Disentangling Hippocampal and Amygdala Contribution to Human Anxiety-Like Behavior.

Anxiety comprises a suite of behaviors to deal with potential threat and is often modeled in approach-avoidance conflict tasks. Collectively, these tests constitute a predominant preclinical model of anxiety disorder. A body of evidence suggests that both ventral hippocampus and amygdala lesions impair anxiety-like behavior, but the relative contribution of these two structures is unclear. A possible reason is that approach-avoidance conflict tasks involve a series of decisions and actions, which may be controlled by distinct neural mechanisms that are difficult to disentangle from behavioral readouts. Here, we capitalize on a human approach-avoidance conflict test, implemented as computer game, that separately measures several action components. We investigate three patients of both sexes with unspecific unilateral medial temporal lobe (MTL) damage, one male with selective bilateral hippocampal (HC), and one female with selective bilateral amygdala lesions, and compare them to matched controls. MTL and selective HC lesions, but not selective amygdala lesions, increased approach decision when possible loss was high. In contrast, MTL and selective amygdala lesions, but not selective HC lesions, increased return latency. Additionally, selective HC and selective amygdala lesions reduced approach latency. In a task targeted at revealing subjective assumptions about the structure of the computer game, MTL and selective HC lesions impacted on reaction time generation but not on the subjective task structure. We conclude that deciding to approach reward under threat relies on hippocampus but not amygdala, whereas vigor of returning to safety depends on amygdala but not on hippocampus.SIGNIFICANCE STATEMENT Approach-avoidance conflict tests are widely investigated in rodents, and increasingly in humans, to understand the neural basis of anxiety-like behavior. However, the contribution of the most relevant brain regions, ventral hippocampus and amygdala, is incompletely understood. We use a human computerized test that separates different action components and find that hippocampus, but not amygdala, lesions impair approach decisions, whereas amygdala, but not hippocampus, lesions impair the vigor of return to safety.

Memory integration in humans with hippocampal lesions.

Adaptive behavior frequently depends on inference from past experience. Recent studies suggest that the underlying process of integrating related memories may depend on interaction between hippocampus and prefrontal cortex. Here, we investigated how hippocampal damage affects memory integration. Subjects with mediotemporal lesions and healthy controls learned a set of overlapping AB- and BC-associations (object-face- and face-object pairs) and were then tested for memory of these associations ("direct" trials) and of inferential AC-associations ("indirect" trials). The experiment consisted of four encoding/retrieval cycles. In direct trials, performance of patients and controls was similar and stable across cycles. By contrast, in indirect trials, patients and controls showed distinct patterns of behavior. Whereas patients and controls initially showed only minor differences, controls increased performance across subsequent cycles, while patient performance decreased to chance level. Further analysis suggested that this deficit was not merely a consequence of impaired associative memory but rather resulted from an additional hippocampal contribution to memory integration. Our findings further suggest that contextual factors modulate this contribution. Patient deficits in more complex memory-guided behavior may depend on the flexible interaction of hippocampus-dependent and -independent mechanisms of memory integration.

Musical expertise shapes visual-melodic memory integration.

Music can act as a mnemonic device that can elicit multiple memories. How musical and non-musical information integrate into complex cross-modal memory representations has however rarely been investigated. Here, we studied the ability of human subjects to associate visual objects with melodies. Musical laypersons and professional musicians performed an associative inference task that tested the ability to form and memorize paired associations between objects and melodies ("direct trials") and to integrate these pairs into more complex representations where melodies are linked with two objects across trials ("indirect trials"). We further investigated whether and how musical expertise modulates these two processes. We analyzed accuracy and reaction times (RTs) of direct and indirect trials in both groups. We reasoned that the musical and cross-modal memory demands of musicianship might modulate performance in the task and might thus reveal mechanisms that underlie the association and integration of visual information with musical information. Although musicians showed a higher overall memory accuracy, non-musicians' accuracy was well above chance level in both trial types, thus indicating a significant ability to associate and integrate musical with visual information even in musically untrained subjects. However, non-musicians showed shorter RTs in indirect compared to direct trials, whereas the reverse pattern was found in musicians. Moreover, accuracy of direct and indirect trials correlated significantly in musicians but not in non-musicians. Consistent with previous accounts of visual associative memory, we interpret these findings as suggestive of at least two complimentary mechanisms that contribute to visual-melodic memory integration. (I) A default mechanism that mainly operates at encoding of complex visual-melodic associations and that works with surprising efficacy even in musically untrained subjects. (II) A retrieval-based mechanism that critically depends on an expert ability to maintain and discriminate visual-melodic associations across extended memory delays. Future studies may investigate how these mechanisms contribute to the everyday experience of music-evoked memories.

Characterizing the temporal discrimination threshold in musician's dystonia.

The temporal discrimination threshold (TDT) has been established as a biomarker of impaired temporal processing and endophenotype in various forms of focal dystonia patients, such as cervical dystonia, writer's cramp or blepharospasm. The role of TDT in musician's dystonia (MD) in contrast is less clear with preceding studies reporting inconclusive results. We therefore compared TDT between MD patients, healthy musicians and non-musician controls using a previously described visual, tactile, and visual-tactile paradigm. Additionally, we compared TDT of the dystonic and non-dystonic hand and fingers in MD patients and further characterized the biomarker regarding its potential influencing factors, i.e. musical activity, disease variables, and personality profiles. Repeated measures ANOVA and additional Bayesian analyses revealed lower TDT in healthy musicians compared to non-musicians. However, TDTs in MD patients did not differ from both healthy musicians and non-musicians, although pairwise Bayesian t-tests indicated weak evidence for group differences in both comparisons. Analyses of dystonic and non-dystonic hands and fingers revealed no differences. While in healthy musicians, age of first instrumental practice negatively correlated with visual-tactile TDTs, TDTs in MD patients did not correlate with measures of musical activity, disease variables or personality profiles. In conclusion, TDTs in MD patients cannot reliably be distinguished from healthy musicians and non-musicians and are neither influenced by dystonic manifestation, musical activity, disease variables nor personality profiles. Unlike other isolated focal dystonias, TDT seems not to be a reliable biomarker in MD.

Integrating across memory episodes: Developmental trends.

Memory enables us to use information from our past experiences to guide new behaviours, calling for the need to integrate or form inference across multiple distinct episodic experiences. Here, we compared children (aged 9-10 years), adolescents (aged 12-13 years), and young adults (aged 19-25 years) on their ability to form integration across overlapping associations in memory. Participants first encoded a set of overlapping, direct AB- and BC-associations (object-face and face-object pairs) as well as non-overlapping, unique DE-associations. They were then tested on these associations and inferential AC-associations. The experiment consisted of four such encoding/retrieval cycles, each consisting of different stimuli set. For accuracy on both unique and inferential associations, young adults were found to outperform teenagers, who in turn outperformed children. However, children were particularly slower than teenagers and young adults in making judgements during inferential than during unique associations. This suggests that children may rely more on making inferences during retrieval, by first retrieving the direct associations, followed by making the inferential judgement. Furthermore, young adults showed a higher correlation between accuracy in direct (AB, BC) and inferential AC-associations than children. This suggests that, young adults relied closely on AB- and BC-associations for making AC decisions, potentially by forming integrated ABC-triplets during encoding or retrieval. Taken together, our findings suggest that there may be an age-related shift in how information is integrated across experienced episodes, namely from relying on making inferences at retrieval during middle childhood to forming integrated representations at different memory processing stages in adulthood.