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The renewal effect of extinction describes the reoccurrence of an extinguished response if recall is performed in a context that is not the same as the extinction context. This learning phenomenon is clinically relevant, since it potentially interferes with therapy success for anxiety disorders or phobias. The propensity to show the renewal effect appears to be a stable processing strategy in context-related extinction, associated with higher BOLD activation in hippocampus, ventromedial PFC (vmPFC) and inferior frontal gyrus (IFG) in individuals who show renewal (REN) compared to those who do not (NoREN). However, evidence on a potential relationship between structural properties such as gray matter volume (GMV) in these regions and the propensity to show renewal is lacking. In this study, we applied voxel-based morphometry (VBM) to investigate whether individuals with and without a propensity for renewal differ regarding their GMV in extinction-related brain regions, and whether such a difference is linked to the renewal level. Results revealed differential GMV in REN and NoREN in adjacent subregions of IFG and vmPFC, respectively. Higher GMV in REN was located predominantly in orbital IFG and in BA10 of vmPFC. Higher GMV in NoREN was located predominantly in triangular IFG and in BA 11 of vmPFC. In bilateral anterior cingulate cortex (ACC) and anterior hippocampus, GMV was overall higher in NoREN. In the complete sample, higher GMV in IFG BA 47, vmPFC BA11, bilateral ACC and bilateral anterior hippocampus was associated with less renewal, and partially with a higher error level in extinction learning in a novel context. The findings suggest that higher GMV in several regions active during extinction learning may support a more thorough processing of extinction trials which in turn could be conducive to an extinction recall solely based on recent extinction memory, disregarding context information. In summary, this study provides first-time evidence for a relationship of GMV in of extinction- and renewal-relevant brain regions with behavioral performance during extinction learning and the propensity to show the renewal effect.

Renewal of extinguished responses is associated with higher activity in specific extinction-relevant brain regions, i.e., hippocampus (HC), inferior frontal gyrus (IFG), and ventromedial PFC (vmPFC). HC is involved in processing of context information, while IFG and vmPFC use such context information for selecting and deciding among competing response options. However, it is as yet unknown to what extent trials with changed versus unchanged outcome, or extinction trials that evoke renewal (i.e., extinction context differs from acquisition and test context: ABA trials) and trials that do not (i.e., same context in all phases: AAA trials) are represented differentially in extinction-relevant brain regions. In this study, we applied representational similarity analysis (RSA) to determine differences in neural representations of these trial types and their relationship to extinction error rates and renewal level. Overall, individuals with renewal (REN) and those without (NoREN) did not differ significantly in their discrimination levels between ABA and AAA extinction trials, with the exception of right posterior HC, where REN exhibited more pronounced context-related discrimination. In addition, higher dissimilarity of representations in bilateral posterior HC, as well as in several IFG regions, during extinction learning was linked to lower ABA renewal rates. Both REN and NoREN benefitted from prediction error feedback from ABA extinction errors for context- and outcome-related discrimination of trials in IFG, vmPFC, and HC, but only the NoREN group also benefitted from error feedback from AAA extinction errors. Thus, while in both groups the presence of a novel context supported formation of distinct representations, only in NoREN the expectancy violation of the surprising change of outcome alone had a similar effect. In addition, only in NoREN context-related discrimination was linked to error feedback in vmPFC. In summary, the findings show that context- and outcome-related discrimination of trials in HC, vmPFC, and IFG is linked to extinction learning errors, regardless of renewal propensity, and at the same time point towards differential context processing strategies in REN and NoREN. Moreover, better discrimination of context-related trials during extinction learning promotes less renewal during extinction recall, suggesting that renewal may be related to suboptimal context-related trial discrimination.

The balance of excitation and inhibition plays a key role in plasticity and learning. A frequently used, reliable approach to assess intracortical inhibition relies on measuring paired-pulse behavior. Moreover, recent developments of magnetic resonance spectroscopy allows measuring GABA and glutamate concentrations. We give an overview about approaches employed to obtain information about excitatory states in human participants and discuss their putative relation. We summarize paired-pulse techniques and basic findings characterizing paired-pulse suppression in somatosensory (SI) and (VI) visual areas. Paired-pulse suppression describes the effect of paired sensory stimulation at short interstimulus intervals where the cortical response to the second stimulus is significantly suppressed. Simultaneous assessments of paired-pulse suppression in SI and VI indicated that cortical excitability is not a global phenomenon, but instead reflects the properties of local sensory processing. We review studies using non-invasive brain stimulation and perceptual learning experiments that assessed both perceptual changes and accompanying changes of cortical excitability in parallel. Independent of the nature of the excitation/inhibition marker used these data imply a close relationship between altered excitability and altered performance. These results suggest a framework where increased or decreased excitability is linked with improved or impaired perceptual performance. Recent findings have expanded the potential role of cortical excitability by demonstrating that inhibition markers such as GABA concentrations, paired-pulse suppression or alpha power predict to a substantial degree subsequent perceptual learning outcome. This opens the door for a targeted intervention where subsequent plasticity and learning processes are enhanced by altering prior baseline states of excitability.

Contextual information is essential for learning and memory processes and plays a crucial role during the recall of extinction memory, and in the renewal effect, which is the context-dependent recovery of an extinguished response. The dopaminergic system is known to be involved in regulating attentional processes by shifting attention to novel and salient contextual cues. Higher dopamine levels are associated with a better recall of previously learned stimulus-outcome associations and enhanced encoding, as well as retrieval of contextual information which promotes renewal. In this fMRI study, we aimed to investigate the impact of processing contextual information and the influence of dopaminergic D2-like receptor activation on attention to contextual information during a predictive learning task as well as upon extinction learning, memory performance, and activity of extinction-related brain areas. A single oral dose of 1.25 mg bromocriptine or an identical-looking placebo was administered to the participants. We modified a predictive learning task that in previous studies reliably evoked a renewal effect, by increasing the complexity of contextual information. We analysed fixations and dwell on contextual cues by use of eye-tracking and correlated these with behavioural performance and BOLD activation of extinction-related brain areas. Our results indicate that the group with dopaminergic D2-like receptor stimulation had higher attention to task-relevant contextual information and greater/lower BOLD activation of brain regions associated with cognitive control during extinction learning and recall. Moreover, renewal responses were almost completely absent. Since this behavioural effect was observed for both treatment groups, we assume that this was due to the complexity of the altered task design.

Animal-fMRI is a powerful method to understand neural mechanisms of cognition, but it remains a major challenge to scan actively participating small animals under low-stress conditions. Here, we present an event-related functional MRI platform in awake pigeons using single-shot RARE fMRI to investigate the neural fundaments for visually-guided decision making. We established a head-fixated Go/NoGo paradigm, which the animals quickly learned under low-stress conditions. The animals were motivated by water reward and behavior was assessed by logging mandibulations during the fMRI experiment with close to zero motion artifacts over hundreds of repeats. To achieve optimal results, we characterized the species-specific hemodynamic response function. As a proof-of-principle, we run a color discrimination task and discovered differential neural networks for Go-, NoGo-, and response execution-phases. Our findings open the door to visualize the neural fundaments of perceptual and cognitive functions in birds—a vertebrate class of which some clades are cognitively on par with primates. Functional magnetic resonance imaging (fMRI) is a powerful method to understand neural mechanisms of cognition but imaging of small animals can be challenging. The authors present an event-related fMRI platform to visualize the neural fundaments of perceptual and cognitive functions in awake birds.

The renewal effect of extinction demonstrates the context-dependency of extinction learning. It is defined as the recovery of an extinguished response occurring when the contexts of extinction and recall differ. Behavioral studies showed that modulating context relevance can strengthen context-specific responses. In our fMRI study, we investigated to what extent a modulation of context salience can alter renewal levels and provide additional information about the neural basis for renewal. In a within-subjects design, participants completed two sessions of an associative learning task in randomized order. In the salient condition (SAL), a context was presented alone at the start of each trial, before being presented together with the stimulus. The regular condition (REG) contained no context-alone phase. In about one-third of participants (SWITCH), the context salience modulation significantly increased renewal rates in the SAL compared to the REG condition. The other participants showed either renewal (REN) or no renewal (NoREN) in both conditions. The modulation did not significantly affect learning performance during the initial forming of associations or extinction learning. In the SWITCH group, activation in left opercular inferior frontal gyrus (iFG) during the recall phase was associated with a renewal effect, together with activity in the bilateral posterior hippocampus and ventromedial prefrontal cortex (vmPFC). Also during the extinction phase, left opercular iFG activation was higher in groups exhibiting renewal in recall, irrespective of the context salience modulation. Besides confirming the participation of vmPFC in extinction recall, our findings provide novel insights regarding an as yet undetected, potentially important role for renewal-supporting processes in left iFG during extinction learning and recall, which are presumably based on the region's proposed function of evaluating competing response options under conditions of ambiguity.

Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans.

Posttraumatic headache (PTH) is common following traumatic brain injury and impacts quality of life. We investigated descending pain modulation as one possible mechanism for PTH and correlated it to clinical measures. Pain-related evoked potentials (PREP) were recorded in 26 PTH-patients and 20 controls after electrical stimulation at the right hand and forehead with concentric surface electrodes. Conditioned pain modulation (CPM) was assessed using painful cutaneous electric stimulation (PCES) on the right hand as test stimulus and immersion of the left hand into 10 °C-cold water bath as conditioning stimulus based on changes in pain intensity and in amplitudes of PCES-evoked potentials. All participants completed questionnaires assessing depression, anxiety, and pain catastrophising. PTH-patients reported significantly higher pain ratings during PREP-recording in both areas despite similar stimulus intensity at pain threshold. N1P1-amplitudes during PREP and CPM-assessment were lower in patients in both areas, but statistically significant only on the hand. Both, PREP-N1-latencies and CPM-effects (based on the N1P1-amplitudes and pain ratings) were similar in both groups. Patients showed significantly higher ratings for anxiety and depression, which did not correlate with the CPM-effect. Our results indicate generalized hyperalgesia for electrical stimuli in both hand and face in PTH. The lacking correlation between pain ratings and EEG parameters indicates different mechanisms of pain perception and nociception.

It has already been described that transcutaneous spinal direct current stimulation (tsDCS) can selectively influence nociceptive evoked potentials. This study is the first aiming to prove an influence of tsDCS on pain-related evoked potentials (PREP) using concentric surface electrodes (CE), whose nociceptive specificity is still under discussion. 28 healthy subjects participated in this sham-controlled, double-blind cross-over study. All subjects underwent one session of anodal and one session of sham low-thoracic tsDCS. Before and after the intervention, PREP using CE, PREP-induced pain perception and somatosensory evoked potentials (SEP) were assessed on the right upper and lower limb. We found a decrease in PREP amplitude at the lower limb after sham stimulation, but not after anodal tsDCS, while SEP remained unchanged under all studied conditions. There was no difference between the effects of anodal tsDCS and sham stimulation on the studied parameters assessed at the upper limb. PREP-induced pain of the upper and lower limb increased after anodal tsDCS. The ability of influencing PREP using a CE at the spinal level in contrast to SEP suggests that PREP using CE follows the spinothalamic pathway and supports the assumption that it is specifically nociceptive. However, while mainly inhibitory effects on nociceptive stimuli have already been described, our results rather suggest that anodal tsDCS has a sensitizing effect. This may indicate that the mechanisms underlying the elicitation of PREP with CE are not the same as for the other nociceptive evoked potentials. The effects on the processing of different types of painful stimuli should be directly compared in future studies.

The levels of the gonadal hormones estradiol and progesterone vary throughout the menstrual cycle thereby affecting cognition, emotion, mood, and social behaviour. However, how these hormones modulate the balance of neural excitation and inhibition, which crucially regulate processing and plasticity, is not fully understood. We here used paired-pulse stimulation to investigate in healthy humans the action of low and high estradiol and progesterone on intracortical inhibition in somatosensory (SI) and visual cortex (V1). We found that paired-pulse suppression in both SI and VI depended on estradiol. During high estradiol levels, paired-pulse suppression was significantly reduced. No comparable effects were found for progesterone, presumably due to a confounding effect of estradiol. Also, no hormone level-depending effects were observed for single-pulse evoked SEPs (somatosensory evoked potentials) and VEPs (visual evoked potentials) indicating a specific hormonal action on intracortical processing. The results demonstrate that estradiol globally modulates the balance of excitation and inhibition of SI and VI cortex.