Friday, September 19, 2008

Modifying shyness-related behavior through symptom misattribution

Brodt, S.E. & Zimbardo, P.G. (1981). Modifying shyness-related behavior through symptom misattribution. Journal of Personality and Social Psychology, 41, 437-449.

In response to anxiety-evoking stimuli, people develop a complex constellation of reactions. Over time, a general categorical label may come to link these components together and serve as a central explanation. For some people, this label may undergo further transformation from its original situational attribution to a broader usage that includes the person's disposition (personal causality). For example, a person may immediately invoke the label "I am afraid of men" which in turn may kick off a response chain and impose constraints upon it, creating self-fulfilling prophecies. The authors of this study wanted to weaken the 3-part link between perceived symptoms of arousal, the corresponding dispositional label, and resultant behaviors by intervening with symptom misattribution.

In this experiment with 46 college women, the dispositional label studied was shyness -- an excessive self-focus in which potential rejection by other people and social anxiety are salient cognitions. Seeking to redirect the arousal from an anxiety-laden source (being alone with a member of the opposite sex) to a nonpsychological source, the researchers exposed all the groups to intense noise and led the "shy misattribution" group to believe that common side effects of noise bombardment was heart-pounding and increased pulse, symptoms normally associated with their social anxiety. Another group, the "shy comparison" group were led to believe the noise only caused dry mouth. Another "non-shy" group, unlike the other groups did not score high on shyness ratings, were given the same story as the "shy misattribution group". Results showed that shy women, when given an alternative explanation for their social anxiety, were able to overcome normal limitations of their shyness, talking significantly more, acting more assertive, and showing a stronger affiliative preference than the comparison group. Thus, misattribution demonstrates the power of social cognitions in controlling behavior.

Monday, September 15, 2008

Hippocampal involvement in contextual modulaton of fear extinction

Ji, J. & Maren, S. (2007). Hippocampal involvement in contextual modulaton of fear extinction. Hippocampus, 17, 749-758.

Responding to an extinguished CS is susceptible to many recovery effects. The first is renewal, in which changing the context favors recall of extinguished fear memory. Examination of its several forms (ABA, AAB, ABC) led researchers to postulate that following extinction the meaning of the CS becomes ambiguous and requires context to disambiguate; inhibitory association is "gated" so that its activation requires the simultaneous presence of the CS and the extinction context. The second is spontaneous recovery, or the return of conditional responding with the passage of time. Studies suggest that renewal and spontaneous recovery appear to result from a similar control mechanism, rather than simply erasure of the original fear memory. Therefore, some see SR as another renewal effect that occurs outside of the "temporal extinction context". Third is reinstatement, in which the extinguished response returns after extinction if the animal is merely exposed to the US alone in a distinct context. This, likewise, appears to be a context-dependent process.

These all suggest that extinction involves new learning, and that this learning is especially sensitive to context. The hippocampus, mPFC, and amygdala have been implicated in this learning. One model holds that when the animal is tested within the extinction context, hippocampus drives mPFC inhibition of LA. When animals are presented with an extinguished CS outside of the extinction context, the hippocampus may inhibit mPFC activation and thus promote excitation in the LA to renew extinguished fear under these conditions. Another model posits direct projection from hippocampus to LA subserving contextual modulation of extinction.

Tuesday, September 9, 2008

Switching on and off fear by distinct neuronal circuits

Herry, C. et al. (2008). Switching on and off fear by distinct neuronal circuits. Nature, 454, 600-605.

Whereas firing of amygdala neurons is necessary for retrieval of conditioned fear memories, extinction of these fear memories is thought to be controlled by constraining this neural activity by local inhibitory circuitry (under the influence of mPFC). However, fear extinction is known to be a fragile behavioral state, readily influenced by context, i.e. changing context can result in spontaneous recovery. This raises the question of whether there are specialized circuits driving behavioral transitions in opposite directions, namely fear-on and fear-off. This paper showed that neurons in the BA could be divided into distinct functional classes: those exhibiting selective increases in CS+ evoked spike firing during and after fear conditioning (fear neurons) and those exhibiting selective increases in CS+ evoked spike firing during extinction (extinction neurons). Further, close analysis revealed that these two groups were not only functionally different but also differentially connected, with (1) fear neurons selectively receiving input from the hippocampus, and (2) extinction neurons being reciprocally connected to the mPFC while fear neurons only projected unidirectionally to the mPFC. This would indicate that co-localized within the same nucleus, two discrete neuronal circuits exist, intermingled in a salt-and-pepper-like manner. Their close anatomical proximity may serve to facilitate local interactions, although these mechanisms remain unexplored. Taken together with evidence showing emotional perseveration (persistent lack of state change) concomitant with inactivation of the BA, results suggest that the BA is unlikely to be associated with the storage, retrieval, or expression of conditioned fear and extinction memories, but is more likely to mediate context-dependent behavioral transitions between low and high fear states.

Monday, September 8, 2008

mPFC neurons signal memory for fear extinction

Milad, M.R. & Quirk, G.J. (7 November 2002). Neurons in the medial prefrontal cortex signal memory for fear extinction. Nature, 420, 70-74.

Extinction is a process thought to form a new memory that inhibits the once-learned conditioned response. This paper suggests that consolidation of extinction learning potentiates activity in the infralimbic cortex (IL) of the mPFC which inhibits fear during subsequent encounters with fear stimuli. Electrophysiological recording showed that IL activity remained unresponsive during the conditioning phase and also during extinction training on Day 1. However, by Day 2, activity in the IL in response to tone was present from the start of the extinction phase. Further, stimulation of the IL paired with tone presentation resulted in less freezing behavior and also accelerated extinction learning. Therefore, enhanced extinction learning could be mediated directly by the stimulation or indirectly by the behavioral feedback of decrease freezing. Since the BLA sends excitatory projections to IL, it is possible that these inputs serve to potentiate IL neurons during the consolidation of extinction. The IL is then likely to inhibit expression of fear behavior via its projections to intercalated (ITC) cells in the CE, dampening the output of the amygdala. Pairing reminder stimuli with activation of the ventral mPFC through transcranial magnetic stimulation (TMS) might help strengthen extinction of fear in clinical settings.

Neural mechanisms of extinction

Quirk, G.J. & Mueller, D. (2007). Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology Reviews, 1-17.

The simplest form of emotional regulation is extinction, is which conditioned responding to a stimulus decreases when the reinforcer is omitted. Exinction, like any learning process, occurs in 3 phases: acquisition, consolidation, and retrieval. Cannabinoid and opioid receptors appear to be implicated in the acquisition of extinction since anandamide and opioid antagonists impair within-session extinction of fear. Consolidation appears to depend on protein synthesis within the BLA, frequency bursting of the infralimbic region (IL) of the vmPFC shortly after extinction, and general involvement of the hippocampus, especially in tasks such as inhibitory avoidance and contextual fear. Retrieval of extinction memories involves the expression of inhibitory circuitry and is highly context-specific. Inhibition circuitry within the amygdala includes local inhibitory neurons within the BLA and CE, as well as islands of GABAergic neurons between these two sites known as the intercalated (ITC) cells. ITC cells could serve as a site of extinction memory since they inhibit CE output neurons and BLA neurons, acting as an off-switch for the amygdala. ITC cells receive strong projection from the IL mPFC, and IL activity is correlated with the extent of extinction retrieval. In fact, electrical stimulation of IL reduces conditioned fear and strengthens extinction memory. The prelimbic (PL) mPFC, on the other hand, excites fear expression and can augment fear expression via projections to the basal nucleus of the amygdala. Thus, the PFC can fully control overall fear expression. Individuals with PTSD show reduced vmPFC and hippocampal volume and activity, as well as increased amygdala activity. Stress may also impair extinction, since chronic stress is shown to decrease dendritic branching and spine count in hippocampus and mPFC, but increase it in BLA, which could be expected to increase conditioning and impair extinction. Pharmacological adjuncts to current extinction-based exposure therapies may accelerate and strengthen extinction. Among them D-cycloserine, yohimbine, sulpiride, and methylene blue show promise. Administration of glucocorticoids such as cortisol before exposure therapy may also help.

Sunday, September 7, 2008

Dopamine gates LTP in lateral amygdala

Bissiere, S., Humeau, Y., & Luthi, A. (June 2003). Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. Nature Neuroscience, 6, 6, 587-591.

It has been known that both long-term potentiation (LTP) and concomitant activation of dopaminergic nerves to the amygdala underlie the acquisition of fear conditioning. In fact, dopamine is known to be released in the amygdala during stress and intra-amygdala injection of dopamine receptor antagonists prevents fear conditioning. This study investigated the mechanisms supporting this and showed how dopamine could modulate fear conditioning by modulating inhibitory synaptic transmission within the amygdala. Specifically, D2 dopamine receptors could enable the induction of LTP by suppressing feedforward inhibition from local inhibitory interneurons.

Friday, September 5, 2008

Neuronal Signalling of Fear Memory

Maren, S. & Quirk, G.J. (November 2004). Neuronal Signalling of Fear Memory. Nature Reviews Neuroscience, 5, 844-850.

Plasticity within the CNS is necessary for the representation of new information, and can range from synthesis and insertion of synaptic proteins to whole-brain synchronization of neuronal activity. Pavlovian fear conditioning is an especially interesting phenomenon since such fear memories are acquired rapidly and are long-lasting. Research first noticed conditioning-induced changes in the midbrain, thalamus, and cortex; however, it was unclear whether or not these were primary sites of plasticity or were simply downstream from other plastic sites. Eventually the lateral nucleus of the amygdala (LA), receiving direct projections from the auditory thalamus, was posited to be vital for auditory fear conditioning. The dorsal subdivision of the nucleus (LAd) seems to be the first site in the auditory pathway to show associative plasticity that is not fed forward passively from upstream sites, is not dependent on downstream sites, and is crucial for conditioned behavior. And LA neurons appear to drive plasticity at both thalamic and cortical levels.

Fear memories are useful to anticipate and respond to dangers within the environment. However, when signals for aversive events no longer predict those events, fear to those signals subsides. This is an inhibitory learning process known as extinction. It appears that although fear subsides after extinction, the fear memory is not erased. Extinction seems to be highly context dependent and sometimes short-lived. Fear responses can be spontaneously recovered over time. It seems biology has deemed it better to fear than not to fear. It is more likely that additional memories which interfere with pre-existing excitatory responses are learned in the extinction process. Again the amygdala seems to be essentially involved here. Further, the mPFC, which has an inhibitory influence on both the LA and the CE (the main output regions of the amygdala) through a rich network of inhibitory interneurons embedded in the amygdala, appears to be a major participant, and is perhaps modulated by context via hippocampus.

Emotion Circuits in the Brain

LeDoux, J.E. (2000). Emotion Circuits in the Brain. Annual Reviews in Neuroscience, 23, 155-184.

Emotion research was largely lost for some time in the wake of the cognitive revolution. However, people soon realized a purely cognitive view of the brain -- leaving out emotions, motivations, and the like -- is likely to paint an unrealistic view of real minds. Unfortunately, attempts to dig into emotions once again were hamstrung by the limbic system concept, a flawed and inadequate theory of the emotional brain: cognition does not only reside in the neocortex and emotions do not only reside within the limbic system (a moving target itself).

Emotion research began its official resurgence with a bottoms-up examination of fear conditioning, with a bulk of the work focused on the auditory modality. Research soon named amygdala as centrally important, a site where transmission of information about the CS and US converged and output projections controlled fear reactions. On the input side, CS sensory inputs terminate in the lateral amygdala (LA), coming from both the auditory thalamus and the auditory cortex, although plasticity seems to occur initially through the thalamic pathway. US information also seems to converge in the amygdala, receiving inputs from the spino-thalamic tract, cortical areas that process somatosensory stimuli including nociceptive stimuli, the parabrachial area, and the spinal cord. On the outbound side, the central nucleus of the amygdala (CE) projects to autonomic (hypothalamus) and defensive motoric (periaqueductal gray) centers. Methodologies used have largely been single unit recordings, long-term potentiation (LTP) studies, and pharmacological experiments which block LTP. Studies have focused on two types of fear learning: simple fear conditioning (a benign tone comes to evoke a fear response) and contextual fear conditioning (fear responsivity to environmental cues). Research agrees that the amygdala seems to be required for Pavlovian fear conditioning to occur, although the site of long-term fear memory storage is still unknown: it may very well exist in the amygdala, but it may also be distributed across multiple structures or transferred off to cortical areas over time. However, plasticity within the amygdala is probably not required for learning cognitive aspects of fear.

Human studies have echoed many of the results from animal literature. Additionally, they have found perceptual deficits of the emotional meaning of faces in patients with amygdalar damage. The amygdala also appears activated more strongly in the presence of fearful and angry faces than of happy ones. Further, when the activity of the amygdala during fear conditioning is cross-correlated with other regions of the brain, the strongest relations are seen in subcortical areas, emphasizing the importance of the direct thalamo-amygdala pathway in the human brain. Although a fear conditioning approach cannot account for all aspects of human fear and anxiety disorders, it may be especially elucidating for PTSD, panic disorders, and phobias. Difficulty in extinguishing fear memories witnessed in human disorders may also involve the medial prefrontal cortex circuitry.

Future research needs to integrate both cognition and emotion. How fear processing in the amygdala can influence perceptual, attentional, and memory functions of the cortex, and vice versa, is begging for additional research, although it is known that the amygdala does receive input from cortical sensory processing regions and projects back to these both directly and indirectly. How conscious emotional feelings are manifest is also relatively unexplored, although the models posit that feelings may arise from interactions between the amygdala and prefrontal working memory areas, sensory processing areas in cortex, long-term memory systems in the temportal lobe, and arousal systems which maintain global projections.