Brain Research

Background. Pain influences motor function and has been proposed to reduce corticospinal and intracortical excitability. At the same time, performance can be maintained during pain, at the cost of increased perceived effort, a centrally generated signal reflecting resource engagement. Here, we tested whether contralateral thermal heat pain-related changes in corticospinal and intracortical excitability contribute to increased effort perception. Methods. In this preregistered transcranial magnetic stimulation (TMS) study, twenty-one healthy participants received single and paired pulse TMS at rest and during submaximal isometric right wrist flexions performed at 20% maximal peak force. Trials were conducted under a control condition or during contralateral thermal stimulation (painful or non-painful warm) applied to the left forearm. After each contraction, participants rated the intensity of their perceived effort. Corticospinal and intracortical excitability of the right wrist flexor was assessed at rest and during submaximal contractions. Results. Contralateral heat pain significantly increased perceived effort compared with the control and warm conditions. Contralateral heat pain did not reduce corticospinal or intracortical excitability. Conversely, contralateral heat pain increased corticospinal excitability, reflected primarily in decreased cortical silent period duration. Perceived effort was associated with the subjective experience of pain rather than with TMS-derived variables. Conclusions. These findings suggest that increased effort during contralateral heat pain cannot be attributed to inhibition of the primary motor cortex or the corticospinal pathway. The higher perceived effort in the presence of contralateral heat pain likely reflects the cognitive cost of pain rather than alterations in the transmission of the motor command.

Neurofeedback (NF) is a promising method for helping individuals overcome choking under pressure. Identifying relevant neural biomarkers is crucial for developing effective NF. In this exploratory study, we aimed to investigate changes in prefrontal hemodynamic signals associated with golf-putting performance under psychological pressure using functional near-infrared spectroscopy. Participants engaged in a one-on-one golf-putting task against an experimenter, with monetary rewards introduced to induce psychological pressure. This manipulation successfully elicited psychological pressure, leading to impaired performance in some participants. Based on performance changes between the practice and competition sessions, participants were categorized into a non-choking group (performance improved) and a choking group (performance declined). Statistical analysis revealed significantly greater increases in prefrontal activation from practice to competition in the non-choking group than in the choking group, especially in the left superior frontal gyrus. Furthermore, moderate but statistically nonsignificant negative correlations were observed between changes in activation in this region and changes in putting error, indicating that greater activation increases tended to accompany less performance deterioration or greater performance improvement. These exploratory findings suggest that the left superior frontal gyrus warrants further investigation as a candidate biomarker for NF interventions aimed at mitigating choking under pressure.

Objective: Aftereffects of 1 Hz repetitive transcranial magnetic stimulation (rTMS) often differ within and between subjects and thus show low reliability. In this study we investigated the mean and individual aftereffects of 1 Hz rTMS using two opposing current directions, their reliability and potential influences of current direction, participants' sex and state on cortical excitability modulations. Methods: Thirteen healthy, right-handed participants underwent four experimental sessions separated by at least 7 days receiving 2000 pulses of suprathreshold 1 Hz rTMS over the primary motor cortex per session. Two sessions were conducted with an induced current direction of anterior-posterior - posterior-anterior (AP-PA) and two sessions with a PA-AP current direction. Before and after rTMS, 100 single TMS pulses were administered with the respective current direction and electromyography was recorded from the first dorsal interosseous. Questionnaires on demographic data and subjective ratings were completed during the experiment. Results: Linear mixed effect model analysis revealed that 1 Hz rTMS induced an excitatory aftereffect when applied with the PA-AP current direction, and no aftereffect with AP-PA. There was a substantial interindividual variability with only three subjects showing an inhibition to 1 Hz rTMS overall. Also, current direction was the only predictor of rTMS aftereffect. Reliability values of these aftereffects were in the poor to moderate range. Conclusions: Current direction plays a crucial role in determining 1 Hz rTMS aftereffects. Reliability was found to be moderate at best. Additional to current direction, more factors need to be considered to tailor the 1 Hz rTMS aftereffects individually.

Objectives: Transcranial magnetic stimulation (TMS) is widely used to probe corticospinal excitability by eliciting motor evoked potential (MEP)s in targeted muscles, with MEP characteristics such as magnitude and latency reflecting the physiological state of the pathways being stimulated. Although numerous studies have examined MEP reliability in upper extremity muscles, less is known about the reliability of this measurement across the lower extremity. We hypothesized that inter-session, test-retest reliability of MEPs recorded simultaneously from multiple lower-limb muscles, from a single TMS location, would differ by muscle, stimulation intensity, and quantification method. Materials and Methods: Ten healthy participants (5 males, 5 females) completed three TMS sessions separated by atleast one week. At each session, the stimulation hotspot was identified using a five-location virtual grid anchored at the vertex, with electromyography (EMG) recorded from all eight muscles of interest at each grid location; the grid location producing the largest and most consistent MEPs in the tibialis anterior (TA), the primary target muscle, was selected as the stimulation site and held constant across all three sessions. MEPs were then recorded bilaterally from the TA, soleus, rectus femoris, and biceps femoris muscles at two stimulation intensities (110% and 120% resting motor threshold (RMT)). MEP size was quantified using mean rectified magnitude and peak-to-peak amplitude, and inter-session reliability was assessed using intraclass correlation coefficients (ICC). Bland-Altman analysis was used to characterize the range of measurement variability across all eight muscles. Results: MEP size differed across sessions, and reliability varied by muscle, intensity, and quantification method. The highest reliability was observed in the right TA, the muscle used to establish the stimulation hotspot, using mean rectified magnitude at 120% RMT. Reliability was comparatively lower in the seven non-target muscles recorded from the same fixed stimulation site, indicating that MEP consistency was not uniform across the lower-limb musculature. Conclusions: MEP reliability in the lower extremity depends heavily on the muscle, stimulation intensity, and quantification method used, and is highest in the muscle for which the stimulation site was optimized. These findings support the interpretation that coil positioning targeted to a specific muscle yields more consistent responses in that muscle than in others recorded from the same fixed site, and underscore the importance of careful muscle selection and hotspot optimization when designing TMS protocols for longitudinal or clinical lower-limb research.

PurposeTo investigate whether rapamycin can regulate microglial activation and polarization via mTOR and its downstream signals via autophagy both in vivo and in vitro. MethodsThe in vivo study used wild type C57BL/6 mice that were intraperitoneally injected with rapamycin (2 mg/kg) plus ONC. The BV2 cell line was used in the in vitro study and the cells were incubated with rapamycin (50 nM) or transfected with a specific mTOR-targeting small interfering RNA (si-mTOR). Immunohistochemical staining was used to observe the changes in the morphology and cell surface area of microglia and Weste blotting analysis was used for detection of the changes in the proteins related autophagy, microglia polarization and mTOR pathway after the retinal tissue or the cell samples were collected. ResultsThese results indicate that rapamycin increases autophagy and M2 polarization by inhibiting p-mTOR in wild-type C57BL/6 mice in vivo. In the BV2 cell line, rapamycin and si-mTOR can enhance autophagy and promote M2 polarization by inhibiting the p-mTOR/p-Unc-51-like kinase 1 (p-ULK1) pathway. ConclusionsIn conclusion, this work contributes to the understanding of the complex interplay among rapamycin, autophagy and microglial activation/polarization, highlights the downstream signaling pathway of mTOR, and highlights the potential therapeutic effects of autophagy-modulating drugs in retinal neuroinflammation and neurodegeneration after TON.

Abstract Introduction: Despite advances in pain management, effective analgesics in pain situations remain elusive. Opioids and non-opioids carry risks of neurotoxic and psychedelic effects with adverse physiological outcomes. Indian instrumental music (IIM) mitigates subacute pain by rewiring neurochemical synergy as an evidence-based, non-invasive, non-pharmacological system to mitigate pain. Objective: Investigating therapeutic efficacy of IIM in mitigating subacute pain by analyzing behavioral, peripheral, and central neurochemical re-tuning. Methods: Mice were divided into Control, Pain, Pain+Music, and Music groups. Pre-treatment behavioral parameters were compared with those observed after 14 days IIM exposure. Evaluations included nociceptive latencies (hot-plate/tail-flick), locomotion (Open Field Test), and anxiety (Elevated Plus Maze). Molecular analyses quantified peripheral neuropeptides (SP, NK-1R, CGRP), serum cortisol, spinal neurotrophic factor, neurotransmitters (glutamate, GABA, dopamine (DA), 5-HT), BDNF, and mRNA expression of BDNF, Ntrk1R/2R, and D1R in cortex, thalamus, hippocampus and hypothalamus. All procedures adhered to IAEC guidelines. Results: IIM yielded 3.9-4.4-fold antinociceptive improvements, 3.3-fold locomotor restoration, and 3.6-4.9-fold anxiolysis. 14 days IIM exposure reduced peripheral nociceptive-neuropeptides 1.3-2.0-fold (SP, NK-1R, CGRP), serum cortisol 1.3-fold, and spinal glutamate, serotonin levels 1.5- and 1.3-fold. An enhanced expression of spinal GABA, DA about 1.5-fold, and BDNF by 1.3-fold was observed after music listening. Brain-region-specific differential mRNA-expression at cortex, thalamus, hypothalamus and hippocampus revealed the neuromodulatory impact of rhythmic music in a formalin-induced murine pain-model. Conclusion: Gross reduction of pain parameters demonstrates therapeutic potential of IIM as multilevel neuromodulator to suppress the multidimensional stressor, pain, via peripheral desensitization, spinal E-I balance, and differential calibration of BDNF/Trk/D1R plasticity at specific brain-regions. Keywords: Pain, Non-Pharmacological Method, Indian Instrumental Music (IIM), Behavior, Neurotransmitters, Neuroplasticity, mRNA Expression.

Consumption of high fat diet (HFD) is linked to reduced cardiac vagal motor output, a main contributor to progression of cardiovascular disease. HFD for 15 days increases extrasynaptic or tonic gamma aminobutyric acid (GABA) current in cardiac projecting neurons in the dorsal motor nucleus of the vagus (CVNDMV), which contributes to dampening cardiac parasympathetic output. However, the mechanism underlying this increased inhibition is unknown. Here, we hypothesize that increased activity of protein kinase C {delta} isoform (PKC{delta}) enhances tonic GABA current in CVNDMV after HFD. Whole-cell patch-clamp recording of retrogradely labeled CVNDMV demonstrated that pan inhibition of PKC activity with GFX, and isoform specific inhibition of PKC{delta} with rottlerin normalize 15-day HFD-induced increases in tonic GABA current, suggesting that PKC{delta} mediates enhanced tonic inhibition. This effect persisted in the presence of dynasore, a clathrin-mediated endocytosis blocker, indicating that the normalization effect of PKC{delta} inhibition on tonic current in HFD is likely independent of clathrin-mediated endocytosis. Furthermore, no differences in PKC{delta} mRNA or protein expression were observed between NFD and HFD, suggesting a post-translational mechanism underpinning increased tonic GABA current after 15 days of HFD. Altogether, this study provides evidence that HFD-induces increased PKC{delta} activity, but not expression, leading to increased tonic GABAergic inhibition in CVNDMV. This increase PKC{delta} activity could explain the cardiac vagal motor output dampening in CVD and be developed into treatments targeting PKC{delta} for CVD.

Heat stroke is characterized by profound central nervous system dysfunction and vascular abnormalities. Previous studies have demonstrated the marked vulnerability of the CNS to thermal stress, resulting in neuronal injury and glial activation. However, the metabolic mechanisms linking acute injury to chronic neurological long-term effects remain understood. The neuropathological changes are closely associated with neuroinflammatory and metabolic disturbances, including dysregulation of the kynurenine pathway, whose metabolites modulate neurotoxicity, neuroprotection, and immune responses. Here, we present the first comprehensive characterization of kynurenine pathway metabolomic profile across both plasma and brain tissue in a mouse model of heat stroke. Using a validated and sensitive LC-MS/MS method, we simultaneously measured and quantified 13 analytes (kynurenine, kynurenic acid, quinolinic acid, nicotinic acid, picolinic acid, xanthurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, indole-3-acetic acid, indole-3-lactic acid, 5-hydroxyindoleacetic acid and neopterin). The findings reveal a biphasic metabolic response, characterized by an acute serotonergic disruption and reduced neuroprotective capacity, followed by chronic activation of the kynurenine pathway, depletion of central serotonin metabolites, and metabolic signatures consistent with gut microbiota dysbiosis. The acute phase is marked by a transient imbalance favoring neurotoxic kynurenine pathway metabolites, whereas the chronic phase reflects sustained pathway activation. Notably, the plasma-brain dissociation of 5-hydroxyindoleacetic acid emerged as the most prominent cross-compartment finding, suggesting a potential biomarker of central serotonergic depletion and a mechanistic link between peripheral and central metabolic changes, with implications for therapeutic targeting during the subacute recovery phase.

The mechanisms of the spinal cord regeneration after complete spinal cord transection were investigated in spiny mice. In some animals, the appearance of quadrupedal overground stepping together with rewiring of the direct propriospinal projections between the cervical and lumbar enlargements was revealed. In others, no stepping recovery was detected, whereas numerous cells labeled by the neuronal proteins NeuN and {beta}III-tubulin were observed within the injury region. We suggest that depending on trauma severity, different repair mechanisms are elicited: only connectome restoration or both connectome restoration and the activation of neurogenesis. To confirm the high neurogenic potential of spiny mice, a primary culture of bone marrow was established. Unlike in other mammals, bone marrow pluripotent cells in the culture differentiated into neuronal cells without any chemical stimulation. These findings provide strong evidence for the high differentiation potential of spiny mouse stem cells toward neural lineages. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/739224v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@1e6f2c1org.highwire.dtl.DTLVardef@14b88f6org.highwire.dtl.DTLVardef@ce5b5org.highwire.dtl.DTLVardef@bcebd9_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LITwo regenerative mechanisms are proposed in spiny mice, depending on the severity the spinal cord transection C_LIO_LIRegular transection evoked the emergence of the direct propriospinal projections C_LIO_LISevere transection evoked the neurogenesis within the primary injured region C_LIO_LIPrimary culture of bone marrow cells from spiny mice exhibits neurogenic differentiation without chemical induction C_LI

The success of stem cell-derived brain repair for Parkinsons is limited by the variable survival and poor maturation of dopaminergic progenitors after transplantation into the Parkinsonian brain. One approach that has been developed to improve this is engraftment of the cells within a neurotrophin-enriched collagen hydrogel. Although this has been shown to improve progenitor survival and maturation in athymic nude rats, the same beneficial effects of the hydrogel were not seen in cyclosporine immunosuppressed rats. To determine the reasons for these differences, the aim of this study was to assess the local and systemic immune responses to progenitor transplantation in these two recipient groups. To do so, human induced pluripotent stem cell-derived dopaminergic progenitors were transplanted into 6-hydroxydopamine-lesioned striatum of athymic or cyclosporine immunosuppressed rats. The cells were transplanted either alone, with the neurotrophins GDNF and BDNF, in an unloaded collagen hydrogel, or in a neurotrophin-loaded collagen hydrogel. Post-mortem assessment included both graft site and blood analysis of immune cell populations. As expected, nude rats showed a pronounced innate immune cell response at the graft site but no T-cell recruitment or activation locally or systemically. In contrast, while the immunosuppressed rats also showed the expected innate immune cells response to the transplant, there was also infiltration of CD4+ and CD8+ T cells at the site of transplantation as well as circulating activated T-cells. Thus, this study suggests that the benefits of the hydrogel that were seen in the athymic nude rats did not manifest in the cyclosporine immunosuppressed rats due to incomplete immunosupression. This study shows the importance of careful optimisation of the immunosuppressive regime chosen before xenotransplantation experiments.

The ventral motor and the centromedian (CM) nuclei receive prominent GABAergic inputs from the basal ganglia, massive glutamatergic projections from motor cortices and significant GABAergic afferents from the reticular thalamic nucleus. There is strong evidence that disrupted processing of information through these connections may contribute to the pathophysiology of the basal ganglia-thalamocortical loop in Parkinson's disease (PD). To further assess potential ultrastructural changes in synaptic connectivity and mitochondrial integrity that may contribute to these network dysfunctions, we used a 3D electron microscopic approach to determine whether the pattern of synaptic innervation and morphological integrity of dendritic mitochondria are altered in the basal ganglia-receiving parvocellular ventral anterior nucleus (VApc) and CM neurons of MPTP-treated parkinsonian monkeys. Three main conclusions can be drawn from our findings: (1) Although the overall pattern of synaptic innervation of VApc and CM neurons is not altered in parkinsonian monkeys, the volume of putative corticothalamic terminals is significantly increased in both nuclei, (2) the prevalence of corticothalamic terminals in contact with distal dendrites is several orders of magnitude higher in VApc than CM in both control and parkinsonian monkeys, (3) the complexity and ultrastructural integrity of dendritic mitochondria is altered in CM, but not in the VApc, of parkinsonian monkeys. These findings lay the foundation for future studies of changes in cortical neuromodulation of VApc and CM neurons in parkinsonism and suggest that mitochondrial defects may contribute to the degeneration of CM neurons in PD.

ObjectiveAging is associated with changes in cortical excitability and altered responsiveness to benzodiazepines, but the effects of benzodiazepine challenge on motor cortical paired-pulse physiology in older adults remain incompletely understood. We examined whether intravenous midazolam differentially modulates corticospinal excitability and short-interval paired-pulse transcranial magnetic stimulation (TMS) responses in younger and older adults. MethodsFifteen younger adults (18-35 years) and fifteen older adults (50-69 years) underwent single-pulse and paired-pulse TMS of the left primary motor cortex at baseline and during intravenous midazolam administration. Single-pulse motor evoked potential (MEP) amplitude was used to assess corticospinal excitability. Short-interval paired-pulse responses were quantified as the ratio of conditioned to unconditioned MEP amplitude. ResultsAt baseline, younger adults showed greater corticospinal excitability than older adults, reflected by larger single-pulse MEP amplitudes (adjusted p = 0.04). Younger adults demonstrated paired-pulse inhibition at baseline, reflected by a conditioned/unconditioned MEP ratio below 1.0 (ratio = 0.73; adjusted p < 0.01), whereas older adults did not show inhibition and instead had a mean ratio above 1.0 (ratio = 1.25). Midazolam reduced single-pulse MEP amplitudes in both groups. During midazolam administration, paired-pulse inhibition was no longer observed in younger adults, and older adults continued to show no evidence of inhibition. ConclusionsYounger and older adults differed in baseline corticospinal excitability and in short-interval paired-pulse TMS responses. Intravenous midazolam reduced corticospinal excitability and altered paired-pulse response patterns, eliminating baseline paired-pulse inhibition in younger adults while producing little measurable change in older adults. These findings suggest that aging may modify the net motor cortical response to benzodiazepine challenge. The results should be interpreted in relation to the paired-pulse stimulation parameters used and support further studies using complementary approaches to characterize age-related differences in inhibitory and facilitatory motor cortical circuits.

Aims & MethodsTranscranial magnetic stimulation (TMS) is a well-established tool for inducing cortical excitation. However, the relevance of current direction on elicited effects is still incompletely understood. Combining TMS with electroencephalography (EEG) and electromyography (EMG) enables non-invasive analysis of evoked potentials both on cortical and peripheral level. In 23 healthy subjects, EEG and EMG responses to biphasic single pulses applied over the left motor cortex with anterior-posterior to posterior-anterior (AP-PA) or PA-AP current direction and 110% resting motor threshold (RMT) intensity were recorded and contrasted between the alternating phases. A cobot-assissted neuronavigation ensured stable coil-placement during the procedure. ResultsRMT was lower and EMG latency was shorter for AP-PA currents compared to PA-AP currents, whereas the EMG amplitude did not differ. For EEG responses, local and global evoked activity was higher for mid-components with PA-AP currents. P60 occurred earlier with PA-AP currents and N100 amplitude was higher in amplitude with AP-PA currents. The trial-wise MEP amplitude correlated significantly with P30 in the AP-PA and for both current directions with the N100 amplitude. ConclusionOur results highlight the directional sensitivity of M1 and the importance of further exploring the role of current direction in TMS protocols to better understand the cortical processes underlying cortico-cortical and cortico-spinal responses.

Source and reality monitoring enable individuals to distinguish the origins of remembered information, including whether information was self- or other-generated and whether it was perceived or imagined. Although the dorsolateral prefrontal cortex (dlPFC) and temporoparietal junction (TPJ) have been implicated in these processes, their independent causal contributions remain unclear. We investigated whether focal transcranial direct current stimulation (f-tDCS) of the left dlPFC and left TPJ differentially modulates source and reality monitoring. One hundred participants were randomly assigned to receive anodal or sham stimulation of the left dlPFC or TPJ before completing an episodic memory task manipulating agent (self, experimenter), context (spoken, imagined), and emotional valence (positive, negative). Discrimination sensitivity (d') and response criterion (c) were examined separately. For source monitoring, stimulation interacted with context and cortical region: anodal dlPFC stimulation was associated with a greater spoken-imagined difference in self-experimenter discrimination than sham stimulation, whereas no equivalent context-dependent effect emerged following TPJ stimulation. For reality monitoring, stimulation effects also differed by cortical target, with reduced spoken-imagined discrimination following anodal relative to sham TPJ stimulation and no significant effect of dlPFC stimulation. These effects were not accompanied by corresponding stimulation effects on response criterion. Independent of stimulation, source discrimination was substantially greater for spoken than imagined information, while reality-monitoring sensitivity was enhanced for self-generated relative to experimenter-generated negative information. Together, these findings provide evidence that the dlPFC and TPJ make dissociable contributions to source and reality monitoring, while highlighting the importance of contextual and affective features in determining how the origins of memories are evaluated.

Facial color is associated with the perceptual evaluation of emotions, and compared with faces with original facial or greenish color, reddish angry faces are often judged as having higher emotion intensity. Although perceptual modulation by the relationship between anger and red has also been reported from the perspective of electroencephalography (EEG), how variations in perceived emotion intensity are reflected in brain activity remains unclear. This study investigated whether EEG activity associated with face and facial expression processing is modulated as a function of the interaction between facial color and perceived emotion intensity. In the experiment, we recorded EEGs while participants evaluated emotion intensity using facial stimuli created by combining morph continua from neutral to angry expressions with three types of facial color conditions (original, red, and green). The results revealed that, in the red facial color condition, the early posterior negativity (EPN) amplitude significantly increased as a function of emotion intensity compared with those in the original and green facial color conditions. These findings suggest that the early, automatic affective processing of facial expressions, reflected in the EPN, is modulated by the combination of facial color and emotion intensity. Our findings provide new evidence that early, automatic affective processing of facial expressions, as indexed by the EPN, is modulated by the congruency between high anger intensity and a reddish facial color. HighlightO_LIReddish angry faces increase the ERP component associated with emotion evaluation. C_LIO_LIThe relationship between anger and red is evident in the left hemisphere. C_LIO_LIThe interaction between facial expression and color occurs at a later cognitive processing stage than facial expression or facial color processing alone. C_LI

IntroductionAction observation modulates corticospinal excitability, with most previous studies indicating an increase in excitability in the muscles involved in the observed movement. In addition, previous work suggests that modulation of corticospinal excitability could be specific to the timing of the stimulation, muscle, and direction of movement. Here we examined the influence of these factors on corticospinal excitability. MethodParticipants observed stimuli presenting a static hand, followed by an image of the endpoint of an index/little finger abduction movement. Transcranial magnetic stimulation was delivered at time points from 100-800ms after movement onset. Stimuli were presented in various orientations to study possible effects of anatomical positioning and movement direction, compared relative to the control condition of a static hand. ResultsCorticospinal excitability was lower at early timings (100-400ms), before rising to a plateau at later timings (500-800ms) which did not differ from the static hand condition. This facilitation was muscle-specific, with higher excitability for the muscle involved in the observed movement. By contrast, the relative direction of movement did not influence corticospinal excitability. DiscussionThese results replicate the time-dependent modulation of corticospinal excitability induced by action observation; however, we argue that simply interpreting such effects as an increase in excitability may be overly simplistic. In line with previous studies, we argue that the choice of control condition used during action observation studies may be critical to the overall direction of effects.

This study investigated the role of the angular gyrus (AG) and its subregions in the elaboration of specific and categoric autobiographical memories (AMs). Using a cue-word fMRI paradigm, thirty-nine participants retrieved and elaborated on episodic (specific) and semantic (categoric) memories, rating the amount of detail of each recollection. Parametric analyses revealed that AG activity, particularly in posterior AG, was positively associated with the amount of detail retrieved, regardless of memory type. Specific memories elicited greater activation in right AG subregions compared to categoric memories. These findings support the AGs involvement in both episodic and semantic memory retrieval and suggest functional differentiation between its subregions.

Graded cognitive tasks are relevant only when increasing nominal difficulty produces measurable changes in performance and a convergent physiological response. This study evaluated a five-level arithmetic paradigm and a five-level linguistic paradigm designed to engage working memory through separate exposure, retention, and response intervals. Thirty-eight healthy young adults completed both paradigms. Behavioral manipulation validity was assessed from accuracy and completion time; linguistic item-level responses were additionally modeled to detect nonlinear floor effects. Bilateral middle cerebral artery blood-flow velocity was recorded with transcranial Doppler ultrasonography. Baseline-normalized mean velocity change was the primary physiological endpoint, with positive and net area under the curve, peak response, time to peak, and early slope as secondary endpoints. Accuracy declined and completion time increased strongly across levels in both domains, with a substantially steeper accuracy decline in the linguistic paradigm. Although the levels were nominally ordered, the higher linguistic levels did not produce equidistant increases due to the ground effect. Transcranial Doppler models showed significant level-dependent changes in mean velocity, positive and net area under the curve, time to peak, and early slope. However, domain-by-level and domain-by-level-by-hemisphere interactions were not significant. Behavioral and physiological measures therefore converged mainly at the level of the graded experimental manipulation, rather than as distinct domain-specific or lateralized hemodynamic signatures. These findings lend support to paradigms as a multimodal framework for manipulating cognitive load experimentally, while also indicating upper-level language saturation and physiological quality-control decisions that should guide further improvement.

This study investigated the hemispheric contributions of the inferior frontal gyrus (IFG) to word production across constrained and unconstrained tasks. In the present study, we used focal ring transcranial direct current stimulation (tDCS) in a sham-controlled, double-blind design, combined with a Picture-Word Interference (PWI) task and a picture description task. Fifty-four healthy young adults completed both tasks within the same stimulation sessions, receiving anodal stimulation over either the left or right IFG. Following task-specific data exclusions, 52 participants were included in each of the two task analyses. In the PWI task, categorically related distractors produced semantic interference and associatively related distractors facilitated naming in response times, consistent with previous findings. Stimulation did not affect response times. In error rates, the two stimulation sites modulated the associative effect in opposite directions. Anodal stimulation of the left IFG enhanced the associative advantage in error rates, whereas anodal stimulation of the right IFG produced the opposite pattern. In the picture description task, anodal stimulation of the right IFG increased speech rate, producing significant effects on words per minute, unpruned words per minute, and syllables per minute. No equivalent effects emerged in the left IFG group. Lexical diversity and utterance length were unaffected by stimulation. Taken together, these findings provide convergent evidence for a hemispheric dissociation in word production. The right IFG appears to contribute to the regulation of speech output and the control of distractor interference, whereas the left IFG appears to support the retrieval and selection of word meanings.

Serotonin (5-HT) is a monoamine which regulates not only central functions but also various peripheral functions. Peripheral 5-HT is primarily derived from the gut, and its synthesis and secretion are regulated by enterochromaffin cells. Stimulation of enterochromaffin cells by food factors may regulate mental functions via the gut-brain axis. We studied whether oleuropein, an olive-derived polyphenol, regulates central functions by stimulating 5-HT secretion from enterochromaffin cells. In QGP-1 cells, which are enterochromaffin-like cells, 10 {micro}M oleuropein stimulated 5-HT secretion via Ca2+ influx through T-type and L-type voltage-dependent Ca2+ channels. Hydroxytyrosol, a metabolite of oleuropein, also promoted 5-HT secretion via the same mechanism. Furthermore, oleuropein stimulated 5-HT secretion from isolated mouse colon via voltage-dependent Ca2+ channels. Finally, oral administration of 200 mg/kg oleuropein acutely increased the depression-like behavior in the mice, which was inhibited by the prior administration of ramosetron, a 5-HT3 receptor antagonist. These findings suggest that oleuropein is a potent stimulant of gut 5-HT secretion, and show that food factors may act to regulate mental function via the secretion of gut 5-HT.