. repeated paradigms with stimuli that did not specifically require relational processing among unrelated items. These data suggest that the process of forming new face-name associations is supported by a distributed network of brain regions, and provide additional evidence for the essential role of the hippocampus in associative memory processes.

"If I had said it I would have remembered it": reducing false memories with a distinctiveness heuristic.

We examined the contributions of decision processes to the rejection of false memories. In two experiments, people studied lists of semantically related words and then completed a recognition test containing studied words, unrelated lure words, and related lure words. People who said words aloud at study were less likely to falsely recognize related lures on the test than were those who heard words at study. We suggest that people who said words at study employed a distinctiveness heuristic during the test whereby they demanded access to distinctive say information in order to judge an item as old. Even when retrieving say information is not perfectly diagnostic of prior study, as in Experiment 2, in which participants both said and heard words at study, people persist in using the distinctiveness heuristic to reduce false memories.

Do amnesics exhibit cognitive dissonance reduction? The role of explicit memory and attention in attitude change.

In two studies, we investigated the roles of explicit memory and attentional resources in the process of behavior-induced attitude change. Although most theories of attitude change (cognitive dissonance and self-perception theories) assume an important role for both mechanisms, we propose that behavior-induced attitude change can be a relatively automatic process that does not require explicit memory for, or consciously controlled processing of, the discrepancy between attitude and behavior. Using a free-choice paradigm, we found that both amnesics and normal participants under cognitive load showed as much attitude change as did control participants.

Can medial temporal lobe regions distinguish true from false? An event-related functional MRI study of veridical and illusory recognition memory.

To investigate the types of memory traces recovered by the medial temporal lobe (MTL), neural activity during veridical and illusory recognition was measured with the use of functional MRI (fMRI). Twelve healthy young adults watched a videotape segment in which two speakers alternatively presented lists of associated words, and then the subjects performed a recognition test including words presented in the study lists (True items), new words closely related to studied words (False items), and new unrelated words (New items). The main finding was a dissociation between two MTL regions: whereas the hippocampus was similarly activated for True and False items, suggesting the recovery of semantic information, the parahippocampal gyrus was more activated for True than for False items, suggesting the recovery of perceptual information. The study also yielded a dissociation between two prefrontal cortex (PFC) regions: whereas bilateral dorsolateral PFC was more activated for True and False items than for New items, possibly reflecting monitoring of retrieved information, left ventrolateral PFC was more activated for New than for True and False items, possibly reflecting semantic processing. Precuneus and lateral parietal regions were more activated for True and False than for New items. Orbitofrontal cortex and cerebellar regions were more activated for False than for True items. In conclusion, the results suggest that activity in anterior MTL regions does not distinguish True from False, whereas activity in posterior MTL regions does.

Perceptual false recognition in Alzheimer's disease.

Previous research has found that patients with probable Alzheimer's disease (AD) show lower levels of false recognition of semantic associates than do healthy older adults. To investigate whether this finding is attributable to semantic impairments in patients with AD, the authors examined false recognition of perceptually related novel objects with little semantic content in patients with AD and healthy older adults. By using corrected recognition scores to control for unrelated false alarms, it was found that patients with AD showed lower levels of both true and false recognition of novel objects than did older adults. These results suggest that the previous difference in false recognition of semantic associates observed between patients with AD and older adults is not entirely attributable to semantic memory deficits in patients with AD but may also involve poorly developed gist information in these patients.

Recognizing identical versus similar categorically related common objects: further evidence for degraded gist representations in amnesia.

Studies have shown lower false recognition of semantically related lure words in patients with global amnesia than in matched controls. This pattern has been interpreted as suggesting that medial temporal and diencephalic structures that are damaged in amnesia and that contribute to veridical memory also contribute to false recognition. It has been argued that whereas controls form and retain a well-organized representation of the semantic gist of studied items, patients with amnesia can retain only a degraded gist representation. However, these studies are subject to an alternative interpretation involving greater source confusions in controls. The authors used a categorized-pictures paradigm to test recognition under conditions in which source confusions were unlikely to occur. Relative to controls, patients with amnesia showed reduced false recognition of categorically related pictorial lures, thereby supporting the notion of degraded gist representations in amnesia.

Directed forgetting of trauma cues in adults reporting repressed or recovered memories of childhood sexual abuse.

An item-cuing directed forgetting task was used to investigate whether women reporting repressed (n = 13) or recovered (n = 13) memories of childhood sexual abuse (CSA) exhibit an avoidant encoding style (and resultant impaired memory) for trauma cues relative to women reporting no CSA experience (n = 15). All participants viewed intermixed trauma (e.g., molested), positive (e.g., confident), and categorized neutral (e.g., mailbox) words on a computer screen and were instructed either to remember or to forget each word. The results provided no support for the hypothesis that people reporting either repressed or recovered memories of CSA are especially adept at forgetting words related to trauma. These groups recalled words they were instructed to remember more often than words they were instructed to forget regardless of whether they were trauma related.

Cortical mechanisms specific to explicit visual object recognition.

The cortical mechanisms associated with conscious object recognition were studied using functional magnetic resonance imaging (fMRI). Participants were required to recognize pictures of masked objects that were presented very briefly, randomly and repeatedly. This design yielded a gradual accomplishment of successful recognition. Cortical activity in a ventrotemporal visual region was linearly correlated with perception of object identity. Therefore, although object recognition is rapid, awareness of an object's identity is not a discrete phenomenon but rather associated with gradually increasing cortical activity. Furthermore, the focus of the activity in the temporal cortex shifted anteriorly as subjects reported an increased knowledge regarding identity. The results presented here provide new insights into the processes underlying explicit object recognition, as well as the analysis that takes place immediately before and after recognition is possible.

Brain potentials reflect behavioral differences in true and false recognition.

People often falsely recognize nonstudied lures that are semantically similar to previously studied words. Behavioral research suggests that such false recognition is based on high semantic overlap between studied items and lures that yield a feeling of familiarity, whereas true recognition is more often associated with the recollection of details. Despite this behavioral evidence for differences between true and false recognition, research measuring brain activity (PET, fMRI, ERP) has not clearly differentiated corresponding differences in brain activity. A median split was used to separate subjects into Good and Poor performers based on their discrimination of studied targets from similar lures. Only Good performers showed late (1000--1500 msec), right frontal event-related brain potentials (ERPs) that were more positive for targets and lures compared with new items. The right frontal differences are interpreted as reflecting postretrieval evaluation processes that were more likely to be engaged by Good than Poor performers. Both Good and Poor performers showed a parietal ERP old/new effect (400--800 msec), but only Poor performers showed a parietal old/lure difference. These results are consistent with the view that the parietal and frontal ERP old/new effects reflect dissociable processes related to recollection.