Levodopa suppresses grid-like activity and impairs spatial learning in novel environments in healthy young adults.

Accumulated evidence from animal studies suggests a role for the neuromodulator dopamine in memory processes, particularly under conditions of novelty or reward. Our understanding of how dopaminergic modulation impacts spatial representations and spatial memory in humans remains limited. Recent evidence suggests age-specific regulation effects of dopamine pharmacology on activity in the medial temporal lobe, a key region for spatial memory. To which degree this modulation affects spatially patterned medial temporal representations remains unclear. We reanalyzed recent data from a pharmacological dopamine challenge during functional brain imaging combined with a virtual object-location memory paradigm to assess the effect of Levodopa, a dopamine precursor, on grid-like activity in the entorhinal cortex. We found that Levodopa impaired grid cell-like representations in a sample of young adults (n = 55, age = 26-35 years) in a novel environment, accompanied by reduced spatial memory performance. We observed no such impairment when Levodopa was delivered to participants who had prior experience with the task. These results are consistent with a role of dopamine in modulating the encoding of novel spatial experiences. Our results suggest that dopamine signaling may play a larger role in shaping ongoing spatial representations than previously thought.

Dopamine differentially modulates medial temporal lobe activity and behavior during spatial navigation in young and older adults.

Aging is associated with changes in spatial navigation behavior. In addition to an overall performance decline, older adults tend to rely more on proximal location cue information than on environmental boundary information during spatial navigation compared to young adults. The fact that older adults are more susceptible to errors during spatial navigation might be partly attributed to deficient dopaminergic modulation of hippocampal and striatal functioning. Hence, elevating dopamine levels might differentially modulate spatial navigation and memory performance in young and older adults. In this work, we administered levodopa (L-DOPA) in a double-blind within-subject, placebo-controlled design and recorded functional neuroimaging while young and older adults performed a 3D spatial navigation task in which boundary geometry or the position of a location cue were systematically manipulated. An age by intervention interaction on the neural level revealed an upregulation of brain responses in older adults and a downregulation of responses in young adults within the medial temporal lobe (including hippocampus and parahippocampus) and brainstem, during memory retrieval. Behaviorally, L-DOPA had no effect on older adults' overall memory performance; however, older adults whose spatial memory improved under L-DOPA also showed a shift towards more boundary processing under L-DOPA. In young adults, L-DOPA induced a decline in spatial memory performance in task-naïve participants. These results are consistent with the inverted-U-shaped hypothesis of dopamine signaling and cognitive function and suggest that increasing dopamine availability improves hippocampus-dependent place learning in some older adults.

L-DOPA enhances neural direction signals in younger and older adults.

Previous studies indicate a role of dopamine in spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not well understood whether dopamine directly affects these representations, or only impacts other aspects of spatial brain function. Moreover, both dopamine and spatial cognition decline sharply during age, raising the question which effect dopamine has on directional signals in the brain of older adults. To investigate these questions, we used a double-blind cross-over L-DOPA/Placebo intervention design in which 43 younger and 37 older adults navigated in a virtual spatial environment while undergoing functional magnetic resonance imaging (fMRI). We studied the effect of L-DOPA, a dopamine precursor, on fMRI activation patterns that encode spatial walking directions that have previously been shown to lose specificity with age. This was done in predefined regions of interest, including the early visual cortex, retrosplenial cortex, and hippocampus. Classification of brain activation patterns associated with different walking directions was improved across all regions following L-DOPA administration, suggesting that dopamine broadly enhances neural representations of direction. No evidence for differences between regions was found. In the hippocampus these results were found in both age groups, while in the retrosplenial cortex they were only observed in younger adults. Taken together, our study provides evidence for a link between dopamine and the specificity of neural responses during spatial navigation. SIGNIFICANCE STATEMENT: The sense of direction is an important aspect of spatial navigation, and neural representations of direction can be found throughout a large network of space-related brain regions. But what influences how well these representations track someone's true direction? Using a double-blind cross-over L-DOPA/Placebo intervention design, we find causal evidence that the neurotransmitter dopamine impacts the fidelity of direction selective neural representations in the human hippocampus and retrosplenial cortex. Interestingly, the effect of L-DOPA was either equally present or even smaller in older adults, despite the well-known age related decline of dopamine. These results provide novel insights into how dopamine shapes the neural representations that underlie spatial navigation.

Contingency awareness as a prerequisite for differential contextual fear conditioning.

Contingency awareness during conditioning describes the phenomenon of becoming consciously aware of the association between a conditioned stimulus (CS) and an unconditioned stimulus (US). Despite the fact that contingency awareness is necessary for associative learning in some conditioning paradigms, its role in contextual fear conditioning, a variant that uses a context-CS (CTX) instead of a cue, has not been characterized thus far. We investigated if contingency awareness is a prerequisite for contextual fear conditioning and if subjects classified as aware differ from unaware subjects on a hemodynamic, autonomic, and behavioral level. We used a computer-generated picture context as CTX and slightly painful electric stimulation as US while we recorded brain responses by functional magnetic resonance imaging (fMRI), and obtained skin conductance responses (SCR) and verbal ratings of emotional valence and arousal. SCR analyses revealed that only aware subjects became conditioned to the US-associated CTX (CTX+). Brain activity related to the CTX+ was more strongly pronounced in fear-associated areas like the insula in the aware relative to the unaware group. Finally, the hippocampus was functionally connected to the cingulate cortex and posterior medial frontal gyrus in aware subjects relative to unaware subjects. These task-related differential connectivity patterns suggest that information exchange between the hippocampus and regions involved in the expression of conditioned fear and decision uncertainty is crucial for the acquisition of contingency knowledge. This study demonstrates the importance of contingency awareness for contextual fear conditioning and points to the hippocampus as a potential mediator for contingency learning in contextual learning.

Simultaneous EEG-fMRI reveals brain networks underlying recognition memory ERP old/new effects.

The mapping of event-related potentials (ERP) on functional magnetic resonance imaging (fMRI) data remains difficult as scalp electroencephalography (EEG) is assumed to be largely insensitive to deep brain structures. Simultaneous recordings of EEG and fMRI might be helpful in reconciling surface ERPs with hemodynamic activations in medial temporal lobe structures related to recognition memory. EEG and imaging studies provide evidence for two independent processes underlying recognition memory, namely recollection and familiarity. Recollection reflects the conscious retrieval of contextual information about a specific episode, while familiarity refers to an acontextual feeling of knowing. Both processes were related to two spatiotemporally different ERP effects, namely the early mid-frontal old/new effect (familiarity) and the late parietal old new effect (recollection). We conducted an exploratory simultaneous EEG-fMRI study using a recognition memory paradigm to investigate which brain activations are modulated in relation to the ERP old/new effects. To this end we examined 17 participants in a yes/no recognition task with word stimuli. Single-trial amplitudes of ERP old/new effects were related to the hemodynamic signal in an EEG-informed fMRI analysis for a subset of 12 subjects. FMRI activation in the right dorsolateral prefrontal cortex and the right intraparietal sulcus was associated with the amplitude of the early frontal old/new effect (350-550ms), and activation in the right posterior hippocampus, parahippocampal cortex and retrosplenial cortex was associated with the amplitude of the late parietal old new effect (580-750ms). These results provide the first direct link between electrophysiological and hemodynamic correlates of familiarity and recollection. Moreover, these findings in healthy subjects complement data from intracranial ERP recordings in epilepsy patients and lesion studies in hypoxia patients.

Contextual fear conditioning in humans using feature-identical contexts.

Contextual fear conditioning studies in animals and humans found an involvement of the hippocampus and amygdala during fear learning. To exclude a focus on elements of the context we employed a paradigm, which uses two feature-identical contexts that only differ in the arrangement of the features and requires configural processing. We employed functional magnetic resonance imaging to determine the role of the hippocampus and neocortical areas during the acquisition of contextual fear in humans. For contextual fear acquisition, we paired one context (CS+) with an aversive electrical stimulus, whereas the other (CS-) was never followed by aversive stimulation. Blood oxygen level dependent activation to the CS+ was present in the insula, inferior frontal gyrus, inferior parietal lobule, superior medial gyrus and caudate nucleus. Furthermore, the amygdala and hippocampus were involved in a time-dependent manner. Psychophysiological interaction analyses revealed functional connectivity of a more posterior hippocampal seed region with the anterior hippocampus, posterior cingulate cortex and superior parietal lobule. The anterior hippocampus was functionally coupled with the amygdala and postcentral gyrus. This study complements previous findings in contextual fear conditioning in humans and provides a paradigm which might be useful for studying patients with hippocampal impairment.

Insights from simultaneous EEG-fMRI and patient data illuminate the role of the anterior medial temporal lobe in N400 generation.

The N400, a negative event-related potential (ERP) peaking approximately 400 ms after stimulus onset, is known to reflect the processing of semantic information. While scalp recordings have contributed to understanding the psychological processes underlying the N400, they have been limited in identifying its neural basis. However, recent intracranial ERP recordings and fMRI studies have shed light on the crucial role of the anterior medial temporal lobe (AMTL) in semantic information processing. These findings suggest that the N400 partially represents activity in the AMTL structures. To investigate the neural underpinnings of the N400 effect, we simultaneously recorded ERPs and event-related fMRI during a semantic priming paradigm in a sample of 12 young, healthy subjects. Additionally, we collected ERPs and structural brain data from older healthy adults and patients with amnestic mild cognitive impairment (aMCI), a population characterized by neurodegenerative changes in the AMTL. In our fMRI results, we identified bilateral loci in the AMTL as the global maxima. Employing an EEG-informed fMRI analysis, we explored trial-to-trial fluctuations in semantic processing by linking single-trial N400 amplitudes to the Blood Oxygen Level Dependent (BOLD) signal. This approach provided the first direct evidence linking the N400 recorded at the scalp level to the corresponding BOLD signal in the AMTL. Consistent with these findings, patients with aMCI exhibited a diminished N400 effect compared to healthy older adults. Furthermore, voxel-based morphometry analysis revealed a correlation between the magnitude of the N400 effect and the integrity of the AMTL. By integrating data from simultaneous EEG-fMRI, and patient studies, our research advances our understanding of the neural substrate of the N400 and highlights the critical involvement of the AMTL in semantic processing.

No evidence for a reciprocal relationship between daily self-control failures and addictive behavior in a longitudinal study.

Introduction: We all experience occasional self-control failures (SCFs) in our daily lives, where we enact behaviors that stand in conflict with our superordinate or long-term goals. Based on the assumption that SCFs share common underlying mechanisms with addictive disorders, we tested the hypothesis that a generally higher susceptibility to daily SCFs predicts more addictive behavior, or vice versa. Methods: At baseline, 338 individuals (19-27 years, 59% female) from a community sample participated in multi-component assessments. These included among others (1) a clinical interview on addictive behaviors (quantity of use, frequency of use, DSM-5 criteria; n = 338) and (2) ecological momentary assessment of SCFs (n = 329, 97%). At the 3-year and 6 year follow-up, participation rates for both assessment parts were 71% (n = 240) and 50% (n = 170), respectively. Results: Controlling for age, gender, IQ, and baseline addiction level, random-intercept cross-lagged panel models revealed that participants who reported more SCFs also showed pronounced addictive behavior at the between-person level, but we found no evidence of a predictive relationship at the within-person level over time. Discussion: A higher rate of SCFs is associated with more addictive behavior, while there is no evidence of an intraindividual predictive relationship. Novel hypotheses suggested by additional exploratory results are that (1) only addiction-related SCFs in daily life are early markers of an escalation of use and thus for addictive disorders and that (2) an explicit monitoring of SCFs increases self-reflection and thereby promotes the mobilization of cognitive control in response to goal-desire conflicts.

Unraveling robust brain-behavior links of depressive complaints through granular network models for understanding heterogeneity.

BACKGROUND: Depressive symptoms are highly prevalent, present in heterogeneous symptom patterns, and share diverse neurobiological underpinnings. Understanding the links between psychopathological symptoms and biological factors is critical in elucidating its etiology and persistence. We aimed to evaluate the utility of using symptom-brain network models to parse the heterogeneity of depressive complaints in a large adolescent sample. METHODS: We used data from the third wave of the IMAGEN study, a multi-center panel cohort study involving 1317 adolescents (52.49 % female, mean ± SD age = 18.5 ± 0.7). Two network models were estimated: one including an overall depressive symptom severity sum score based on the Adolescent Depression Rating Scale (ADRS), and one incorporating individual ADRS item scores. Both networks included measures of cortical thickness in several regions (insula, cingulate, mOFC, fusiform gyrus) and hippocampal volume derived from neuroimaging. RESULTS: The network based on individual item scores revealed associations between cortical thickness measures and specific depressive complaints, obscured when using an aggregate depression severity score. Notably, the insula's cortical thickness showed negative associations with cognitive dysfunction (partial cor. = -0.15); the cingulate's cortical thickness showed negative associations with feelings of worthlessness (partial cor. = -0.10), and mOFC was negatively associated with anhedonia (partial cor. = -0.05). LIMITATIONS: This cross-sectional study relied on the self-reported assessment of depression complaints and used a non-clinical sample with predominantly healthy participants (19 % with depression or sub-threshold depression). CONCLUSIONS: This study showcases the utility of network models in parsing heterogeneity in depressive complaints, linking individual complaints to specific neural substrates. We outline the next steps to integrate neurobiological and cognitive markers to unravel MDD's phenotypic heterogeneity.

Adolescent maturation of cortical excitation-inhibition balance based on individualized biophysical network modeling.

The balance of excitation and inhibition is a key functional property of cortical microcircuits which changes through the lifespan. Adolescence is considered a crucial period for the maturation of excitation-inhibition balance. This has been primarily observed in animal studies, yet human in vivo evidence on adolescent maturation of the excitation-inhibition balance at the individual level is limited. Here, we developed an individualized in vivo marker of regional excitation-inhibition balance in human adolescents, estimated using large-scale simulations of biophysical network models fitted to resting-state functional magnetic resonance imaging data from two independent cross-sectional (N = 752) and longitudinal (N = 149) cohorts. We found a widespread relative increase of inhibition in association cortices paralleled by a relative age-related increase of excitation, or lack of change, in sensorimotor areas across both datasets. This developmental pattern co-aligned with multiscale markers of sensorimotor-association differentiation. The spatial pattern of excitation-inhibition development in adolescence was robust to inter-individual variability of structural connectomes and modeling configurations. Notably, we found that alternative simulation-based markers of excitation-inhibition balance show a variable sensitivity to maturational change. Taken together, our study highlights an increase of inhibition during adolescence in association areas using cross sectional and longitudinal data, and provides a robust computational framework to estimate microcircuit maturation in vivo at the individual level.

The genetic architecture of the human hypothalamus and its involvement in neuropsychiatric behaviours and disorders.

Despite its crucial role in the regulation of vital metabolic and neurological functions, the genetic architecture of the hypothalamus remains unknown. Here we conducted multivariate genome-wide association studies (GWAS) using hypothalamic imaging data from 32,956 individuals to uncover the genetic underpinnings of the hypothalamus and its involvement in neuropsychiatric traits. There were 23 significant loci associated with the whole hypothalamus and its subunits, with functional enrichment for genes involved in intracellular trafficking systems and metabolic processes of steroid-related compounds. The hypothalamus exhibited substantial genetic associations with limbic system structures and neuropsychiatric traits including chronotype, risky behaviour, cognition, satiety and sympathetic-parasympathetic activity. The strongest signal in the primary GWAS, the ADAMTS8 locus, was replicated in three independent datasets (N = 1,685-4,321) and was strengthened after meta-analysis. Exome-wide association analyses added evidence to the association for ADAMTS8, and Mendelian randomization showed lower ADAMTS8 expression with larger hypothalamic volumes. The current study advances our understanding of complex structure-function relationships of the hypothalamus and provides insights into the molecular mechanisms that underlie hypothalamic formation.

Unravelling Robust Brain-Behavior Links of Depressive Symptoms Through Granular Network Models: Understanding Heterogeneity and Clinical Implications.

Background: Depressive symptoms are highly prevalent, present in heterogeneous symptom patterns, and share diverse neurobiological underpinnings. Understanding the links between psychopathological symptoms and biological factors is critical in elucidating its etiology and persistence. We aimed to evaluate the utility of using symptom-brain networks to parse the heterogeneity of depressive symptomatology in a large adolescent sample. Methods: We used data from the third wave of the IMAGEN study, a multi-center panel cohort study involving 1,317 adolescents (52.49% female, mean±SD age=18.5±0.72). Two network models were estimated: one including an overall depressive symptom severity sum score based on the Adolescent Depression Rating Scale (ADRS), and one incorporating individual ADRS symptom/item scores. Both networks included measures of cortical thickness in several regions (insula, cingulate, mOFC, fusiform gyrus) and hippocampal volume derived from neuroimaging. Results: The network based on individual symptom scores revealed associations between cortical thickness measures and specific symptoms, obscured when using an aggregate depression severity score. Notably, the insula's cortical thickness showed negative associations with cognitive dysfunction (partial cor.=-0.15); the cingulate's cortical thickness showed negative associations with feelings of worthlessness (partial cor. = -0.10), and mOFC was negatively associated with anhedonia (partial cor. = -0.05). Limitations: This cross-sectional study included participants who were relatively healthy and relied on the self-reported assessment of depression symptoms. Conclusions: This study showcases the utility of network models in parsing heterogeneity in depressive symptoms, linking individual symptoms to specific neural substrates. We outline the next steps to integrate neurobiological and cognitive markers to unravel MDD's phenotypic heterogeneity.

Reward modulates the association between sensory noise and brain activity during perceptual decision-making.

Perceptual decisions entail the accumulation of evidence until a decision criterion is reached. The amount of noise in this process is inversely related to the behavioral performance of the decision-maker. Hence, reducing the amount of perceived noise could improve performance in perceptual decisions. In this study, we investigated whether providing monetary reward for correct responses in a perceptual decision-making task would enhance performance based on prior research linking noise reduction to the administration of reward. To this end, thirty-one healthy young adults carried out an incentivized dot tracking task (iDT) during recording of functional magnetic resonance imaging (fMRI). Behavioral responses were fitted to a Bayesian version of the drift-diffusion model that, among other parameters, also includes an estimate of sensory noise. Fifty percent of the trials were incentivized to compare rewarded with unrewarded trials regarding behavior, brain responses and estimates of model parameters. In order to establish a link between the noise parameter and fMRI activity, we correlated percent signal change (PSC) values from nucleus accumbens and caudate nucleus with noise levels in rewarded and unrewarded trials respectively. Although reward did not affect behavioral performance and model parameters, the fMRI analyses showed notable differences in nucleus accumbens, caudate nucleus and rostral anterior cingulate cortex in rewarded relative to unrewarded trials. Furthermore, higher PSC within nucleus accumbens was significantly associated with lower sensory noise levels, which was specific to rewarded trials. This work is consistent with previous findings on reward modulation of brain responses and marks a first step towards elucidating the effects of reward-induced noise suppression during perceptual decision-making.

Interactive effects of dopamine transporter genotype and aging on resting-state functional networks.

Aging and dopamine modulation have both been independently shown to influence the functional connectivity of brain networks during rest. Dopamine modulation is known to decline during the course of aging. Previous evidence also shows that the dopamine transporter gene (DAT1) influences the re-uptake of dopamine and the anyA9 genotype of this gene is associated with higher striatal dopamine signaling. Expanding these two lines of prior research, we investigated potential interactive effects between aging and individual variations in the DAT1 gene on the modular organization of brain acvitiy during rest. The graph-theoretic metrics of modularity, betweenness centrality and participation coefficient were assessed in 41 younger (age 20-30 years) and 37 older (age 60-75 years) adults. Age differences were only observed in the participation coefficient in carriers of the anyA9 genotype of the DAT1 gene and this effect was most prominently observed in the default mode network. Furthermore, we found that individual differences in the values of the participation coefficient correlated with individual differences in fluid intelligence and a measure of executive control in the anyA9 carriers. The correlation between participation coefficient and fluid intelligence was mainly shared with age-related differences, whereas the correlation with executive control was independent of age. These findings suggest that DAT1 genotype moderates age differences in the functional integration of brain networks as well as the relation between network characteristics and cognitive abilities.

Do alcohol-dependent patients show different neural activation during response inhibition than healthy controls in an alcohol-related fMRI go/no-go-task?

RATIONALE: Alcohol dependence is associated with impaired response inhibition and heightened cue reactivity towards alcohol-related stimuli. Several brain areas, but mainly prefrontal structures, have been linked to response inhibition in addiction. This study aimed at combining both aspects: salience of drug-associated cues and response inhibition using a go/no-go task with alcohol-associated stimuli during functional magnetic resonance imaging (fMRI). OBJECTIVES: Nineteen abstinent alcohol-dependent patients (ADP) and 21 healthy control subjects (HC) were compared on blood oxygen level-dependent (BOLD) responses during successful inhibition of no-go stimuli and successful reactions to go stimuli. RESULTS: ADP and HC did not significantly differ in their behavioural performance in the task. However, both groups performed worse during the inhibition of alcoholic-associated stimuli compared to neutral stimuli. On the neural level, ADP displayed enhanced BOLD activity relative to HC during successful response inhibition in several areas involved in visual processing, cognitive and impulse control, including occipital structures, anterior cingulate gyrus, medial frontal gyrus and medial orbitofrontal cortex. CONCLUSIONS: We interpret these findings as a possible compensation strategy for impaired cognitive processing. Furthermore, the results underline the impact of salience of alcohol-related stimuli on response inhibition, which seems to affect both ADP and HC.