Cardiorespiratory rhythm-contingent trace eyeblink conditioning in elderly adults.

Learning outcome is modified by the degree to which the subject responds and pays attention to specific stimuli. Our recent research suggests that presenting stimuli in contingency with a specific phase of the cardiorespiratory rhythm might expedite learning. Specifically, expiration-diastole (EXP-DIA) is beneficial for learning trace eyeblink conditioning (TEBC) compared with inspiration-systole (INS-SYS) in healthy young adults. The aim of this study was to investigate whether the same holds true in healthy elderly adults (n = 50, aged >70 yr). Participants were instructed to watch a silent nature film while TEBC trials were presented at either INS-SYS or EXP-DIA (separate groups). Learned responses were determined as eyeblinks occurring after the tone conditioned stimulus (CS), immediately preceding the air puff unconditioned stimulus (US). Participants were classified as learners if they made at least five conditioned responses (CRs). Brain responses to the stimuli were measured by electroencephalogram (EEG). Memory for the film and awareness of the CS-US contingency were evaluated with a questionnaire. As a result, participants showed robust brain responses to the CS, acquired CRs, and reported awareness of the CS-US relationship to a variable degree. There was no difference between the INS-SYS and EXP-DIA groups in any of the above. However, when only participants who learned were considered, those trained at EXP-DIA (n = 11) made more CRs than those trained at INS-SYS (n = 13). Thus, learned performance could be facilitated in those elderly who learned. However, training at a specific phase of cardiorespiratory rhythm did not increase the proportion of participants who learned.NEW & NOTEWORTHY We trained healthy elderly individuals in trace eyeblink conditioning, either at inspiration-systole or at expiration-diastole. Those who learned exhibited more conditioned responses when trained at expiration-diastole rather than inspiration-systole. However, there was no difference between the experimental groups in the proportion of individuals who learned or did not learn.

Conceptual-level disgust conditioning in contamination-based obsessive-compulsive disorder.

Pavlovian fear conditioning and extinction represent learning mechanisms underlying exposure-based interventions. While increasing evidence indicates a pivotal role of disgust in the development of contamination-based obsessive-compulsive disorder (C-OCD), dysregulations in conditioned disgust acquisition and maintenance, in particular driven by higher-order conceptual processes, have not been examined. Here, we address this gap by exposing individuals with high (HCC, n = 41) or low (LCC, n = 41) contamination concern to a conceptual-level disgust conditioning and extinction paradigm. Conditioned stimuli (CS+) were images from one conceptual category partially reinforced by unconditioned disgust-eliciting stimuli (US), while images from another category served as non-reinforced conditioned stimuli (CS-). Skin conductance responses (SCRs), US expectancy and CS valence ratings served as primary outcomes to quantify conditioned disgust responses. Relative to LCC, HCC individuals exhibited increased US expectancy and CS+ disgust experience, but comparable SCR levels following disgust acquisition. Despite a decrease in conditioned responses from the acquisition phase to the extinction phase, both groups did not fully extinguish the learned disgust. Importantly, the extinction resilience of acquired disgust was more pronounced in HCC individuals. Together, our findings suggest that individuals with high self-reported contamination concern exhibit increased disgust acquisition and resistance to extinction. The findings provide preliminary evidence on how dysregulated disgust learning mechanism across semantically related concepts may contribute to C-OCD.

Rats bred for low intrinsic aerobic exercise capacity link obesity with brain inflammation and reduced structural plasticity of the hippocampus.

BACKGROUND: Increasing evidence shows obesity and poor metabolic health are associated with cognitive deficits, but the mechanistic connections have yet to be resolved. We studied rats selectively bred for low and high intrinsic aerobic capacity in order to test the association between low physical fitness, a genetic predisposition for obesity, and brain health. We hypothesized that low-capacity runner (LCR) rats with concurrently greater levels of adiposity would have increased hippocampal inflammation and reduced plasticity compared to the more physically fit high-capacity runner (HCR) rats. METHODS: We examined markers for inflammation and brain plasticity in the hippocampi of LCR rats and compared them to HCR rats. The effect of age was determined by studying the rats at a young age (8 weeks) and later in life (40 weeks). We used western blots and immunohistochemistry to quantify the expression of target proteins. RESULTS: Our study showed that the number of adult-born new neurons in the hippocampus was significantly lower in LCR rats than it was in HCR rats already at a young age and that the difference became more pronounced with age. The expression of synaptic proteins was higher in young animals relative to older ones. Brain inflammation tended to be higher in LCR rats than it was in the HCR rats, and more prominent in older rats than in young ones. CONCLUSION: Our study is the first to demonstrate that low intrinsic aerobic fitness that is associated with obesity and poor metabolic health is also linked with reduced hippocampal structural plasticity at a young age. Our results also suggest that inflammation of the brain could be one factor mediating the link between obesity and poor cognitive performance.

Learning by heart: cardiac cycle reveals an effective time window for learning.

Cardiac cycle phase is known to modulate processing of simple sensory information. This effect of the heartbeat on brain function is likely exerted via baroreceptors, the neurons sensitive for changes in blood pressure. From baroreceptors, the signal is conveyed all the way to the forebrain and the medial prefrontal cortex. In the two experiments reported, we examined whether learning, as a more complex form of cognition, can be modulated by the cardiac cycle phase. Human participants ( experiment 1) and rabbits ( experiment 2) were trained in trace eyeblink conditioning while neural activity was recorded. The conditioned stimulus was presented contingently with either the systolic or diastolic phase of the cycle. The tone used as the conditioned stimulus evoked amplified responses in both humans (electroencephalogram from "vertex," Cz) and rabbits (hippocampal CA1 local field potential) when its onset was timed at systole. In humans, the cardiac cycle phase did not affect learning, but rabbits trained at diastole learned significantly better than those trained at a random phase of the cardiac cycle. In summary, our results suggest that neural processing of external stimuli and also learning can be affected by targeting stimuli on the basis of cardiac cycle phase. These findings might be useful in applications aimed at maximizing or minimizing the effects of external stimulation. NEW & NOTEWORTHY It has been shown that rapid changes in bodily states modulate neural processing of external stimulus in brain. In this study, we show that modulation of neural processing of external stimulus and learning about it depends on the phase of the cardiac cycle. This is a novel finding that can be applied to optimize associative learning.

Phase matters: responding to and learning about peripheral stimuli depends on hippocampal θ phase at stimulus onset.

Hippocampal θ (3-12 Hz) oscillations are implicated in learning and memory, but their functional role remains unclear. We studied the effect of the phase of local θ oscillation on hippocampal responses to a neutral conditioned stimulus (CS) and subsequent learning of classical trace eyeblink conditioning in adult rabbits. High-amplitude, regular hippocampal θ-band responses (that predict good learning) were elicited by the CS when it was timed to commence at the fissure θ trough (Trough group). Regardless, learning in this group was not enhanced compared with a yoked control group, possibly due to a ceiling effect. However, when the CS was consistently presented to the peak of θ (Peak group), hippocampal θ-band responding was less organized and learning was retarded. In well-trained animals, the hippocampal θ phase at CS onset no longer affected performance of the learned response, suggesting a time-limited role for hippocampal processing in learning. To our knowledge, this is the first study to demonstrate that timing a peripheral stimulus to a specific phase of the hippocampal θ cycle produces robust effects on the synchronization of neural responses and affects learning at the behavioral level. Our results support the notion that the phase of spontaneous hippocampal θ oscillation is a means of regulating the processing of information in the brain to a behaviorally relevant degree.

Effects of hippocampal state-contingent trial presentation on hippocampus-dependent nonspatial classical conditioning and extinction.

Hippocampal local field potentials are characterized by two mutually exclusive states: one characterized by regular θ oscillations (∼4-8 Hz) and the other by irregular sharp-wave ripples. Presenting stimuli during dominant θ oscillations leads to expedited learning, suggesting that θ indexes a state in which encoding is most effective. However, ripple-contingent training also expedites learning, suggesting that any discrete brain state, much like the external context, can affect learning. We trained adult rabbits in trace eyeblink conditioning, a hippocampus-dependent nonspatial task, followed by extinction. Trials were delivered either in the presence or absence of θ or regardless of hippocampal state. Conditioning in the absence of θ led to more animals learning, although learning was slower compared with a yoked control group. Contrary to expectations, conditioning in the presence of θ did not affect learning. However, extinction was expedited both when it was conducted contingent on θ and when it was conducted in a state contrary to that used to trigger trials during conditioning. Strong phase-locking of hippocampal θ-band responses to the conditioned stimulus early on during conditioning predicted good learning. No such connection was observed during extinction. Our results suggest that any consistent hippocampal oscillatory state can potentially be used to regulate learning. However, the effects depend on the specific state and task at hand. Finally, much like the external environment, the ongoing neural state appears to act as a context for learning and memory retrieval.

The cardiac cycle modulates learning-related interoception.

Behavior is guided by the compatibility of expectations based on past experience and the outcome. In a recent study, Fouragnan and colleagues report that absolute prediction error (PE)-related heart-evoked potentials (HEPs) differ according to the cardiac cycle phase at outcome, and that the magnitude of this effect positively correlates with reward learning in healthy adults.

Neurocognitive mechanisms of mental imagery-based disgust learning.

Disgust imagery represents a potential pathological mechanism for disgust-related disorders. However, it remains controversial as to whether disgust can be conditioned with disgust-evoking mental imagery serving as the unconditioned stimulus (US). Therefore, we examined this using a conditioned learning paradigm in combination with event-related potential (ERP) analysis in 35 healthy college students. The results indicated that the initial neutral face (conditioned stimulus, CS+) became more disgust-evoking, unpleasant, and arousing after pairing with disgust-evoking imagery (disgust CS+), compared to pairing with neutral (neutral CS+) and no (CS-) imagery. Moreover, we observed that mental imagery-based disgust conditioning was resistant to extinction. While the disgust CS + evoked larger P3 and late positive potential amplitudes than CS- during acquisition, no significant differences were found between disgust CS+ and neutral CS+, indicating a dissociation between self-reported and neurophysiological responses. Future studies may additionally acquire facial EMG as an implicit index of conditioned disgust. This study provides the first neurobiological evidence that associative disgust learning can occur without aversive physical stimuli, with implications for understanding how disgust-related disorders may manifest or deteriorate without external perceptual aversive experiences, such as in obsessive-compulsive disorder (OCD).

Cardiorespiratory fitness is linked with heart rate variability during stress in "at-risk" adults.

BACKGROUND: Physiological mechanisms explaining why cardiorespiratory fitness (CRF) predicts cardiovascular morbidity and mortality are incompletely understood. We examined if CRF modifies vagally mediated heart rate variability (HRV) during acute physical or psychosocial stress or night-time sleep in adults with cardiovascular risk factors. METHODS: Seventy-eight adults (age 56 years [IQR 50-60], 74% female, body mass index 28 kg/m2 [IQR 25-31]) with frequent cardiovascular risk factors participated in this cross-sectional study. They went through physical (treadmill cardiopulmonary exercise test [CPET]) and psychosocial (Trier Social Stress Test for Groups [TSST-G]) stress tests and night-time sleep monitoring (polysomnography). Heart rate (HR) and vagally mediated HRV (root mean square of successive differences between normal R-R intervals [RMSSD]) were recorded during the experiments and analyzed by taking account of potential confounders. RESULTS: CRF (peak O2 uptake) averaged 99% (range 78-126) in relation to reference data. From pre-rest to moderate intensities during CPET and throughout TSST-G, HR did not differ between participants with CRF below median (CRFlower) and CRF equal to or above median (CRFhigher), whereas CRFhigher had higher HRV than CRFlower, and CRF correlated positively with HRV in all participants. Meanwhile, CRF had no independent associations with HR or HRV levels during slow-wave sleep, the presence of metabolic syndrome was not associated with recorded HR or HRV levels, and single factors predicted HRV responsiveness independently only to limited extents. CONCLUSIONS: CRF is positively associated with prevailing vagally mediated HRV at everyday levels of physical and psychosocial stress in adults with cardiovascular risk factors.

Intrinsic running capacity associates with hippocampal electrophysiology and long-term potentiation in rats.

Good aerobic and metabolic fitness associates with better cognitive performance and brain health. Conversely, poor metabolic health predisposes to neurodegenerative diseases. Our previous findings indicate that rats selectively bred for Low Capacity for Running (LCR) show less synaptic plasticity and more inflammation in the hippocampus and perform worse in tasks requiring flexible cognition than rats bred for High Capacity for Running (HCR). Here we aimed to determine whether hippocampal electrophysiological activity related to learning and memory would be impaired in LCR compared to HCR rats. We also studied whether an exercise intervention could even out the possible differences. We conducted in vivo recordings from the dorsal hippocampus under terminal urethane anesthesia in middle-aged sedentary males and female rats, and in females allowed to access running wheels for 6 weeks. Our results indicate stronger long-term potentiation (LTP) in the CA3-CA1 synapse in HCR than LCR rats, and in female than male rats. Compared to LCR rats, HCR rats had more dentate spikes and more gamma epochs, the occurrence of which also correlated positively with the magnitude of LTP. Voluntary running reduced the differences between female LCR and HCR rats. In conclusion, low innate fitness links to reduced hippocampal function and plasticity which can seems to improve with voluntary aerobic exercise even in middle age.

Rapture of the deep: gas narcosis may impair decision-making in scuba divers.

Introduction: While gas narcosis is familiar to most divers conducting deep (> 30 metres) dives, its effects are often considered minuscule or subtle at 30 metres. However, previous studies have shown that narcosis may affect divers at depths usually considered safe from its influence, but little knowledge exists on the effects of gas narcosis on higher cognitive functions such as decision-making in relatively shallow water at 30 metres. Impaired decision-making could be a significant safety issue for a multitasking diver. Methods: We conducted a study exploring the effects of gas narcosis on decision-making in divers breathing compressed air underwater. The divers (n = 22) were evenly divided into 5-metre and 30-metre groups. In the water, we used underwater tablets equipped with the Iowa Gambling Task (IGT), a well-known psychological task used to evaluate impairment in decision-making. Results: The divers at 30 metres achieved a lower score (mean 1,584.5, standard deviation 436.7) in the IGT than the divers at 5 metres (mean 2,062.5, standard deviation 584.1). Age, body mass index, gender, or the number of previous dives did not affect performance in the IGT. Conclusions: Our results suggest that gas narcosis may affect decision-making in scuba divers at 30 metres depth. This supports previous studies showing that gas narcosis is present at relatively shallow depths and shows that it may affect higher cognitive functions.

Genotype determining aerobic exercise capacity associates with behavioral plasticity in middle-aged rats.

Good aerobic fitness associates positively with cognitive performance and brain health and conversely, low aerobic fitness predisposes to neurodegenerative diseases. To study how genotype together with exercise, started at older age, affects brain and behavior, we utilized rats that differ in inherited aerobic fitness. Rats bred for Low Capacity for Running (LCR) are shown to display less synaptic plasticity and more inflammation in the hippocampus and perform worse than rats bred for a High Capacity for Running (HCR) in tasks requiring flexible cognition. Here we used middle-aged (∼ 16 months) HCR and LCR rats to study how genotype and sex associate with anxiety and neural information filtering, termed sensory gating. Further, we assessed how inherited aerobic capacity associates with hippocampus-dependent learning, measured with contextual fear conditioning task. In females, we also investigated the effects of voluntary wheel running (5 weeks) on these characteristics. Our results indicate that independent of sex or voluntary running, HCR rats were more anxious in open-field tasks, exhibited lower sensory gating and learned more efficiently in contextual fear conditioning task than LCR rats. Voluntary running did not markedly affect innate behavior but slightly decreased the differences between female LCR and HCR rats in fear learning. In conclusion, inherited fitness seems to determine cognitive and behavioral traits independent of sex. Although the traits proved to be rather resistant to change at adult age, learning was slightly improved following exercise in LCR females, prone to obesity and poor fitness.

Project DyAdd: classical eyeblink conditioning in adults with dyslexia and ADHD.

In this study of the project DyAdd (Adult Dyslexia and Attention Deficit Disorder in Finland), classical eyeblink conditioning (EBC) was investigated in both delay and trace paradigms in adults (18-55 years) with dyslexia (n = 37), attention deficit-hyperactivity disorder (ADHD; n = 21), their comorbid combination (n = 8), and healthy controls (n = 35). In addition, the profiles of three participants with a rare autosomal dominant cerebellar disease were assessed (episodic ataxia type 2, EA-2). We found that participants with dyslexia were overall slower learners than controls in eyeblink conditioning. Further, they were the only group that had a reduced number of CRs in mediotemporal-dependent trace paradigm compared to the more cerebellum-dependent delay paradigm. Second, ADHD was found to be related to larger CR amplitude. Third, those with a comorbid condition learned faster and manifested CRs that were not well timed. Fourth, the cerebellar patients showed nearly no conditioning at all. Correlations between EBC and various neuropsychological domains (phonological processing, reading, spelling, arithmetic, executive functions, attention, and fine motor control) over all participants resulted in significant relations only for the delay paradigm: Increased amount of reading errors related with later peak latency and increased amount of self-corrections in fine motor control related with larger response magnitude. Within those who conditioned, relations emerged only for the trace paradigm: better spelling was related to larger response magnitude. These results do not lend support to the cerebellar hypothesis of dyslexia. On the contrary, dyslexia in its pure form seems to be related to a relative dysfunction of a larger hippocampal-cerebellar network. Further, larger responses in the ADHD group are suggested to result from their lowered responding threshold.

Cardiorespiratory Fitness Estimation Based on Heart Rate and Body Acceleration in Adults With Cardiovascular Risk Factors: Validation Study.

BACKGROUND: Cardiorespiratory fitness (CRF) is an independent risk factor for cardiovascular morbidity and mortality. Adding CRF to conventional risk factors (eg, smoking, hypertension, impaired glucose metabolism, and dyslipidemia) improves the prediction of an individual's risk for adverse health outcomes such as those related to cardiovascular disease. Consequently, it is recommended to determine CRF as part of individualized risk prediction. However, CRF is not determined routinely in everyday clinical practice. Wearable technologies provide a potential strategy to estimate CRF on a daily basis, and such technologies, which provide CRF estimates based on heart rate and body acceleration, have been developed. However, the validity of such technologies in estimating individual CRF in clinically relevant populations is poorly known. OBJECTIVE: The objective of this study is to evaluate the validity of a wearable technology, which provides estimated CRF based on heart rate and body acceleration, in working-aged adults with cardiovascular risk factors. METHODS: In total, 74 adults (age range 35-64 years; n=56, 76% were women; mean BMI 28.7, SD 4.6 kg/m2) with frequent cardiovascular risk factors (eg, n=64, 86% hypertension; n=18, 24% prediabetes; n=14, 19% type 2 diabetes; and n=51, 69% metabolic syndrome) performed a 30-minute self-paced walk on an indoor track and a cardiopulmonary exercise test on a treadmill. CRF, quantified as peak O2 uptake, was both estimated (self-paced walk: a wearable single-lead electrocardiogram device worn to record continuous beat-to-beat R-R intervals and triaxial body acceleration) and measured (cardiopulmonary exercise test: ventilatory gas analysis). The accuracy of the estimated CRF was evaluated against that of the measured CRF. RESULTS: Measured CRF averaged 30.6 (SD 6.3; range 20.1-49.6) mL/kg/min. In all participants (74/74, 100%), mean difference between estimated and measured CRF was -0.1 mL/kg/min (P=.90), mean absolute error was 3.1 mL/kg/min (95% CI 2.6-3.7), mean absolute percentage error was 10.4% (95% CI 8.5-12.5), and intraclass correlation coefficient was 0.88 (95% CI 0.80-0.92). Similar accuracy was observed in various subgroups (sexes, age, BMI categories, hypertension, prediabetes, and metabolic syndrome). However, mean absolute error was 4.2 mL/kg/min (95% CI 2.6-6.1) and mean absolute percentage error was 16.5% (95% CI 8.6-24.4) in the subgroup of patients with type 2 diabetes (14/74, 19%). CONCLUSIONS: The error of the CRF estimate, provided by the wearable technology, was likely below or at least very close to the clinically significant level of 3.5 mL/kg/min in working-aged adults with cardiovascular risk factors, but not in the relatively small subgroup of patients with type 2 diabetes. From a large-scale clinical perspective, the findings suggest that wearable technologies have the potential to estimate individual CRF with acceptable accuracy in clinically relevant populations.

Measuring psychosocial stress with heart rate variability-based methods in different health and age groups.

Objective.Autonomic nervous system function and thereby bodily stress and recovery reactions may be assessed by wearable devices measuring heart rate (HR) and its variability (HRV). So far, the validity of HRV-based stress assessments has been mainly studied in healthy populations. In this study, we determined how psychosocial stress affects physiological and psychological stress responses in both young (18-30 years) and middle-aged (45-64 years) healthy individuals as well as in patients with arterial hypertension and/or either prior evidence of prediabetes or type 2 diabetes. We also studied how an HRV-based stress index (Relax-Stress Intensity, RSI) relates to perceived stress (PS) and cortisol (CRT) responses during psychosocial stress.Approach.A total of 197 participants were divided into three groups: (1) healthy young (HY,N = 63), (2) healthy middle-aged (HM,N = 61) and (3) patients with cardiometabolic risk factors (Pts,N = 73, 32-65 years). The participants underwent a group version of Trier Social Stress Test (TSST-G). HR, HRV (quantified as root mean square of successive differences of R-R intervals, RMSSD), RSI, PS, and salivary CRT were measured regularly during TSST-G and a subsequent recovery period.Main results.All groups showed significant stress reactions during TSST-G as indicated by significant responses of HR, RMSSD, RSI, PS, and salivary CRT. Between-group differences were also observed in all measures. Correlation and regression analyses implied RSI being the strongest predictor of CRT response, while HR was more closely associated with PS.Significance.The HRV-based stress index mirrors responses of CRT, which is an independent marker for physiological stress, around TSST-G. Thus, the HRV-based stress index may be used to quantify physiological responses to psychosocial stress across various health and age groups.

Hippocampal ripple-contingent training accelerates trace eyeblink conditioning and retards extinction in rabbits.

There are at least two distinct oscillatory states of the hippocampus that are related to distinct behavioral patterns. Theta (4-12 Hz) oscillation has been suggested to indicate selective attention during which the animal concentrates on some features of the environment while suppressing reactivity to others. In contrast, sharp-wave ripples ( approximately 200 Hz) can be seen in a state in which the hippocampus is at its most responsive to any kind of afferent stimulation. In addition, external stimulation tends to evoke and reset theta oscillation, the phase of which has been shown to modulate synaptic plasticity in the hippocampus. Theoretically, training on a hippocampus-dependent learning task contingent upon ripples could enhance learning rate due to elevated responsiveness and enhanced phase locking of the theta oscillation. We used a brain-computer interface to detect hippocampal ripples in rabbits to deliver trace eyeblink conditioning and extinction trials selectively contingent upon them. A yoked control group was trained regardless of their ongoing neural state. Ripple-contingent training expedited acquisition of the conditioned response early in training and evoked stronger theta-band phase locking to the conditioned stimulus. Surprisingly, ripple-contingent training also resulted in slower extinction in well trained animals. We suggest that the ongoing oscillatory activity in the hippocampus determines the extent to which a stimulus can induce a phase reset of the theta oscillation, which in turn is the determining factor of learning rate in trace eyeblink conditioning.

Rats with elevated genetic risk for metabolic syndrome exhibit cognitive deficiencies when young.

Metabolic syndrome (MetS) is a known risk factor for cognitive decline. Using polygenic rat models selectively bred for high and low intrinsic exercise capacity and simultaneously modelling as low and high innate risk factor for MetS respectively, we have previously shown that adult animals with lower exercise capacity/higher MetS risk perform poorly in tasks requiring flexible cognition. However, it is not known whether these deficits in cognition are present already at young age. Also, it is unclear whether the high risk genome is related also to lower-level cognition, such as sensory gating measured as prepulse inhibition. In this study, young and adult (5-8 weeks and ~9 months) rats selectively bred for 36 generations as High-Capacity Runners (HCR) or Low-Capacity Runners (LCR) were tested for behavior in an open field task, modulation of startle reflex, and spatial learning in a T-maze. HCR rats were more active in the open field than LCR rats independent of age. Responses to the startle stimulus habituated to the same extent in LCR compared to HCR rats when young, but as adults, stronger habituation was seen in the HCR animals. The prepulse inhibition of startle response was equally strong in young HCR and LCR animals but the effect was shorter lasting in HCR animals. In T-maze, adult HCR animals unexpectedly showed attenuated learning, but we interpret this finding to stem from differences in motivation rather than learning ability. Overall, in the LCR rats with the risk genome for poor aerobic fitness and MetS, indications of compromised cognitive function are present already at a young age.

Hippocampal theta activity is selectively associated with contingency detection but not discrimination in rabbit discrimination-reversal eyeblink conditioning.

The relative power of the hippocampal theta-band ( approximately 6 Hz) activity (theta ratio) is thought to reflect a distinct neural state and has been shown to affect learning rate in classical eyeblink conditioning in rabbits. We sought to determine if the theta ratio is mostly related to the detection of the contingency between the stimuli used in conditioning or also to the learning of more complex inhibitory associations when a highly demanding delay discrimination-reversal eyeblink conditioning paradigm is used. A high hippocampal theta ratio was not only associated with a fast increase in conditioned responding in general but also correlated with slow emergence of discriminative responding due to sustained responding to the conditioned stimulus not paired with an unconditioned stimulus. The results indicate that the neural state reflected by the hippocampal theta ratio is specifically linked to forming associations between stimuli rather than to the learning of inhibitory associations needed for successful discrimination. This is in line with the view that the hippocampus is responsible for contingency detection in the early phase of learning in eyeblink conditioning.

Event-related potentials reveal rapid registration of features of infrequent changes during change blindness.

BACKGROUND: Change blindness refers to a failure to detect changes between consecutively presented images separated by, for example, a brief blank screen. As an explanation of change blindness, it has been suggested that our representations of the environment are sparse outside focal attention and even that changed features may not be represented at all. In order to find electrophysiological evidence of neural representations of changed features during change blindness, we recorded event-related potentials (ERPs) in adults in an oddball variant of the change blindness flicker paradigm. METHODS: ERPs were recorded when subjects performed a change detection task in which the modified images were infrequently interspersed (p = .2) among the frequently (p = .8) presented unmodified images. Responses to modified and unmodified images were compared in the time window of 60-100 ms after stimulus onset. RESULTS: ERPs to infrequent modified images were found to differ in amplitude from those to frequent unmodified images at the midline electrodes (Fz, Pz, Cz and Oz) at the latency of 60-100 ms even when subjects were unaware of changes (change blindness). CONCLUSIONS: The results suggest that the brain registers changes very rapidly, and that changed features in images are neurally represented even without participants' ability to report them.

Anodal tDCS Over the Left Prefrontal Cortex Does Not Cause Clinically Significant Changes in Circulating Metabolites.

BACKGROUND: Transcranial direct current stimulation (tDCS), a putative treatment for depression, has been proposed to affect peripheral metabolism. Metabolic products from brain tissue may also cross the blood-brain barrier, reflecting the conditions in the brain. However, there are no previous data regarding the effect of tDCS on circulating metabolites. OBJECTIVE: To determine whether five daily sessions of tDCS modulate peripheral metabolites in healthy adult men. METHODS: This double-blind, randomized controlled trial involved 79 healthy males (aged 20-40 years) divided into two groups, one receiving tDCS (2 mA) and the other sham stimulated. The anode was placed over the left dorsolateral prefrontal cortex and the cathode over the corresponding contralateral area. Venous blood samples were obtained before and after the first stimulation session, and after the fifth stimulation session. Serum levels of 102 metabolites were determined by mass spectrometry. The results were analysed with generalised estimating equations corrected for the family-wise error rate. In addition, we performed power calculations estimating sample sizes necessary for future research. RESULTS: TDCS-related variation in serum metabolite levels was extremely small and statistically non-significant. Power calculations indicated that for the observed variation to be deemed significant, samples sizes of up to 11,000 subjects per group would be required, depending on the metabolite of interest. CONCLUSION: Our study found that five sessions of tDCS induced no major effects on peripheral metabolites among healthy men. These observations support the view of tDCS as a safe treatment that does not induce significant changes in the measured peripheral metabolites in healthy male subjects.