Development of Classical Conditioning by Pavlov and Its Current Use in Treating Anxiety

¶ … classical conditioning by Pavlov and its current use in treating anxiety

The paper focuses on the development of classical conditioning being used, as suggested by Pavlov, in treating anxiety through using fear-induced techniques. The paper talks about the past experiments that were done on animals and human, those who were suffering from anxiety and those who weren't, and highlights how anxiety is treated through fear induced conditioning.

Combination of neutral stimulus with aversive U.S. (unconditioned stimulus) is what we see involved in fear conditioning. In the first stance, there is no emotional response seen from a neutral stimulus, but after the recurring coupling with unconditioned stimulus, the neutral stimulus turn out to be a CS (conditioned stimulus). CS gives indication about the forth coming unconditioned stimulus and brings to mind the nervousness and expectancy with regard to U.S.. Fear conditioning is commonly an adaptive type of learning. When an uneasy response to the conditioned stimulus takes place in the nonexistence of a CS/U.S. possibility then there are chances that fear conditioning may lead to pathology (Lissek et al., 2005).

For the minimum of eighty years, the formal theories have mixed up fear conditioning in the pathogeneses of disorders relating to nervousness (Pavlov, 1927; Watson & Rayner, 1920). Improved quality of work (e.g., Gorman, Kent, Sullivan, & Coplan, 2000; Grillon & Morgan, 1999; Pine, 1999) is trailed from the prologue of extra composite conditioning models where both the aspects of fear and anxiety are noticeable (e.g., Mineka & Zinbarg, 1996). Introduction is followed with research done on animals which define particular lobe circuits which are occupied by terror (reviewed by Blair, Schafe, Bauer, Rodrigues, & LeDoux, 2001). This is followed by facts which support the assistance of related brain parts to fear learning in human beings (e.g., Bechara et al., 1995; LaBar, Gatenby, Gore, LeDoux, & Phelps, 1998). The fear conditioning disparity identified within the anxiety patients is liable to promote the future endeavors which are subject to the explication of neurobiological loci of clinical anxiety.

The declaration of classical conditioning model of anxiety disorders is that the pathological anxiety (neurosis) is developed by simple classical conditioning (Pavlov, 1927; Watson & Rayner, 1920). After the submission of this theory other writers gave an extension to it by stating that classically conditioned model also acts as an instrument which stimulates prevention (Eysenck, 1976, 1979; Eysenck & Rachman, 1965; Miller, 1948; Mowrer, 1947, 1960). The other versions of this theory stress on the birth and the intensification of terror (Eysenck, 1979), the aversive associations prepared on evolutionary basis (e.g., o hman, 1986; Seligman, 1971), failure to slow down the response to safety signs (Davis, Falls & Gewirtz, 2000), related learning shortfall (Grillon, 2002), stimulus generalization (Mineka & Zinbarg, 1996; Watson & Rayner, 1920), and improved condition ability in the arrangement and perseverance of anxiety disorder (Orr et al., 2000; Peri, Ben Shakhar, Orr, & Shalev, 2000),.

Classical Fear Conditioning

Ivan Pavlov (1927) has the honor of demonstrating the original classical conditioning model most eminently. The model starts with the description of certain stimuli which are considered to be unconditional ones, and tend to bring a consistently yielded UR (unconditional response). The model goes beyond to explain that trough training a neutral stimulus could also give the same response when coupled with U.S.. So, under such a situation the neutral stimulus is regarded as the conditioned one and the response generated is the CR (conditioned response). Pavlov performed an experiment on a dog where the food worked as a U.S. And the salivated mouth of the dog was a UR (Pavlov, 1927).

The next time Pavlov offered the food he also rang the bell (neutral stimulus); he repeated this action many times. Finally, he just rang the bell (CS) without presenting the food; just the mere sound of bell produces saliva in the dog's mouth (conditioned response) (Pavlov, 1927).

When the pairing of neutral stimulus is done with aversive one, it is known as Pavlovian fear conditioning. This can be explained with help of an example related to a little eleven-month-old boy, Albert. Once Albert was provided with a rat to play (CS), the boy showed no response of terror. Second time Albert was given the same rat to play but concurrently with a loud sound (U.S.), Albert started to cry (CR). The second step was repeated a number of times and then finally, in the end Albert started crying (CR) just on the mere glance at the rat, with no presence of any sound (CS). Very small stimuli like rat could bring in such a fearing response on part of a boy. Where on one side reaction to fear can serve as a precious task in protection from possible hazard, but on the other hand it may also act to be maladaptive. Under a maladaptive condition, a contextual stimulus can become linked with recurrent terror and nervousness (i.e. generalization). Under typical models on fear conditioning, a meek electric shock brings out a freezing reaction or a rise in the blood pressure or causes the heart beat to rise (CR) (Pavlov, 1927).

Neuroanatomy of Anxiety

Amygdala is that part of the brain which is liable for getting hold of the fear conditioning (Pare et al., 2004). Amygdala is present in the medial temporal lobe of the brain. Three of the nuclei out of a total of 13 present in amygdala are; basal amygdala (BA), lateral amygdala (LA) and central nuclei. These three nuclei are implicated in the way of fear response (Rosen, 2004). LA receives stimulus from the sensory thalamus which is then transferred to the central nuclei (CA) (short loop pathway). A linkage between LA and central nucleus is made by BA. LA receives signals from the sensory cortex, insula and prefrontal cortex; this is what undergoes in the long loop path (LeDoux, 2000; Sotres-Bayon et al., 2006). From LA information is transferred to the effectors side of the brain and the hypothalamus. Hypothalamus creates involuntary signs of fear responses (Cahill et al., 1998). LA is found to be the part of brain which is accountable for remembrance consolidation and flexibility within fear conditioning (Shumyatsky et al., 2002). A severe memory loss could occur if LA or CA is damaged due to some injury (Wallace et al., 2001; Blair et al., 2005; Goosens and Maren, 2001). Evidences have proved that the damage of BA can adversely affect reactions to fear (Anglada-Figueroa and Quirk, 2005). The molecular mechanism through which fear acquisition takes place within LA is termed as enduring potentiation (LTP) (Chapman et al., 1990). When calcium takes entry into the cell through N- methyl-D-aspartate (NMDA) receptors and voltage-gated calcium channels (VGCCs) (Bauer et al., 2002) then the consolidation of memory takes place. The blockage or damage of VGCCs will have no affect on the long-term memory but will greatly disturb the short-term memory. This clearly signifies that the presence of NMDA receptors is essential for the pathway to be affective (Rodrigues et al., 2001; Walker and Davis, 2000; Cain et al., 2002). The research work which was carried out on animals revealed that when the antagonist blocked the NMDA receptor, L-2-amino-5-phosphonovaleric acid (APV, AP5), acquisition of fear stopped but no harm was caused to expressions (Roesler et al., 2000; Fendt, 2001; Miserendino et al., 1990). But if the latest studies are considered then we get to know that both the processes are stopped (Jasnow et al., 2004; Maren et al., 1996; Lee et al., 2001). The studies of genetic materials have exposed that there is high appearance of NMDA receptors within the hippocampus too. This, thus signifies the worth of this brain structure under Pavlovian conditioning (Mei et al., 2005). Whereas, if inside amygdala, blockage with these receptors takes place, then the result would be the disturbed responses of fear conditioning (Zhao et al., 2005; Melik et al., 2006).

The use of preclinical findings is currently restricted on human beings. But the usage of NMDA receptors and calcium channel blockers is taking place in order to solve damaged memory issues and also for the cure of anxiety indicators. Nowadays, the usage of non-competitive NMDA receptors is becoming very common. These receptors are widely used as agents who carry out the memory enhancement task within the patients who are suffering from Alzheimers disease, which is ranging from a reasonable to a severe level. The receptors accomplish this task by bringing improvement in the neuronal flexibility and also by decreasing excitotoxity within the hippocampus (Parsons et al., 1999). Within few of the animal studies the existence of anxiolytic properties is seen (Bertoglio et al., 2003; 2004), however not in all (Karcz-Kubicha et al., 1997; Harvey et al., 2005). This has not been considered as a primary anxiolytic mediator in humans. Zarate as well as colleagues (Zarate et al., 2006) who initiated a double-blind, placebo-controlled test were not proved to be successful in the treatment of major depressive orders. This thus gave unusual paths for the tone of the mood. For the treatment of seizures as well as bipolar disorders, Lamotrigine is used. It is basically a glutmate antagonist, which acts by creating obstruction of voltage-dependent sodium and calcium channels. Conditioned emotional response (CER) model was used in rates by Mirza and some others. Under this model, houselights (CR) were used with electric foot shocks. This was done to check whether this CS would result in compact lever pressing for getting the food. Through research it was confirmed that Na+ agonist caused blockage of the anxiolytic possessions of lamotrigine while Ca+ channels failed to do so. Therefore, a conclusion was reached that axxiolytic traits can be removed by the usage of Na+ channels (Mirza et al., 2005). When lamotrigine was used with PTSD by Hertzberg and colleagues, under the petite double blind test of patients, it was found to be more effective than placebo. It removed the symptoms of PTSD up to a greater extent, such that the chances of re-occurrence were also reduced (Hertzberg et al., 1999). One more treatment for the anxiety disorders is offered by VGCC inhibitors (see table 1). Pregabalin is considered to be the therapeutic mediator for the generalized anxiety disorders (GAN) (Rickels et al., 2005). Pregabalin is actually anticonvulsant that joins to the alpha-2-delta protein order to obstruct VGCC. It may also achieve appreciation by the ending of 2007.

Theoretical and empirical support

The theories of the past have explicit prophecy regarding the bond between fear conditioning and clinical anxiety. Whenever there is a failure in the fear conditioned response (CR), a pathological anxiety takes place; this has been said by Eysenck (1979). There is an argument given by Eysenck which states that CR, which is regarded as an inner state of terror, is uncomfortable and may act as an aversive U.S. substitute. Therefore, the strengthening of CS should carry on during EXT. The theories presented by Eysenck apply only to the Pavlovian B type conditionin. Under B type, the conditioned response mainly produces the unconditioned response to the U.S. A complete description of type A and B. is given in Grant (1964).

The formulation presented by Eysenck (1979) state that all of the anxiety patients will get stronger learning of terror rather than controls, thus resulting in further strengthening of CS in the nonexistence of U.S. (i.e., stronger CRs during EXT). This thus leads to declining rates of EXT within the individuals who were bearing anxiety disorders. This theory comes up with two suggestions; one, that all of the patients suffering from anxiety disorders would be displaying better conditioned fear responses during achievement (AQC), and two, there will be more confrontation shown to EXT when the competition between anxiety patients and controls is there (e.g., Annau & Kamin, 1961; Hilgard & Marquis, 1940).

According to Davis et al. (2000), when there are no safety signals, fear response may not be exhibited, which ultimately leads to pathological anxiety. Various experiements related to fear conditioning have agreed to this idea. This idea is also mentioned in a study regarding FPS (fear potention startle) when anxiety patients were exposed to CS (Conditioned Stimulus provides safety signal when unpaired with U.S. In aversive learning models) (Grillon & Morgan, 1999). However, it was under unhealthy controls. Contrary to this, in case of low anxious participants receiving safety signals, FPS decreased (Grillon & Ameli, 2001). In addition to this, larger electrodermal responses to CS was larger electrodermal responses to CS were found among anxiety patients vs. control in 2 studies (Orr et al., 2000; Peri et al., 2000). Similarly, 2 reports identified that subjective anticipatory anxiety was increased when exposed to CS presentations among anxiety patients vs. controls (Clum, 1969; Hermann, Ziegler, Birbaumer, & Flor, 2002). Like other theories, Davis's theory is not applicable in this study as it fails to do any comparison of the impact fear inhibition has on patients and controls. However, as mentioned below, the levels of discrimination fear conditioning affecting anxiety patients in the presence or absence of healthy controls will be discussed.

In simple conditioning, a CS is paired with U.S. frequently. Under subject conditioning, the effects are indexed when ITI (inter-trial-interval) levels of arousal or baseline is subtracted from CS arousal levels. There are 2 CS aspects that are mostly found in discrimination paradigms. CS is not paired with U.S., but CS+ is. Difference between CRs to CS and CS+ is indexed to be discrimination learning. In case patients do not show fear even when safety cues are provided, they should have fear response to CS and CS+. This would mean low levels of discrimination, though they depict conditioning to CS+. On the other hand, discrimination learning may increase in the presence of healthy controls, as they hold back the fear response generated under CS presentations. It must be kept in mind that patient's responses to CS and CS+ can be regarded as stimulus generalization. However, predictions concerning discriminative learning that have been mentioned above are supported by either conceptualization (i.e. not showing any fear; and stimulus generalization) (Lissek et al., 2005).

Orr and colleagues opposed prediction for discrimination effects across patients and controls by stating that healthy patients may be less conditional than to the individuals going through pathological anxiety (Orr et al., 2000; Peri et al., 2000). Condition ability over here means the degree to which responses for CS is less than that to CS+ during EXT and/or AQC. This model has been empirically tested for predicting higher discrimination conditioning among patients experiencing anxiety at EXT and AQC, which was not evident in the predictions of Davis's model (Orr et al., 2000; Pitman & Orr, 1986). The current research would analyze predictions of both, Orr and Davis.

As inhibitory effects have no influence over simple conditioning (only measurement of excitatory conditioning to CS is undertaken); and higher AQC, followed by greater resistance to EXT of excitatory fear associations in patients is identified by the models of Orr and Eysenck, simple fear conditioning is much stronger tool of prediction across patients vs. controls in both EXT and AQC. Inhibitory mechanisms in the pathogenesis of anxiety disorders have been discussed in theory of Davis and colleagues. In addition to this, their formulation did not reveal any information about the predictions of excitatory learning, such as simple conditioning (Lissek et al., 2005).

Phobic anxiety and preparedness

Human beings have the blessed capability to avoid the situations which can cause danger to life. For example, approximation to spiders, snakes and staying in closed spaces. This study was first presented by Seligman (1971) though at later stages many scholars supported it through empirical evidence (see Mineka & o hman, 2002 for instance). Gradually the concept emerged as the focal point of phobic anxiety related studies. This paper does not discuss the element of preparedness of human being to avoid the dangerous stimuli. The reason is limited availability of literature upon the subject.

Consolidation and Reconsolidation

Memories are stored in the mind though their relative association with each other. Every memory forms an associated complex with other memories to restore in the mind. Short-term memory is also known as labile. It can be converted to long-term memory with the help of protein synthesis. This process is called consolidation. Usually, this process is supposed to take place once only. But, when the transient information is retrieved, protein synthesis is to be done again. When information is retrieved from the memory, the trace of memory becomes unstable. In order to restore the information in the memory, reconsolidation is a mandatory process. Debiec and colleagues (2006) recently applied the concept of second-order fear conditioning (SOFC) paradigm to see if the protein synthesis is blocked, does it disrupt the whole network of memories or the single one. As per paradigm, CS linked with each other to create U.S.. The memories which were directly reactivated were short-term but there occurred no affect on the complex network of memories. This experiment led to the conclusion that unpleasant memories which revive themselves with fear stimulus can be erased from the memory even without lapse of short-term memory (as cited in Garakani, 2006).

If a stimuli is linked with emotions, it is quite possible that it will recall the past experience and the person will forget the words he was about to speak before that memory. It does not happen in case of normal stimuli. The repeated retrieval of memory makes it long-term. If U.S. are not present, fear related memories cause anxiety and the unpleasant memories become permanent (as cited in Garakani, 2006).

The involvement of beta-adrenergic receptors and NMDA receptors cause reconsolidation to occur. Cyclic adenosine monophosphate response element binding protein (CREB) also plays its role. Propranolol is a major receptor antagonist which is beta-adrenergic in nature. It blocks recognition of unpleasant memories and hinders retrieval of emotional stimuli. However, it preserves the neutral words. The emotional memories create loss of short-term memory which can be restored through drugs. Propranolol plays its role in blocking conversion of short-term memory into long-term memory. It is important to note here that Propranolol tampers with old memories only. It does not affect the new memory and its consolidation process (as cited in Garakani, 2006).

Medical science is trying to take the advantage of these findings for treatment of trauma patients who are unfit because of unpleasant memories. The efficacy of beta blocker is still to be measured. Propranolol was experimented in a controlled way on the patients of acute trauma by Pitman and colleagues. The patients were given the medicine or placebo in the period of trauma exposure and this practice was repeated for ten days. The outcome was not significant in statistical terms. After three months, both types of patients receiving propranolol or placebo were diagnosed for PTSD. As per Clinician-Administered PTSD Scale (CAPS), the symptoms of PTSD were not found to be highly severe. This is the single instance of measuring efficiency of beta blocker. The next research study followed better design with larger size of sample (as cited in Garakani, 2006).

Extinction

The theory of classical conditioning is based on the Pavlovs experiment made on dog which used to salivate upon hearing the bell ringing (CS). It was like an indication of food time for it. Once, the bell rung but no food provided (i.e. The incidence of U.S. was obvious) (Pavlov, 1927). This revise action is called extinction. It does not tamper with the old memory but creates altogether a new memory. mPFC helps in regulating the extinction of old, long-term memories. Through reaction of dendrites, the ability of mPFCs which helps is modulating extinction can be used in chronic stress. Hippocampus, medial prefrontal cortex (mPFC) and the amygdale are used for fear extinction. The modulation of the hippocampus reduces dismissal of amygdala neurons while LA reduces dismissal through continued presentation of the CS (Sotres-Bayon et al., 2006). Extinction can be blocked by any loss of mPFC and tampering with protein synthesis taking place in the mPFC. The experiment was done by Miracle and colleagues on the rats, which were exposed to controlled stress. The result showed slow down of extinction process in 24 hours after initial extinction (as cited in Garakani, 2006).