Daniela B. Fenker

The Dopaminergic Midbrain Participates in Human Episodic Memory Formation: Evidence from Genetic Imaging

Recent data from animal studies raise the possibility that dopaminergic neuromodulation promotes the encoding of novel stimuli. We investigated a possible role for the dopaminergic midbrain in human episodic memory by measuring how polymorphisms in dopamine clearance pathways affect encoding-related brain activity (functional magnetic resonance imaging) in an episodic memory task. In 51 young, healthy adults, successful episodic encoding was associated with activation of the substantia nigra. This midbrain activation was modulated by a functional variable number of tandem repeat (VNTR) polymorphism in the dopamine transporter (DAT1) gene. Despite no differences in memory performance between genotype groups, carriers of the (low expressing) 9-repeat allele of the DAT1 VNTR showed relatively higher midbrain activation when compared with subjects homozygous for the 10-repeat allele, who express DAT1 at higher levels. The catechol-O-methyl transferase (COMT) Val108/158Met polymorphism, which is known to modulate enzyme activity, affected encoding-related activity in the right prefrontal cortex (PFC) and in occipital brain regions but not in the midbrain. Moreover, subjects homozygous for the (low activity) Met allele showed stronger functional coupling between the PFC and the hippocampus during encoding. Our finding that genetic variations in the dopamine clearance pathways affect encoding-related activation patterns in midbrain and PFC provides strong support for a role of dopaminergic neuromodulation in human episodic memory formation. It also supports the hypothesis of anatomically and functionally distinct roles for DAT1 and COMT in dopamine metabolism, with DAT1 modulating rapid, phasic midbrain activity and COMT being particularly involved in prefrontal dopamine clearance.

Recapitulating emotional context: activity of amygdala, hippocampus and fusiform cortex during recollection and familiarity

The amygdala is thought to enhance long‐term memory for emotionally arousing events by modulating memory formation and storage in the hippocampus and in neocortical areas. Recent animal studies have raised the possibility that cooperativity between amygdala and hippocampus contributes to the retrieval of fear memories. The functional contributions of the amygdala to the retrieval of emotional memories in humans are less well known. Here, in a functional magnetic resonance imaging experiment, 20 healthy subjects studied neutral words in the context of a fearful or a neutral human face. In a subsequent test, they made ‘remember’ (conscious recollection of the study context), ‘know’ (familiarity in the absence of conscious recollection) and ‘new’ judgements on the studied and newly presented neutral words, in the absence of face stimuli. At test, bilateral amygdala, hippocampus and fusiform face area (FFA) were more strongly activated during recollection than during familiarity. Higher activity for fearful than for neutral study context was found in bilateral FFA during recollection but not during familiarity. This difference recapitulated higher activity for fearful than for neutral context in the FFA during study. These data suggest that the amygdalae and hippocampi contribute to the retrieval of emotion‐laden context memories by coordinating the reactivation of stored representations in neocortical areas, such as the FFA. However, there also was a recapitulation of emotional study context in the right amygdala during familiarity only, which might therefore be related to affective implicit memory.

An fMRI study of causal judgments

The capacity to evaluate causal relations is fundamental to human cognition, and yet little is known of its neurocognitive underpinnings. A functional magnetic resonance imaging study was performed to investigate an hypothesized dissociation between the use of semantic knowledge to evaluate specifically causal relations in contrast to general associative relations. Identical pairs of words were judged for causal or associative relations in different blocks of trials. Causal judgments, beyond associative judgments, generated distinct activation in left dorsolateral prefrontal cortex and right precuneus. These findings indicate that the evaluation of causal relations in semantic memory involves additional neural mechanisms relative to those required to evaluate associative relations.

Accessing causal relations in semantic memory

Most studies investigating semantic memory have focused on taxonomic or associative relations. Little is known about how other relations, such as causal relations, are represented and accessed. In three experiments, we presented participants with pairs of words one after another, describing events that referred to either a cause (e.g.,spark) or an effect (e.g.,fire). We manipulated the temporal order of word presentation and the question participants had to respond to. The results revealed that questions referring to the existence of a causal relation are answered faster when the first word refers to a cause and the second word refers to its effect than vice versa. However, no such asymmetry was observed with questions referring to the associative relation. People appear to distinguish the roles of cause and effect when queried specifically about a causal relation, but not when the same information is evaluated for the presence of an associative relation.

The role of hippocampus dysfunction in deficient memory encoding and positive symptoms in schizophrenia

BACKGROUND Declarative memory disturbances, known to substantially contribute to cognitive impairment in schizophrenia, have previously been attributed to prefrontal as well as hippocampal dysfunction. AIMS To characterize the role of prefrontal and mesolimbic/hippocampal dysfunction during memory encoding in schizophrenia. METHOD Neuronal activation in schizophrenia patients and controls was assessed using functional magnetic resonance imaging (fMRI) during encoding of words in a deep (semantic judgement) and shallow (case judgment) task. A free recall (no delay) and a recognition task (24h delay) were performed. RESULTS Free recall, but not recognition performance was reduced in patients. Reduced performance was correlated with positive symptoms which in turn were related to increased left hippocampal activity during successful encoding. Furthermore, schizophrenia patients displayed a hippocampal hyperactivity during deep encoding irrespective of encoding success along with a reduced anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (DMPFC) activity in successful encoding but an intact left inferior frontal cortex (LIFC) activity. CONCLUSIONS This study provides the first evidence directly linking positive symptoms and memory deficits to dysfunctional hippocampal hyperactivity. It thereby underscores the pivotal pathophysiological role of a hyperdopaminergic mesolimbic state in schizophrenia.

The relationship between level of processing and hippocampal-cortical functional connectivity during episodic memory formation in humans

New episodic memory traces represent a record of the ongoing neocortical processing engaged during memory formation (encoding). Thus, during encoding, deep (semantic) processing typically establishes more distinctive and retrievable memory traces than does shallow (perceptual) processing, as assessed by later episodic memory tests. By contrast, the hippocampus appears to play a processing‐independent role in encoding, because hippocampal lesions impair encoding regardless of level of processing. Here, we clarified the neural relationship between processing and encoding by examining hippocampal–cortical connectivity during deep and shallow encoding. Participants studied words during functional magnetic resonance imaging and freely recalled these words after distraction. Deep study processing led to better recall than shallow study processing. For both levels of processing, successful encoding elicited activations of bilateral hippocampus and left prefrontal cortex, and increased functional connectivity between left hippocampus and bilateral medial prefrontal, cingulate and extrastriate cortices. Successful encoding during deep processing was additionally associated with increased functional connectivity between left hippocampus and bilateral ventrolateral prefrontal cortex and right temporoparietal junction. In the shallow encoding condition, on the other hand, pronounced functional connectivity increases were observed between the right hippocampus and the frontoparietal attention network activated during shallow study processing. Our results further specify how the hippocampus coordinates recording of ongoing neocortical activity into long‐term memory, and begin to provide a neural explanation for the typical advantage of deep over shallow study processing for later episodic memory. Hum Brain Mapp, 2013.

Novel scenes improve recollection and recall of words

Exploring a novel environment can facilitate subsequent hippocampal long-term potentiation in animals. We report a related behavioral enhancement in humans. In two separate experiments, recollection and free recall, both measures of hippocampus-dependent memory formation, were enhanced for words studied after a 5-min exposure to unrelated novel as opposed to familiar images depicting indoor and outdoor scenes. With functional magnetic resonance imaging, the enhancement was predicted by specific activity patterns observed during novelty exposure in parahippocampal and dorsal prefrontal cortices, regions which are known to be linked to attentional orienting to novel stimuli and perceptual processing of scenes. Novelty was also associated with activation of the substantia nigra/ventral tegmental area of the midbrain and the hippocampus, but these activations did not correlate with contextual memory enhancement. These findings indicate remarkable parallels between contextual memory enhancement in humans and existing evidence regarding contextually enhanced hippocampal plasticity in animals. They provide specific behavioral clues to enhancing hippocampus-dependent memory in humans.

virus and epidemic: Causal knowledge activates prediction error circuitry

Knowledge about cause and effect relationships (e.g., virus–epidemic) is essential for predicting changes in the environment and for anticipating the consequences of events and ones own actions. Although there is evidence that predictions and learning from prediction errors are instrumental in acquiring causal knowledge, it is unclear whether prediction error circuitry remains involved in the mental representation and evaluation of causal knowledge already stored in semantic memory. In an fMRI study, participants assessed whether pairs of words were causally related (e.g., virus–epidemic) or noncausally associated (e.g., emerald–ring). In a second fMRI study, a task cue prompted the participants to evaluate either the causal or the noncausal associative relationship between pairs of words. Causally related pairs elicited higher activity in OFC, amygdala, striatum, and substantia nigra/ventral tegmental area than noncausally associated pairs. These regions were also more activated by the causal than by the associative task cue. This network overlaps with the mesolimbic and mesocortical dopaminergic network known to code prediction errors, suggesting that prediction error processing might participate in assessments of causality even under conditions when it is not explicitly required to make predictions.

Aggressiveness of martial artists correlates with reduced temporal pole grey matter concentration

Perception and practice of violence have hedonistic aspects associated with positive arousal (appetitive aggression). Earlier studies have mainly investigated the aetiology of aggressive behaviour in forensic/psychiatric patients. The present study examined structural brain characteristics in healthy people practicing violent sports (martial artists) compared to controls not showing violent behaviour. Aggressiveness was assessed in 21 male healthy martial artists and 26 age-matched male healthy controls using the aggressivity factors questionnaire (FAF). Participants underwent structural T1-weighted MRI. Grey matter (GM) differences were analysed using voxel-based morphometry. Whole-brain analyses of the main effects of group and aggressiveness and their interaction were computed. An interaction effect between group and aggressiveness was evident in a brain cluster comprising the left temporal pole and left inferior temporal gyrus. In martial artists, aggressiveness was inversely related to mean GM concentration in this cluster while in controls the opposite pattern was evident. Since these temporal brain regions are relevant for emotion/aggression regulation and threat appraisal, the increased GM concentration in aggressive controls might reflect a stronger cognitive top-down inhibition of their aggressiveness. Lower GM concentration in more aggressive martial artists may indicate a reduced need of inhibitory cognitive control because of their improved self-regulation skills.