Neural correlates of subjective CS/UCS association in appetitive conditioning

Explicit knowledge of conditioned stimulus (CS)/unconditioned stimulus (UCS) associations is proposed as important factor in classical conditioning. However, while previous studies have focused on its roles in fear conditioning, it has been neglected in the context of appetitive conditioning. The present functional magnetic resonance study aimed to investigate neural activation and functional connectivity linked to subjective CS/UCS association in appetitive conditioning. In total, 85 subjects participated in an appetitive acquisition procedure in which a neutral stimulus (CS+) was paired with a monetary reward, while another neutral stimulus (CS‐) was never paired with the reward. Directly afterwards, subjective CS/UCS association was assessed by measuring the extent to which the CS+ was thought to be associated with the UCS compared to the CS‐. Close relationships were established between subjective CS/UCS association and activations in the primary visual cortex (V1) during the early phase of conditioning and in the striatum during the late conditioning phase. In addition, we observed inverse relationships between subjective CS/UCS association and both V1/ventromedial prefrontal cortex (vmPFC) and striatal/vmPFC connectivity. The results suggest the involvement of decoupling vmPFC connectivity in reward learning in general and the roles of attentional processes in the formation of the subjective CS/UCS association during the early phase and reward prediction during the late phase of appetitive conditioning.     

Conditioned orienting (alpha) and delayed behavioral and evoked neural responses during classical conditioning

A differentiation of short-latency (alpha) and long-latency (delayed) classically conditioned behavioral and evoked neural (hippocampal) responses was attempted. Further, facilitation and retardation of these responses were studied in an experimental design in which 10 paired conditioning sessions either preceded (CC-CO group) or followed (CO-CC group) 10 randomly unpaired presentations of conditioned stimuli (CS) and unconditioned stimuli (UCS). A 2024-ms tone (1000 Hz) was delivered directly through a miniature earphone to the left ear, eliciting an orienting head movement ('alpha' response) to the left. The unconditioned stimulus (UCS) was a direct 1024-ms stimulation of the lateral hypothalamic area overlapping the CS (delayed paradigm) so that both stimuli terminated simultaneously. The UCS elicited approach behavior and a specific head movement in each animal. The latency and the direction of the head movement were used as criteria for a differentiation of the short-latency and long-latency conditioned responses (CR). All cats showed conditioned short-latency responses. Pairing specific long-latency head movements were observed in 10 of 13 cats and 6 of them showed a long-latency CR which was a head movement to the right, while the short-latency CR on the same trials was a head movement to the left. Hippocampal (subiculum, dentate fascia and CA1) evoked responses also showed pairing specific CRs appearing as increased negativity (short-latency CR), or increased positivity (long-latency CR). Additional reversed stimulus order (backward) sessions supported an assumption of the different nature of the short-latency and long-latency CRs: the long-latency CRs showed extinction while the short-latency CRs remained. The unpaired pre-exposure to the CSs and UCSs in the CO-CC group resulted in the retarded acquisition of the behavioral responses during the subsequent paired sessions.     

Evoked response amplitudes from somatosensory cortices do not determine reaction times to tactile stimuli

Sensory events cause changes in brain activity, which underlie the perception of and behavioural responses to sensory stimuli. Evoked cortical responses are an important measure of these stimulus-evoked changes in brain activity. However, evidence on the relationship between behavioural responses and evoked responses is inconsistent. Therefore, we used magnetoencephalography to reinvestigate the relationship between evoked responses from somatosensory cortices and behavioural responses to somatosensory stimuli. We characterized modulations of somatosensory-evoked responses exerted by preceding painful and tactile conditioning stimuli (CS), and related these modulations of evoked responses to modulations of reaction times. Our results show that painful CS yield a long-lasting (> 4 s) facilitation of evoked responses, whereas tactile CS result in a shorter lasting (1-2 s) suppression of evoked responses to tactile stimuli. These contrary physiological effects were both associated with a significant shortening of reaction times. These findings indicate that the conditioning effects of painful and tactile stimuli represent essentially different modulatory mechanisms. Moreover, our results show that amplitudes of evoked responses from somatosensory cortices do not determine reaction times to tactile stimuli.     

Pre-stimulus spectral EEG patterns and the visual evoked response.

The relationship between the latencies and amplitudes of the N1 and P2 components of the visual evoked potential (VEP) and the psychophysiological state of the brain immediately preceding the time of the stimulus has been investigated in 7 male subjects. Power spectral measures in the delta, theta, alpha and beta bands of the 1 sec pre-stimulus EEG were used to assess the brain state, and low intensity flashes, delivered randomly between 2 and 6 whole seconds, were used as the stimuli. Trials were ranked separately according to the relative amounts of pre-stimulus power in each EEG band and were partitioned into groups by an equal pre-stimulus spectral power criterion. Averaged EPs were computed from these groups and multiple regression analysis was used to relate pre-stimulus spectral power values to EP features. Five of the 7 subjects displayed consistent increases in N1-P2 amplitude as a function of increasing pre-stimulus relative alpha power. The between-subjects effect of pre-stimulus EEG on N1 latency was small, but was moderate for P2 latency (both significant). Both N1 and P2 latency were found to decrease with increasing amounts of pre-stimulus relative delta and theta power.     

Dopamine efflux in nucleus accumbens shell and core in response to appetitive classical conditioning

Dopamine transmission within the nucleus accumbens has been implicated in associative reinforcement learning. We investigated the effect of appetitive classical conditioning on dopamine efflux in the rat nucleus accumbens shell and core, as dopamine may be differentially activated by conditioned and unconditioned stimuli (CS, US) in these subregions. After implantation of microdialysis cannulae, rats were food restricted and trained for three consecutive days with three acquisition sessions per day. A 10-s noise (CS) was immediately followed by the delivery of two reward pellets (US) for the conditioned group (paired presentation), whereas conditioned stimuli and unconditioned stimuli were presented at random for the control group (unpaired presentation). On the fourth day, all rats were given a further CS + US session and two CS-alone sessions, and extracellular dopamine concentrations were measured (7.5 min/per sample). Behavioural measures (number of nose pokes, latency to nose poke after conditioned stimuli onset, locomotor activity) demonstrated that the paired groups showed a high level of conditioning. CS + US presentation increased dopamine equally in both shell and core of the paired and unpaired groups. CS alone presentation induced a conditioned dopamine release only in the paired groups. No significant difference was found between shell and core. Unlike previous conditioning paradigms involving either a more salient US (foot shock, addictive drug) or a more complex CS, the present paradigm, using normal reward pellets as US and a discrete auditory stimulus as CS, did not lead to differential responses in dopamine efflux in shell and core subregions of the nucleus accumbens.     

Hippocampal correlates of a conditioned sniffing response

Eight white rats were trained on a discriminative classical conditioning paradigm and then on a counter-conditioning paradigm using ESB (electrical stimulation of the brain) as the UCS (unconditioned stimulus) and two incandescent lights as the rewarded (S_D) and non-rewarded (S_Δ) stimulus. Hippocampal EEG correlates of both stimuli in the CS (conditioned stimulus) position were analyzed in Early Conditioning, Late Conditioning, and Early and Late Counter-conditioning.     

Visual and somatosensory evoked potentials characteristics of patients undergoing hemodialysis and kidney transplantation.

The effects of prolonged hemodialysis and kidney transplantation on visual and somatosensory evoked potentials and EEG frequency were assessed. Significant changes were found in both amplitude and latency characteristics of evoked potentials recorded from eight hemodialysis patients. Their evoked potentials tended to be of longer latency and larger amplitude when compared to responses of an age-matched control group. This was true for visual and somatosensory responses recorded from several scalp locations. A correlational analysis revealed no consistent relationship between blood chemistries and evoked potential characteristics. EEG power spectral analysis showed that the dominant frequency of five of the eight dialysis patients was in the 8-10 c/sec range. Two other patients demonstrated EEG frequencies which were scattered across the 3-12 c/sec range while for another subject the dominant frequency was 7-8 c/sec. The evoked potential latencies and amplitudes of patients with successful kidney transplant tended to return to the normal range and their predominant EEG frequency increased to around 10 c/sec. A depression of function in those neural systems underlying the visual and somatosensory modalities, along with a reduction in the cortical suppression of afferent stimulation normally exerted by the thalamic reticular system and the basal ganglia were postulated to account for the reported findings.     

Developmental aspects of fear generalization – A MEG study on neurocognitive correlates in adolescents versus adults

BackgroundFear generalization is pivotal for the survival-promoting avoidance of potential danger, but, if too pronounced, it promotes pathological anxiety. Similar to adult patients with anxiety disorders, healthy children tend to show overgeneralized fear responses.ObjectiveThis study aims to investigate neuro-developmental aspects of fear generalization in adolescence – a critical age for the development of anxiety disorders.MethodsWe compared healthy adolescents (14–17 years) with healthy adults (19–34 years) regarding their fear responses towards tilted Gabor gratings (conditioned stimuli, CS; and slightly differently titled generalization stimuli, GS). In the conditioning phase, CS were paired (CS+) or remained unpaired (CS-) with an aversive stimulus (unconditioned stimuli, US). In the test phase, behavioral, peripheral and neural responses to CS and GS were captured by fear- and UCS expectancy ratings, a perceptual discrimination task, pupil dilation and source estimations of event-related magnetic fields.ResultsClosely resembling adults, adolescents showed robust generalization gradients of fear ratings, pupil dilation, and estimated neural source activity. However, in the UCS expectancy ratings, adolescents revealed shallower generalization gradients indicating overgeneralization. Moreover, adolescents showed stronger visual cortical activity after as compared to before conditioning to all stimuli.ConclusionVarious aspects of fear learning and generalization appear to be mature in healthy adolescents. Yet, cognitive aspects might show a slower course of development.     

Value of visual and somatosensory evoked potentials and the electroencephalogram in chronic respiratory insufficiency

The visual evoked potentials (VEPs), somatosensory evoked potentials (SEPs) and the electroencephalogram (EEG) have been studied in 16 subjects presenting chronic respiratory insufficiency (CRI) with normal consciousness. The SEPs latencies were increased but the VEPs latencies were not. The EEG was little disturbed and did not seem to provide useful information in CRI without encephalopathy.     

Enhancement and diminution of the evoked responses to conditioned stimuli during discrimination conditioning

The purpose of the present paper is to demonstrate the interaction between the acquisition of the conditioned response (CR) and the wave forms in cortical evoked potentials (EPs) for conditioned stimuli (CS). Visual EPs (VEPs) for CS (two geometrical figures) were studied in 14 normal adults. The unconditioned stimuli (UCS) were a corneal air puff or sharp tone.During discrimination eyelid conditioning, the amplitude of EPs decreased for positive CS, whereas they did not decrease for negative ones, during the established stage of the CR. This diminution reflects the establishment of a neural association between the cortical responses to the stimuli.     

Modification of the initiation of locomotion inHermissenda: Behavioral analysis

We have examined the effect of a conditioning procedure on various components of visually guided locomotion inHermissenda. Temporally specific stimulation of the visual system and gravity detecting system (statocysts) with light and rotation produced long-term changes in locomotor behavior. We found that the latency to initiate locomotion in the presence of light was significantly increased for the conditioned group as compared to baseline pre-test latencies and groups that received random presentations of the conditioning stimuli. The variability in the time taken by animals to enter a central illuminated area as reported in earlier studies can be accounted for by the increase in the latency to initiate locomotion. The modifications of visually influenced locomotion exhibits stimulus (CS) specificity since locomotor behavior is not changed following conditioning in the absence of light. In addition, conditioned animals remained in the brightest part of the light gradient significantly less than pre-test measurements. Since this response (initiation of locomotion) can be studied in a semi-intact preparation, it should be possible to investigate how this example of learning generates changes in behavior.     

Patterns of unit activity in the rostral thalamus of cats related to short-latency discrimination between different auditory stimuli.

Short-latency auditory-responsive units were found in the rostral thalamus of cats during performance of conditioned eyeblink responses (CRs) elicited discriminatively by a forward-paired, 70-dB-click conditioned stimulus (CS) as opposed to a backward-paired, 70-dB-hiss discriminative stimulus (DS). Discharges in response to the CS or DS were found in 57% of 138 units tested. Forty-one percent of units responding to the CS did so at latencies of less than 40 msec. After conditioning a discriminative CR to click CS, an increase in the ratio of CS-evoked activity to baseline activity was found relative to that before conditioning. This increase was attributable, in part, to a decrease in baseline activity and, in part, to an increase in the magnitude of response to the CS. These responses preceded early components of the electromyographically measured motor responses with latencies sufficient to contribute to initiation of the movement. After acquisition of the CR, the proportion of CS responsive units also increased. We conclude that this area of the thalamus, a region thought to support thalamocortical reverberatory activity, also functions to transmit short-latency auditory signals. Our evidence further suggests that this region may participate in the elicitation of conditioned responses by specific auditory stimuli and in discrimination between auditory stimuli of different significance.     

Evoked potentials in olivopontocerebellar atrophy

Pattern-reveral visual evoked potentials, far-field and cortical somatosensory evoked potentials, and auditory brainstem potentials were recorded in two patients with olivopontocerebellar atrophy. In one patient, visual evoked potentials exhibited prolonged latency and interocular latency differences in the absence of clinical visual dysfunction. Median and tibial nerve evoked cortical potentials were severely attenuated in the absence of somatosensory deficit or peripheral nerve slowing. The far-field somatosensory potentials, however, were well preserved. All components of the auditory brain-stem potentials had latencies within normal limits. In the other, more severely afflicted, patient, all visual, somatosensory, and auditory evoked potentials were abnormal.     

Subcortical correlates of differential classical conditioning of aversive emotional reactions in social phobia.

BACKGROUND: Conditioning processes have been proposed to play a role in the development of anxiety disorders. As yet, the neurobiologic correlates of emotional learning have not been fully understood in these patients. Accordingly, brain activity was studied in subcortical and cortical regions involved in the processing of negative affect during differential aversive classical conditioning. METHODS: Twelve patients with social phobia and 12 healthy control subjects were presented with paired conditioned (CS; neutral facial expressions) and unconditioned stimuli (US; negative odor vs unmanipulated air). Functional magnetic resonance imaging (fMRI) was utilized to examine regional cerebral activity during habituation, acquisition,a nd extinction trials. Activity was measured with echo-planar-imaging (EPI), and signal intensity in individually defined anatomic regions were analyzed. RESULTS: Subjective ratings of emotional valence to the CS indicated that behavioral conditioning occurred in both groups. The presentation of CS associated with negative odor led to signal decreases in the amygdala and hippocampus of normal subjects, whereas an opposite increased activation in both regions was observed in patients. Regional differences were not found during habituation and extinction. CONCLUSIONS: Results suggest that conditioned aversive stimuli are processed in subcortical regions, with phobic patients differing from control subjects.     

Cortical evoked potential changes during classical conditioning of morphine dependence in rats

A classical conditioning experiment was designed to determine if a conditioned neural response would develop and persist in cortical evoked potentials elicited by a foreleg stimulus (CS+) that was paired with morphine administration during the development of dependence and subsequent withdrawal. A stimulus to the other foreleg (CS-) was presented explicitly unpaired with morphine delivery. After dependence was established, the rats were taken from the experimental chamber and withdrawn from morphine for 6 days in their home cages. Finally, during the testing phase, the animals were returned to the experimental chamber and the foreleg stimuli were presented. The CS+ was paired with either morphine or saline injections. Changes due to both morphine effects only and conditioning were observed. The conditioned response, however, was present only in the cortical evoked potentials recorded from those animals receiving contralateral foreleg stimulation as the CS+. The conditioned neural response persisted after withdrawal and was present in both the drug-free and morphine-intoxicated animals. These results provide support for the relapse theory that a nonextinguished conditioned response is retained after withdrawal. However, further experiments are necessary to determine if these conditioned responses can elicit drug-seeking behavior.     

Fear conditioned potentiation of the acoustic blink reflex in patients with cerebellar lesions

OBJECTIVE: To investigate whether the human cerebellum takes part in fear conditioned potentiation of the acoustic blink reflex. METHODS: A group of 10 cerebellar patients (eight patients with lesions involving the medial cerebellum, two patients with circumscribed lesions of the cerebellar hemispheres) was compared with a group of 16 age and sex matched healthy control subjects. The fear conditioned potentiation paradigm consisted of three phases. During the first, habituation phase subjects received 20 successive acoustic blink stimuli. In the subsequent fear conditioning phase, subjects passed through 20 paired presentations of the unconditioned fear stimulus (US; an electric shock) and the conditioned stimulus (CS; a light). Thereafter, subjects underwent the potentiation phase, which consisted of a pseudorandom order of 12 trials of the acoustic blink stimulus alone, 12 acoustic blink stimuli paired with the conditioned stimulus, and six conditioned stimuli paired with the unconditioned stimulus. The EMG of the acoustic blink reflex was recorded at the orbicularis oculi muscles. The potentiation effect was determined as the difference in normalised peak amplitude of the blink reflex evoked by pairs of CS and acoustic blink stimuli and evoked by the acoustic stimulus alone. RESULTS: In the habituation phase, short term habituation of the acoustic blink reflex was preserved in all cerebellar patients. However, in the potentiation phase, the potentiation effect of the blink reflex was significantly reduced in patients with medial cerebellar lesions compared with the controls (mean (SD) potentiation effect (%), patients: -6.4 (15.3), controls: 21.6 (35.6)), but was within normal limits in the two patients with lateral lesions. CONCLUSIONS: The present findings suggest that the human medial cerebellum is involved in associative learning of non-specific aversive reactions-that is, the fear conditioned potentiation of the acoustic blink reflex.     

Identification of differently timed motor components of conditioned blink responses.

Electromyographic recordings were made from the orbicularis oculi muscles of cats in order to identify differently timed motor components of conditioned eye blink responses (CRs). Conditioning was established rapidly by pairing electrical stimulation of the hypothalamus (HS) with a click conditioned stimulus (CS) and a glabella tap unconditioned stimulus (US). Analysis of the EMG responses disclosed five different motor components of the CR that could be distinguished and characterized according to their latencies of occurrence. Four were associated with an increase in EMG activity elicited by the CS (16-48 ms, alpha(1); 48-80 ms, alpha(2); 80 to 120 ms, beta; >/=120 ms, gamma), and one was associated with a decrease in activity (16 to 60 ms, alpha(i)). Analysis of the amplitudes of the different components of the CR during the course of conditioning and extinction disclosed that short latency, alpha(1) components of the CRs were acquired and extinguished in a manner equivalent to longer latency components of the CRs. The observations supported the hypothesis that short and long latency components of blink responses represented comparable rather than substantially different forms of Pavlovian conditioning. The alpha(2) response was present before conditioning began, and increased with other components after conditioning. The alpha(i) response component was also observed prior to conditioning, and represents a previously undetected, inhibitory consequence of presenting weak (70 dB) acoustic stimuli. It could play a role in conditioned inhibition, latent inhibition and blocking as well as suppression of the conditioned motor response during extinction.     

Differential c-fos expression in the brain of male Japanese quail following exposure to stimuli that predict or do not predict the arrival of a female

We investigated the effects of presenting a sexual conditioned stimulus on the expression of c-fos in male Japanese quail. Eight brain sites were selected for analysis based on previous reports of c-fos expression in these areas correlated with sexual behaviour or learning. Males received either paired or explicitly unpaired presentations of an arbitrary stimulus and visual access to a female. Nine conditioning trials were conducted, one per day, for each subject. On the day following the ninth trial, subjects were exposed to the conditional stimulus (CS) for 5 min. Conditioning was confirmed by analysis of rhythmic cloacal sphincter movements (RCSM), an appetitive sexual behaviour, made in response to the CS presentation. Subjects in the paired condition performed significantly more RCSM than subjects in the unpaired group. Brains were collected 90 min following the stimulus exposure and stained by immunohistochemistry for the FOS protein. Significant group differences in the number of FOS-immunoreactive (FOS-ir) cells were found in two brain regions, the nucleus taeniae of the amygdala (TnA) and the hippocampus (Hp). Subjects in the paired condition had fewer FOS-ir cells in both areas than subjects in the unpaired condition. These data provide additional support to the hypothesis that TnA is implicated in the expression of appetitive sexual behaviours in male quail and corroborate numerous previous reports of the involvement of the hippocampus in conditioning. Further, these data suggest that conditioned and unconditioned sexual stimuli activate different brain regions but have similar behavioural consequences.     

Enhanced long-latency somatosensory potentials in major depressive disorder

Bodily misperceptions are a frequent symptom in major depressive disorder. A reduced ability to deflect attention from somatosensory stimuli may contribute to the generation of unpleasant bodily sensations and co-occur with altered habituation of the brain electric reactions to somatosensory stimuli. The aim of the present study was to explore whether attention-related components of somatosensory evoked potentials (SSEP) and the habituation of these components are altered in major depression. Fifteen patients with major depressive disorder were compared to an age- and gender-matched group of 15 healthy controls. A series of identical, intrusive but not painful electric stimuli were applied to the left index finger for 48 min. Averaged SSEP were computed from multichannel EEG recordings for consecutive recording blocks of the experiment, each block containing 162 stimuli. Based on these data the habituation process of late components of the SSEP was analysed in two latency intervals (50-150, 170-370 ms). Patients showed significantly enhanced reactions throughout the entire experiment. The persistence of enhanced SSEP components throughout the habituation process may be caused by a deficit in reducing the activity of attention-related brain processes concerned with intrusive, yet behaviourally irrelevant, continued stimulation in the state of major depression.     

Developmental and aging changes in somatosensory, auditory and visual evoked potentials

To assess developmental and aging changes in human sensory systems, components of short-latency somatosensory, brain-stem auditory and pattern-reversal visual evoked potentials, thought to originate in specific structures of these systems, were recorded in 286 normal subjects ranging in age from 4 to 95 years. Analysis was primarily restricted to peak and interpeak latencies; visual evoked potential amplitudes were also analyzed. Major results and conclusions are: (1) 'Developmental' changes (that is, decreases in latency attributable to decreased conduction time in younger subjects) were not seen in the median nerve, in brain-stem auditory pathways, or in some portions of visual cortex. Small developmental changes were seen in the somatosensory afferent pathway from the cervical spinal cord to thalamus, and large changes were seen in somatosensory and visual cortex. Cortical developmental changes appeared not to be complete until 17 years of age or later. (2) 'Aging' changes (that is, increases in latency attributable to increased conduction time in older subjects) were observed in the median nerve, cervical spinal cord, brain-stem auditory pathways, and somatosensory and visual cortex. (3) Visual evoked potential amplitudes tended to decrease with age, particularly during development; amplitude and latency effects were dissimilar for most components. (4) Males tended to show larger aging effects than females. (5) The results suggest that age-related changes in human sensory systems are not uniform, but rather are different in specific portions of these systems, different at particular epochs of the life span, and stronger in males than in females.