Aging effects on the encoding/retrieval flip in associative memory: fMRI evidence from incidental contingency learning.

Introduction: Associative memory is arguably the most basic memory function and therein constitutes the foundation of all episodic and semantic memory processes. At the same time, the decline of associative memory represents a core feature of age-related cognitive decline in both, healthy and pathological (i.e., dementia-related) aging. The neural mechanisms underlying age-related impairments in associative memory are still not fully understood, especially regarding incidental (i.e., non-intentional) learning. Methods: We investigated the impact of age on the incidental learning and memory retrieval of face-name combinations in a total sample of 46 young (N = 23; mean age = 23.39 years) and elderly (N = 22, mean age = 69.05 years) participants. More specifically, particular interest was placed in age-related changes in encoding/retrieval (E/R) flips, which denote a neural antagonism of opposed activation patterns in the same brain region during memory encoding and retrieval, which were assessed using fMRI. Results: According to our hypothesis, the results showed a significant age-related decline in the retrieval performance in the old group. Additionally, at the neural level, we discovered an abolished E/R flip in the right anterior insula and a joint but reduced E/R flip activation magnitude in the posterior middle cingulate cortex in older subjects. Discussion: In conclusion, the present findings suggest that the impaired neural modulation of the E/R flip in the right aIC might be a sensitive marker in the early detection of neural aging.

Correlation Between Hippocampal Volume and Autobiographical Memory Depending on Retrieval Frequency in Healthy Individuals and Patients with Alzheimer's Disease.

The hippocampus plays an indispensable role in episodic memory, particularly during the consolidation process. However, its precise role in retrieval of episodic memory is still ambiguous. In this study, we investigated the correlation of hippocampal morphometry and the performance in an autobiographical memory task in 27 healthy controls and 24 patients suffering from Alzheimer's disease (AD). Most importantly, correlations were defined separately and comparatively for memory contents with different retrieval frequency in the past. In healthy subjects, memory performance for seldom retrieved autobiographical events was significantly associated with gray matter density in the bilateral hippocampus, whereas this correlation was not present for events with high retrieval frequency. This pattern of findings confirms that retrieval frequency plays a critical role in the consolidation of episodic autobiographical memories, thereby making them more independent of the hippocampal system. In AD patients, on the other hand, successful memory retrieval appeared to be related to hippocampal morphometry irrespective of the contents' retrieval frequency, comprising events with high retrieval frequency, too. The observed differences between patients and control subjects suggest that AD-related neurodegeneration not only impairs the function, but also decreases the functional specialization of the hippocampal memory system, which, thus, may be considered as marker for AD.

The Neural Mechanisms of Associative Memory Revisited: fMRI Evidence from Implicit Contingency Learning.

The literature describes a basic neurofunctional antagonism between episodic memory encoding and retrieval with opposed patterns of neural activation and deactivation, particularly in posterior midline regions. This has been coined the encoding/retrieval (E/R) flip. The present fMRI study uses an innovative task paradigm to further elucidate neurofunctional relations of encoding and retrieval in associative memory. Thereby, memory encoding is implemented as implicit (non-deliberate) cognitive process, whereas the prior literature focused mainly on explicit encoding. Moreover, instead of defining brain activations related to successful (vs. unsuccessful) memory performance, the task paradigm provides proper no-memory baseline conditions. More specifically, the encoding task includes trials with non-contingent (not learnable) stimulus combinations, while the retrieval task uses trials with a simple matching exercise with no mnemonic requirements. The analyses revealed circumscribed activation in the posterior middle cingulate cortex (pMCC) together with prominent deactivation in the anterior insula cortex (aIC) as core neural substrate of implicit memory encoding. Thereby, the pMCC exhibited positive functional connectivity to the hippocampus. Memory retrieval was related to an activation pattern exactly opposed to memory encoding with deactivation in the pMCC and activation in the aIC, while the aIC additionally exhibited a negative (i.e., arguably inhibitive) functional connectivity to the pMCC. Important to note, the observed pattern of activations/de-activations in the pMCC appears to conflict with prevalent E/R flip findings. The outlined results and their (alleged) discrepancies with prior study reports are discussed primarily in the context of the default mode network's functioning and its context-sensitive regulation. Finally, we point out the relevance of the present work for the understanding and further investigation of the neurofunctional aberrations occurring during normal and pathological aging.

A common challenge in older adults: Classification, overlap, and therapy of depression and dementia.

Late-life depression is frequently associated with cognitive impairment. Depressive symptoms are often associated with or even precede a dementia syndrome. Moreover, depressive disorders increase the risk of persistence for mild cognitive impairment and dementia. Here, we present both the current state of evidence and future perspectives regarding the integration and value of clinical assessments, neuropsychological, neurochemical, and neuroimaging biomarkers for the etiological classification of the dementia versus the depression syndrome and for the prognosis of depression relating to dementia risk. Finally, we summarize the existing evidence for both pharmacotherapy and psychotherapy of depression in demented patients. There is an urgent need for large-scale collaborative research to elucidate the role and interplay of clinical and biological features in elderly individuals with depressive disorders who are at elevated risk for developing dementia. To overcome barriers for successful drug development, we propose the introduction of the precision medicine paradigm to this research field.

Autobiographical Memory Performance in Alzheimer's Disease Depends on Retrieval Frequency.

Alzheimer's disease (AD) is characterized by memory disturbances primarily caused by pathogenic mechanisms affecting medial temporal lobe structures. As proposed by current theories of memory formation, this decrease is mediated by the age of the acquired knowledge. However, they cannot fully explain specific patterns of retrograde amnesia in AD. In the current study we examined an alternative approach and investigated whether the extent and severity of retrograde amnesia in AD is mediated by the frequency of memory retrieval or whether it depends on the mere age of knowledge. We compared recall of autobiographical incidents from three life periods in patients with amnestic mild cognitive impairment (aMCI), patients with early dementia of Alzheimer type (eDAT), and healthy control (HC) individuals using the Autobiographical Memory Interview. Retrieval frequency was operationalized by a paired comparison analysis. In contrast to HC individuals, recall of autobiographical incidents was impaired in patients with aMCI and eDAT following Ribot's gradient, with a reduced memory loss for remote compared to more recent life events. However, there was a strong effect of retrieval frequency on memory performance with frequently retrieved incidents memorized in more detail than less frequently retrieved episodes. Remote memories were recalled more often than recent ones. These findings suggest that more frequently retrieved autobiographical memories generally become more independent of the hippocampal complex and might thus be better protected against early hippocampal damage related to AD. Hence, the extent of retrograde amnesia in AD appears mainly mediated by the frequency of memory retrieval, which could plausibly explain why cognitive activity can effectively delay the onset of memory decline in AD.

Gender Differences in Verbal and Visuospatial Working Memory Performance and Networks.

BACKGROUND: Working memory (WM) has been a matter of intensive basic and clinical research for some decades now. The investigation of WM function and dysfunction may facilitate the understanding of both physiological and pathological processes in the human brain. Though WM paradigms are widely used in neuroscientific and psychiatric research, conclusive knowledge about potential moderating variables such as gender is still missing. METHODS: We used functional magnetic resonance imaging to investigate the effects of gender on verbal and visuospatial WM maintenance tasks in a large and homogeneous sample of young healthy subjects. RESULTS: We found significant gender effects on both the behavioral and neurofunctional level. Females exhibited disadvantages with a small effect size in both WM domains accompanied by stronger activations in a set of brain regions (including bilateral substantia nigra/ventral tegmental area and right Broca's area) independent of WM modality. As load and task difficulty effects have been shown for some of these regions, the stronger activations may reflect a slightly lower capacity of both WM domains in females. Males showed stronger bilateral intraparietal activations next to the precuneus which were specific for the visuospatial WM task. Activity in this specific region may be associated with visuospatial short-term memory capacity. CONCLUSION: These findings provide evidence for a slightly lower capacity in both WM modalities in females.

Functional characteristics of control adaptation in intermodal sensory processing.

The present work investigated functional characteristics of control adjustments in intermodal sensory processing. Subjects performed an interference task that involved simultaneously presented visual and auditory stimuli which were either congruent or incongruent with respect to their response mappings. In two experiments, trial-by-trial sequential congruency effects were analysed for specific conditions that allowed ruling out "non-executive" contributions of stimulus or response priming to the respective RT fluctuations. In Experiment 1, conflict adaptation was observed in an oddball condition in which interference emanates from a task-irrelevant and response-neutral low-frequency stimulus. This finding characterizes intermodal control adjustments to be based - at least partly - on increased sensory selectivity, which is able to improve performance in any kind of interference condition which shares the same or overlapping attentional requirements. In order to further specify this attentional mechanism, Experiment 2 defined analogous conflict adaptation effects in non-interference unimodal trials in which just one of the two stimulus modalities was presented. Conflict adaptation effects in unimodal trials exclusively occurred for unimodal task-switch trials but not for otherwise equivalent task repetition trials, which suggests that the observed conflict-triggered control adjustments mainly consist of increased distractor inhibition (i.e., down-regulation of task-irrelevant information), while attributing a negligible role to target amplification (i.e., enhancement of task-relevant information) in this setup. This behavioral study yields a promising operational basis for subsequent neuroimaging investigations to define brain activations and connectivities which underlie the adaptive control of attentional selection.

Common and disease-specific dysfunctions of brain systems underlying attentional and executive control in schizophrenia and bipolar disorder.

Schizophrenia and bipolar disorder broadly overlap in multiple areas involving clinical phenomenology, genetics, and neurobiology. Still, the investigation into specific elementary (sub-)processes of executive functioning may help to define clear points of distinction between these categorical diagnoses to validate the nosological dichotomy and, indirectly, to further elucidate their pathophysiological underpinnings. In the present behavioral study, we sought to separate common from diagnosis-specific deficits in a series of specific elementary sub-functions of executive processing in patients with schizophrenia and bipolar disorder. For our purpose, we administered a modern and multi-purpose neuropsychological task paradigm to equal-sized and matched groups of schizophrenia patients, patients with bipolar disorder, and healthy control subjects. First, schizophrenia patients compared to the bipolar group exhibited a more pronounced deficit in general measures of task performance comprising both response speed and accuracy. Additionally, bipolar patients showed increased advance task preparation, i.e., were better able to compensate for response speed deficits when longer preparation intervals were provided. Set-shifting, on the other hand, was impaired to a similar degree in both patient groups. Finally, schizophrenia patients exhibited a specific deficit in conflict processing (inhibitory control) and the shielding of task-relevant processing from distraction (i.e., attentional maintenance). The present investigation suggests that specific neuropsychological measures of elementary executive functions may represent important points of dissociation between schizophrenia and bipolar disorder, which may help to differentiate the pathophysiological underpinnings of these major psychiatric disorders. In this context, the present findings highlight the measures of inhibitory control and attentional maintenance as promising candidates.

Antagonistic modulatory influences of negative affect on cognitive control: Reduced and enhanced interference resolution capability after the induction of fear and sadness.

The present behavioral study investigated the influence of negative affect on the neural mechanisms of cognitive control. We expected to find evidence for an antagonistic modulation of cognition by threat-relevant and threat-irrelevant negative affect (i.e. fear and sadness) that should promote bottom-up monitoring and top-down selection, respectively. Subjects performed one of three conflict tasks (Stroop, Flanker, or Simon) that tap distinct control mechanisms of conflict resolution, comprising specific attentional and motor control processes. On each task trial, target stimuli were preceded by a face stimulus exhibiting a fearful, sad, or neutral expression, providing three affect conditions. Our data provides strong evidence for substantially increased selection (attentional and motor selection) after priming of threat-irrelevant negative affect (sadness). Deviating from the results of previous studies, our analysis did not consistently yield increased monitoring after fear priming. We discuss these findings with respect to the effectiveness of different experimental affect priming procedures (i.e. stimuli) and the role of the task context, among others.

How negative affect influences neural control processes underlying the resolution of cognitive interference: an event-related fMRI study.

In this event-related fMRI study, we sought to investigate the influence of negative affect on the processing of two kinds of cognitive interference: Stroop-interference and oddball interference. For our purpose, we adopted an oddball variant of the Stroop task in which Stroop-interference and oddball interference conditions were created by presenting incongruent and rarely occurring word meanings, respectively. Immediately preceding the target stimuli, we presented pictures of the International Affective Picture System which were either emotionally negative and arousing or emotionally neutral, providing two affective conditions under which the cognitive task was administered. Both the behavioral and the neuroimaging data exhibited an interaction effect between emotional and cognitive condition. First, the emotion induction selectively impaired behavioral performance on interference trials while behavioral measures on non-interference trials were roughly identical in both emotional conditions. Second, in the negative emotional condition there was incremental interference-related activation in control-related regions (fronto-parietal cortices). Taken together, findings suggest that negative affect specifically disturbs the neural control processes that in a neutral affective state allow to select task-relevant information and to shield its processing from task-irrelevant distraction. Accordingly, agents in a negative affective state have to exert enhanced control efforts to resolve cognitive interference. Additional connectivity analyses revealed that a negative coupling between lateral PFC on the one hand and amygdala and OFC on the other is related to enhanced interference resolution which can be tentatively interpreted as evidence that emotional regulation is an integrated part of an agent's efforts to preserve cognitive performance in affective situations.

Adaptive control of ideomotor effect anticipations.

According to ideomotor theory, voluntary actions are selected and initiated by means of anticipated action effects. Prior experiments yielded evidence for these effect anticipations with response-effect (R-E) compatibility phenomena using blocked R-E relations. Daily actions, however, typically evoke different effects depending on the situational context. In the present study, we accounted for this natural variability and investigated R-E compatibility effects by a trial-by-trial variation of R-E compatibility relations. In line with recent observations regarding ideomotor learning, R-E compatibility influenced responding only when participants responded in free choice trials assuming that participants then adopted an intention-based action control mode. In contrast, R-E compatibility had no impact when participants responded according to imperative stimuli throughout the experiment, thus when participants adopted a stimulus-based action control mode. Interestingly, once an intention-based mode was established because of free choice trials within an experimental block, we observed response compatibility effects in free as well as forced choice trials. These findings extend and refine theoretical assumptions on different action control modes in goal-directed behavior and the specific contribution of ideomotor processes to intention-based action control.

Brain mechanisms associated with background monitoring of the environment for potentially significant sensory events.

Background monitoring is a necessary prerequisite to detect unexpected changes in the environment, while being involved in a primary task. Here, we used fMRI to investigate the neural mechanisms that underlie adaptive goal-directed behavior in a cued task switching paradigm during real response conflict or, more generally, when expectations on the repetitive features of the environment were violated. Unexpected changes in sensory stimulus attributes in the currently unattended stimulus dimension thereby led to activations in a bilateral network comprising inferior lateral frontal, intraparietal, and posterior medial frontal brain regions, independent of whether these attributes elicited a factual response conflict or not. This fronto-parietal network may thus play an important role in adaptive responding to potentially significant events outside the current focus of attention.

Decomposing interference during Stroop performance into different conflict factors: an event-related fMRI study.

In the current event-related functional magnetic resonance imaging (fMRI) study, we sought to trace back Stroop-interference to circumscribed properties of task-irrelevant word information - response-incompatibility, semantic incongruency and task-reference - that we conceive as conflict factors. Thereby, we particularly wanted to disentangle intermingled contributions of semantic conflict and response conflict to the overall Stroop-interference effect. To delineate neural substrates of single factors, we referred to the logics of cognitive subtraction and cognitive conjunction. Moreover, in a second step, we conducted correlation analyses to determine the relationship between neural activations and behavioral interference costs (i.e., conflict-related reaction time (RT) slowing) so as to further elucidate the functional role of the respective brain regions in conflict processing. Response-incompatibility was associated with activation in the left premotor cortex which can be interpreted as indicating motor competition or conflict, i.e., the presence of competing response tendencies. Accordingly, this activation was positively correlated with behavioral conflict costs. Semantic incongruency exhibited specific activation in the anterior cingulate cortex (ACC), the bilateral insula, and thalamus as well as in left somatosensory cortex. As supported by the consistent negative correlation with behavioral conflict costs, these activations most probably reflect strengthened control efforts to overcome interference and to ensure adequate task performance. Finally, task-reference elicited activation in the left temporo-polar cortex (TPC) and the right medial superior as well as in left rostroventral prefrontal cortex (rvPFC, sub-threshold activation). As strongly supported by prior studies' findings, this neural activation pattern may underlie residual semantic processing of the task-irrelevant word information.

Functional brain abnormalities in psychiatric disorders: neural mechanisms to detect and resolve cognitive conflict and interference.

In the present article, we review functional neuroimaging studies on interference processing and performance monitoring in three groups of psychiatric disorders, (1) mood disorders, (2) schizophrenia, and (3) obsessive-compulsive disorder (OCD). Ad (1) Behavioral performance measures suggest an impaired interference resolution capability in symptomatic bipolar disorder patients. A series of neuroimaging analyses found alterations in the ACC-DLPFC system in mood disorder (unipolar depressed and bipolar) patients, putatively reflective of an abnormal interplay of monitoring and executive neurocognitive functions. Other studies of euthymic bipolar patients showed relatively decreased interference-related activation in rostroventral PFC which conceivably underlies defective inhibitory control. Ad (2) Behavioral Stroop studies revealed a specific performance pattern of schizophrenia patients (normal RT interference but increased error interference and RT facilitation) suggestive of a deficit in ignoring irrelevant (word) information. Moreover, reduced/absent behavioral post-error and post-conflict adaptation effects suggest alterations in performance monitoring and/or adjustment capability in these patients. Neuroimaging findings converge to suggest a disorder-related abnormal neurophysiology in ACC which consistently showed conflict- and error-related hypoactivation that, however, appeared to be modulated by different factors. Moreover, studies suggest a specific deficit in context processing in schizophrenia, evidently related to activation reduction in DLPFC. Ad (3) Behavioral findings provide evidence for impaired interference resolution in OCD. Neuroimaging results consistently showed conflict- and error-related ACC hyperactivation which--conforming OCD pathogenesis models--can be conclusively interpreted as reflecting overactive performance monitoring. Taken together, interference resolution and performance monitoring appeared to be fruitful concepts in the investigation of neurocognitive deficits in psychiatric disorders.

The neural substrate of the ideomotor principle: an event-related fMRI analysis.

The present fMRI study sought to investigate the neural basis of perceiving learned action effects and thereby to test for hypotheses based on the ideomotor principle. For this purpose, we had subjects undergo a two-phase experimental procedure comprising an acquisition and a test phase, the latter administered inside the MR scanner. During the acquisition phase, free-choice button presses were contingently followed by one of two tones of different pitch which thereby should become "learned action effects". During the following test phase, subjects were presented with the action effects either when in a passive (non-acting) state or when they carried out forced-choice button presses. Conform to our expectations, we found evidence for a motor effector activation following the passive perception of effect tones which elicited activation in the neural motor system (premotor and somatosensory cortices, SMA, and cerebellum). Surprisingly, however, this activation was observed for left-hand effect tones only, suggesting a basic asymmetry in the impact of ideomotor learning. Moreover, we found activation in the posterior prefrontal and temporo-parietal cortex in response to action effects during the pursuit of goal-directed action. This suggests that action effects attracted special attention and thereby engaged selective cognitive control processes to ensure task-appropriate performance. Finally, there was reduced premotor activation for response-compatible as compared to response-incompatible action effects which can be taken as indication for differential requirements on the motor system and thus for behavioral interference and/or facilitation by learned action effects.

Oddball and incongruity effects during Stroop task performance: a comparative fMRI study on selective attention.

The aim of this fMRI study was to investigate and compare the neural mechanisms of selective attention during two different operationalizations of competition between task-relevant and task-irrelevant information: Stroop-incongruity and oddballs. For this purpose, we employed a Stroop-like oddball task in which subjects responded to the font size of presented word stimuli. Stroop-incongruity was created by (response-)incongruent word information while oddballs comprised low-frequency events in a task-irrelevant, unattended dimension. Thereby, in order to elucidate the influence of processing domain from which competition emanates, oddball conditions were created in two different attribute dimensions, color and word meaning. Either oddball condition was expected to evoke an orienting response, which participants would have to override in order to maintain adequate performance. Incongruent Stroop trials were expected to produce Stroop-interference so that subjects would have to override the predominant tendency to read and respond to word meaning. All competition conditions exhibited significantly prolonged reaction times compared to control trials, demonstrating that our experimental manipulation was indeed effective. fMRI data analyses delineated two discriminative components of competition: one component mainly related to motor preparation and another, primarily attentional component. Regarding the first, Stroop-interference increased activation mainly in regions implicated in motor control or response preparation. Regarding the second, Word-oddballs increased activation in a frontoparietal "attention network". Furthermore, Word-oddballs and Color-oddballs exhibited striking activation overlap mainly in prefrontal regions but also in posterior processing areas. Here, the data emphasized a prominent role of posterior lateral PFC in implementing top-down attentional control.