How to Detect Amygdala Activity with Magnetoencephalography using Source Imaging

Previous functional magnetic resonance imaging (fMRI) studies with human subjects have explored the neural substrates involved in forming associations in Pavlovian fear conditioning. Most of these studies used delay procedures, in which the conditioned stimulus (CS) and unconditioned stimulus (UCS) coterminate. Less is known about brain regions that support trace conditioning, a procedure in which an interval of time (trace interval) elapses between CS termination and UCS onset. Previous work suggests significant overlap in the neural circuitry supporting delay and trace fear conditioning, although trace conditioning requires recruitment of additional brain regions. In the present event-related fMRI study, skin conductance and continuous measures of UCS expectancy were recorded concurrently with whole-brain blood oxygenation level-dependent (BOLD) imaging during direct comparison of delay and trace discrimination learning. Significant activation was observed within the visual cortex for all CSs. Anterior cingulate and medial thalamic activity reflected associative learning common to both delay and trace procedures. Activations within the supplementary motor area (SMA), frontal operculum, middle frontal gyri, and inferior parietal lobule were specifically associated with trace interval processing. The hippocampus displayed BOLD signal increases early in training during all conditions; however, differences were observed in hippocampal response magnitude related to the accuracy of predicting UCS presentations. These results demonstrate overlapping patterns of activation within the anterior cingulate, medial thalamus, and visual cortex during delay and trace procedures, with additional recruitment of the hippocampus, SMA, frontal operculum, middle frontal gyrus, and inferior parietal lobule during trace conditioning. These data suggest that the hippocampus codes temporal information during trace conditioning, whereas brain regions supporting working memory processes maintain the CS-UCS representation during the trace interval.

OPINION article Front. Integr. Neurosci., 18 August 2011 Volume 5 - 2011 | https://doi.org/10.3389/fnint.2011.00040

Paired pulse depression in the somatosensory cortex: Associations between MEG and BOLD fMRI

Squire and colleagues have proposed that trace and delay eyeblink conditioning are fundamentally different kinds of learning: trace conditioning requires acquisition of a conscious declarative memory for the stimulus contingencies whereas delay conditioning does not. Declarative memory in trace conditioning is thought to generate conditioned responding through the activation of a conscious expectancy for when the unconditioned stimulus (US) is going to occur. Perruchet (1985) has previously shown that in a 50% partial reinforcement design it is possible to dissociate single cue delay eyeblink conditioning from conscious expectancy for the US by examining performance over runs of reinforced and nonreinforced trials. Clark, Manns, and Squire (2001) claim that this dissociation does not occur in trace eyeblink conditioning. In the present experiment we examined the Perruchet effect for short, moderate, and long trace intervals (600, 1000, and 1400 ms) and for the equivalent interstimulus intervals (ISIs) in a delay conditioning procedure. We found evidence for a dissociation of eyeblink CRs and US expectancy over runs regardless of whether there was a delay or a trace arrangement of cues. The reasons for the Perruchet effect are still unclear, but the present data suggest that it does not depend on a separate nondeclarative system of the type proposed by Squire and colleagues.

In four experiments, it was shown that the onset and offset of a tone conditioned stimulus (CS) in trace conditioning interact in much the same way as a sequence of two stimuli from different sensory sources, such as a tone and a light. The duration of the tone was manipulated across values ranging from 400 to 30,000 msec, whereas the trace interval between the tone offset and the US was fixed at 400 msec. The rate and level of total CR acquisition were high and constant across all tone durations. Likewise, responding during the trace interval on paired trials was relatively constant. However, when the tone onset and tone offset were tested in relative isolation from each other on test trials using a 30,000-msec tone, there was a reciprocal relationship in responding to tone onset and tone offset. When training had been conducted with shorter tone durations, responding to tone onset was only moderate but, nonetheless, higher than responding to tone offset, which was negligible. At the longer tone durations, responding to tone onset declined to lower levels, whereas responding to tone offset rose to a high level equal to the total level of responding. These effects were consistent across manipulations of tone intensity and prior delay conditioning, in which only tone onset could function as a CS. Consequently, the trace CS appears to act as a compound stimulus that engages complex associative processes as well as simple associative processes. The implications of the present results for understanding the susceptibility of trace conditioning to hippocampal damage in the rabbit nictitating membrane preparation are discussed.

Undernutrition during the brain growth period of the rat significantly delays the development of processes mediating pavlovian trace conditioning

Comparisons of dorsal and ventral hippocampus cornu ammonis region 1 pyramidal neuron activity during trace eye-blink conditioning in the rabbit

Classical (trace) conditioning is a specific variant of associative learning in which a neutral stimulus leads to the subsequent prediction of an emotionally charged or noxious stimulus after a temporal gap. When conditioning is concurrent with a distraction task, only participants who can report the relationship (the contingency) between stimuli explicitly show associative learning. This suggests that consciousness is a prerequisite for trace conditioning. We review and question three main controversies concerning this view. Firstly, virtually all animals, even invertebrate sea slugs, show this type of learning; secondly, unconsciously perceived stimuli may elicit trace conditioning; and thirdly, some vegetative state patients show trace learning. We discuss and analyze these seemingly contradictory arguments to find the theoretical boundaries of consciousness in classical conditioning. We conclude that trace conditioning remains one of the best measures to test conscious processing in the absence of explicit reports.

Impact of fornix lesions on tone-off delay vs tone-on trace eyeblink conditioning in rats

Temporal contiguity between conditioned (CS) and unconditioned stimuli (US) is a crucial factor in Pavlovian learning, yet little is known about its role in appetitive conditioning and extinction. In a within-subject design, 60 participants underwent both a delay (DC) and trace conditioning (TC) session with partial reinforcement (75%) by monetary rewards (US) and varying interval between CS offset and US onset (DC: 0s; TC: 4s). In addition to self-report indices (reward expectancy, arousal, valence), psychophysiological markers (pupil dilation, heart-period and startle reflex modulation) were recorded during acquisition and extinction training. For most measures, significant differential conditioned responses emerged, irrespective of temporal contiguity, with no major differences observed between TC and DC during acquisition (except for potentially diminished startle attenuation in TC). Despite overall similar patterns in conditioned responding (with small to moderate effects on physiological measures), there was no intraindividual concordance between sessions, yet evidence for differential TC effects on extinction learning. Specifically, smaller reductions in differential reward expectancy, heart-period deceleration and startle modulation after extinction in TC suggested relatively diminished extinction learning. Conditioned pupil dilation (0–2 s after CS onset) remained comparatively stable. Taken together, our findings extend evidence of differences in underlying learning mechanisms between TC and DC to the context of reward learning.

Three experiments examined the effect of distribution form of the trace intervalon trace conditioning. In Experiments 1 and 2, two groups of rats wereconditioned to a fixed-duration conditioned stimulus (CS) in a trace intervalprocedure; rats in Group Fix received a fixed-duration trace interval, whereasfor rats in Group Var the trace interval was of variable duration. Respondingduring the CS was higher in Group Var than in Group Fix, whereas during thetrace interval this difference in responding reversed—Group Fix showed higherresponse rates than Group Var. Experiment 3 examined whether the greaterresponse rate observed during the CS in Group Var was due to a performanceeffect or the acquisition of greater associative strength by the CS. Followingtrace conditioning, the rats from Experiment 1 underwent a second phase of delayconditioning with the same CS; a 5-s auditory stimulus was presented in compoundwith the last 5 s of the 15-s CS, and the unconditioned stimulus (US) wasdelivered at the offset of the CSs. On test with the auditory stimulus alone,subjects in Group Var showed lower response rates during the auditory stimulusthan subjects in Group Fix. We interpreted these findings as evidence that thesuperior responding in Group Var during the CS was a result of it acquiringgreater associative strength than in Group Fix.

To examine the effect of acetazolamide, known to increase cerebral blood flow (CBF) and glyceryl trinitrate (GTN), known to increase cerebral blood volume (CBV) on the blood oxygenation level-dependent (BOLD) response in humans using 3 T magnetic resonance imaging (MRI), and to evaluate how pharmacological agents may modulate cerebral hemodynamic and thereby possibly the BOLD signal. Six subjects were randomly allocated to receive acetazolamide, GTN, or placebo in a double-blind three-way crossover controlled study. Before, during, and after drug administration we recorded the BOLD response during visual stimulation with reversing checkerboard. We found that acetazolamide caused significant depression of the BOLD response (P = 0.0066). The maximum decrease occurred at 5 minutes after infusion and was 51.9% (95% confidence interval [CI], 22.03-81.76). GTN did not influence the BOLD response (P = 0.55). The BOLD response is decreased during increased CBF by acetazolamide, suggesting an inverse relationship between global CBF and the BOLD response. GTN does not change the BOLD response. This indicates that GTN exerts an effect on the large vessels only and that CBV changes in the microvascular system are necessary to alter the BOLD response.

Trace fear conditioning is an important research paradigm to model aversive learning in biological or clinical scenarios, where predictors (conditioned stimuli, CS) and aversive outcomes (unconditioned stimuli, US) are separated in time. The optimal measurement of human trace fear conditioning, and in particular of memory retention after consolidation, is currently unclear. We conducted two identical experiments (N1 = 28, N2 = 28) with a 15‐s trace interval and a recall test 1 week after acquisition, while recording several psychophysiological observables. In a calibration approach, we explored which learning and memory measures distinguished CS+ and CS− in the first experiment and confirmed the most sensitive measures in the second experiment. We found that in the recall test without reinforcement, only fear‐potentiated startle but not skin conductance, pupil size, heart period, or respiration amplitude, differentiated CS+ and CS−. During acquisition without startle probes, skin conductance responses and pupil size responses but not heart period or respiration amplitude differentiated CS+ and CS−. As a side finding, there was no evidence for extinction of fear‐potentiated startle over 30 trials without reinforcement. These results may be useful to inform future substantive research using human trace fear conditioning protocols.

Post-training ethanol disrupts trace conditioned fear in rats: Effects of timing of ethanol, dose and trace interval duration

In simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), increased neuronal activity from epileptiform spikes commonly elicits positive blood oxygenation level-dependent (BOLD) responses. Negative responses are also occasionally seen and have not been explained. Recent studies describe BOLD signal changes before focal EEG spikes. We aimed to systematically study if the undershoot of a preceding positive response might explain the negative BOLD seen in the focus. Eighty-two patients with focal epilepsy who underwent EEG-fMRI at 3T were retrospectively studied. Studies with a focal negative BOLD response in the region of the spike field were reanalyzed using models with hemodynamic response functions (HRFs) peaking from -9 to +9 s around the spike. Eight patients met the inclusion criteria, showing negative BOLD responses in the spike field on standard analysis. None had positive BOLD responses immediately adjacent to the areas of deactivation. Regions of deactivation were found to have congruent preceding positive responses in two cases. These early activations were seen at the combined maps of -5 to -9 s. This study indicates that in a small proportion of patients with focal epilepsy in whom the standard analysis reveals focal negative responses, an earlier positive BOLD response is probably the cause. The origin of negative BOLD signal changes in the focus as a result of an epileptic event remains, however, unexplained in most of the patients in whom it occurs.