Conference 2002

Workshop I
Workshop II
Workshop III
Workshop IV
Final Group Discussion and Summary
Schedule

Photos of the June 2002 Meeting

Workshop II: What is the Contribution of the Nucleus Accumbens in Processing Emotion?
Chair: A. Hariri; Scribe; J. Salamone

The workshop agreed to focus on one particular question: What are the cellular and synaptic events/interactions that contribute to the role of this structure in the elaboration of "emotion"?

One of the key issues discussed was the convergence of inputs onto nucleus accumbens neurons from various regions, including prefrontal cortex, amygdala and subiculum. Researchers speculated about the relative impact of each of these inputs, and if one of them provided the primary synaptic drive for accumbens neurons. It was suggested that the roles of these different inputs could be distinct in different subregions of the accumbens. In addition, it was suggested that behaviorally-relevant conditions, such as level of deprivation, could influence the responsiveness of accumbens neurons to glutamatergic inputs.

It was emphasized that dopaminergic inputs to the accumbens are activated by stressful or aversive conditions. The discussion turned to recent human imaging data demonstrating that areas of the so-called "reward" system, including accumbens, also are activated by painful stimuli. Several of the discussants argued that this appellation is really a misnomer, and the accumbens should not simply be referred to as a "reward" area in view of its involvement in various aspects of motivation, including responsiveness to aversive stimuli. Yet despite the fact that neurochemical indices with dialysis and voltammetric methods demonstrate that dopamine activity is increased in at least some areas of accumbens during stressful stimuli, there is a relative lack of information about the responsiveness of accumbens neurons to aversive stimuli.

An important topic for discussion was the specific behavioral conditions that affect the activity of accumbens neurons. It was recognized that this is an exceedingly complex area of research, but findings are beginning to emerge. Evidence indicates that different neurons respond to distinct conditions, and different stimuli, within the overall context of operant performance. Even within the same task, neurons can show distinct patterns of activity, and data were discussed showing that cross correlation patterns for accumbens neurons could change as a function of the particular stage in a Progressive Ratio schedule at which the animal was responding. Additional data were presented in detail in order to illustrate some of the patterns of responsiveness that could be shown by accumbens neurons in relation to particular aspects of instrumental response procedures. It was reported that accumbens neurons in rats respond to different features of the environment, with some responding to Conditioned Stimuli, some responding during performance of the instrumental response, and some responding to the reinforcer (typically showing a decrease in activity with reinforcer presentation). Inactivation of the Ventral Tegmental Area, which presumably reduced activity of dopaminergic inputs into the accumbens, mainly tended to reduce the activity of the neurons that respond to Conditioned cues. These observations (provided by S. Nicola) were viewed as consistent with some of the results previously reported by W. Schultz. Again, it was emphasized that dopaminergic inputs do not seem particularly important for modulating the cellular responses to natural primary rewards in animals that have prior experience with the behavioral procedure. Various discussants then noted that various findings in the literature support the notion that accumbens neuron activity is important for responding to cues, while other researchers emphasized that accumbens neurons are important for responding to uncertainty and unpredictability.

Various discussion points were raised in terms of the possible involvement of accumbens neurons in mediating behavioral responses in relation to time. For example, it was suggested that the accumbens may be particularly important for helping animals to bridge time gaps, and to facilitate responding for delayed or intermediate reinforcement. Nevertheless, it also was pointed out that accumbens dopamine depletions do not make animals particularly sensitive to interval operant schedules (which have substantial time delays), and that, in fact, ratio schedules were much more sensitive to dopamine depletions. Overall, it was recognized that manipulations of the accumbens affect different instrumental tasks in substantially different ways, but the specific characteristics that make some tasks sensitive to interference with the accumbens remain uncertain. The presence of time delays, as well as work requirements, may be important. Nucleus accumbens may be involved in aspects of behavioral activation that are related to appetitive and aversive tasks. The old notion of nucleus accumbens as an interface between emotional processing and behavioral control was reviewed. In addition, it was recognized that the relation between studies that focus on lesions, drugs and dopamine depletions and those studies that involve recording of individual accumbens neurons need to be further explored.

Finally, it was emphasized that the patterns of activity of accumbens neurons must be seen in the context of the activity of the neurons that project to the accumbens from structures such as the amygdala or the subiculum.

Workshop II: What is the Contribution of the Prefrontal Cortex in Processing Emotion?
Chair: C. Napier; Scribe: S. Sesack; Spokesperson; P. Courceyro

The session began with Anne-Marie Thierry and Suzanne Haber reviewing the main anatomical circuits to which the PFC contributes. Anne-Marie focused on basal ganglia circuitry that would be similar between rodents and primates. Suzanne focused on species differences that result from the larger PFC territory in primates. She also emphasized the important contributions of the thalamus to this circuitry, which is often overlooked. Ruediger Veh asked Suzanne to elaborate on the thalamic projections, which involve midline and intralaminar nuclei with heavy projections to the cortex and basal ganglia that extend beyond the specific thalamic groups. Susan Sesack pointed out that when considering the role of the PFC in emotions, it was important to include the projections of this region that go beyond the basal ganglia, most notably projections to the amygdala, hypothalamus and monoamine cell groups in the brainstem. Anne-Marie Thierry agreed and noted that the projections of the basal ganglia itself are not directed solely to thalamus and cortex but include projections to the brainstem mesencephalic extrapyramidal area that may drive certain behaviors.

Nicola Mercuri asked what were the neuronal correlates of emotion, to which Ron Dahl added that one would have to first define which aspects of emotion to consider. He then asked as an example how (in terms of circuitry) the PFC might regulate the amygdala and fear emotions especially. Does it stimulate them or inhibit them? Susan Sesack replied that, based on preliminary circuit analyses, a case could be made for both. The PFC synapses both onto excitatory pyramidal neurons in the basolateral amygdala and onto inhibitory neurons in the intercalated cell masses. However, physiological studies such as those of Tony Grace suggest that the main influence of the PFC on the amygdala is inhibitory. Susan Sesack then noted that the anatomical and physiological levels of analysis needed to be better coordinated.

Bita Moghaddam described some of her latest data that shed some light on this subject. She stimulated the amygdala of rats whose prefrontal function was either intact or shut off with AMPA antagonists or lidocaine. The amygdala stimulation produced mild freezing behavior that was more intense if the PFC was off-line. However, more important differences in the animals’ behavior occurred after the stimulation was ended. In this case, rats with an intact PFC switched from anxious freezing to behaviors that could be considered coping or adaptive, such as rearing, sniffing, grooming, etc. Rats with inactivation of the PFC did not switch to adaptive behaviors post-stimulus; instead they remained in postures of anxious freezing. This study emphasizes the importance of the PFC for task-switching, an impression that is supported by additional studies by Moghaddam in a rodent version of the Wisconsin Card Sorting task. In this task, animals with inactivation of the PFC from NMDA receptor blockade exhibit perseveration. Ahmad Hariri mentioned that this phenomenon sounded similar to LeDoux's demonstration that PFC lesions impair extinction on tasks known to involve the amygdala.

Ron Dahl noted that the reported persistence of anxious behavior after amygdala stimulation has important clinical relevance to anxiety disorders, especially in children. Anxious children often have a hard time breaking off from fear provoking stimuli.

Nicola Mercuri pointed out that loss of breaking function (response inhibition?) also accompanied lesions of the PFC and that this problem was associated with changes in personality, depression and depersonalization.

The question was then raised as to what imaging studies might add to the discussion. Affective stimuli do not only activate PFC regions but also the insular cortex, perhaps as a representation of internal state. Even the somatosensory cortex can show activation as a representation of internal state. Anne-Marie Thierry indicated that the PFC has neurons that respond to pain and that mesocortical dopamine neurons are also pain sensitive. Someone noted in this regard that schizophrenics report higher tolerance to pain, an effect reminiscent of the action of opiates.

The group then reviewed the pain hypnosis imaging study, in which subjects were hypnotized to expect lesser or greater intensities of painful stimuli even though they were all exposed to the same stimulus. In this case, the somatosensory cortex correctly registered the actual amount of the stimulation, whereas activity in the anterior cingulate cortex varied with the subjects' perception of the intensity of pain. It was noted that the cingulate may not have been registering perceived pain as much as conflict. In other words, the greater the perceived pain, the greater the desire to move, requiring greater conflict resolution to remain still and hence, more activity in the anterior cingulate cortex. Susan Sesack then mentioned that suppressing the desire to move was consistent with the role of the PFC as a frontal motor control structure. This region provides executive control of movement that would include the decision to withhold motion.

Ron Dahl asked whether recordings in animals had established the importance of frontal cortical neurons for conflict. Steve Grant mentioned that some orbitofrontal neurons in primates are highly responsive to novelty and conflict and that these neurons are also active in go/no go tasks and reward learning. Suzanne Haber added that recordings from neurons in the visual system also support the idea that different cells can have different functions depending on the situation or task. For example, when color is the relevant variable in a task, parietal neurons that usually track only the spatial encoding of an object will respond to color.

Cyriel Pennartz asked whether there were conditions in which the PFC would actually drive behavior, not just suppress inappropriate behaviors. Steve Grant replied that one of the key functions of the PFC is to prevent animals from being stimulus-bound. When a particular stimulus is present, the PFC may keep an alternate response set dominant so that this response can be driven when the stimulus is no longer present. In this case, the PFC is both suppressing immediate behavior and driving or de-suppressing subsequent behavior. Steve also noted that the PFC is responsible for keeping the rules of the situation active during task performance. It was mentioned by another person that the PFC may sometimes drive other brain regions abnormally in pathological conditions. For example, the PFC might stimulate the amygdala in depression when there is no relevant reason for the activation. Bita Moghaddam asked Steve Grant if he would broaden his description of PFC function to include behavioral switching. Steve replied that the concept of switching is a subset of the delay activity function of the PFC.

The question was then raised of how the PFC might regulate positive emotions. Clinical disorders like depression and schizophrenia are typically associated with negative PFC activity states. Are there clinical conditions in which people are overly happy? Ron Dahl pointed out that one should not confuse symptoms with disorders. For example, depression involves the symptom of excessive sadness, whereas the disorder itself probably consists of failure to seek reward. Likewise, there are people who are very happy (a symptom?) and others with the disorder of mania.

It was suggested that the PFC might maintain homeostasis between states of approach and avoidance.

Whalen noted that the PFC might be needed primarily for complex emotions and for situations of ambiguity wherein lower centers like the amygdala might be insufficient to regulate behavior.

The question was then raised as to how the PFC "manages" other regions like the amygdala or accumbens. What is the sequence? Steve Henriksen described recordings by Don Woodward from the PFC in freely moving rats receiving natural and drug rewards. In those studies, the earliest neuronal changes were seen first in the PFC, i.e., before the amygdala or accumbens. However, it was noted that some component of this could be due to attention mechanisms or the perception of novelty. Steve Grant added that recordings from the cingulate sulcus of monkeys also revealed neurons that respond to the presence or absence of reward with 10-20 second tonic changes in activity.

Steve Henriksen indicated that the timing of activity changes was important but not yet known, getting back to the question of who is activated first. Suzanne Haber thought that an answer to this question might come from simultaneous recordings from the PFC, amygdala, and accumbens. Henriksen added that what is actually needed are recordings from learning animals during the acquisition of task rules.

Cyriel Pennartz mentioned that reward responses have been recorded from cells in the visual cortex and so may be all over the cortex and operating in a top-down manner. Ron Dahl asked whether the cerebellum shows activation under reward conditions. Steve Grant replied that in many human imaging studies, the cerebellum and dorsolateral PFC showed concurrent activation. Suzanne Haber added that the basal ganglia and cerebellum may overlap in their projections to the thalamus (hence cortex) much more than is commonly thought. Moreover, some thalamostriatal projections might actually carry information from the cerebellum.

Ahmad Hariri suggested that the pathology question (#4) was ill-posed. He felt that the PFC is more susceptible to mental disorders than other cortical areas in a way similar to the greater susceptibility of some cortical regions to stroke damage or the greater vulnerability of the hippocampus to epilepsy. The functions of the PFC demand that it is extremely flexible and plastic. Hence, subtle effects like dopamine malfunction might uniquely affect anterior cortical areas more than others. Bita Moghaddam mentioned that the switching function of the PFC might also make it more vulnerable to dysfunction. Specifically, failure of the PFC in decision making might underlie anxiety and addiction disorders.

Steve Henriksen suggested that humans have a tremendous need for PFC capacity because of intraspecies communication and social interactions. Steve Grant agreed that the evolutionary force driving behind executive function might not have been working memory but social cognition. In this sense, working memory evolved in order to guide and keep track of social behaviors and social obligations.

Ron Dahl noted that anxiety disorders involve both bottom-up and top-down changes in the brain that drive anxious behavior, suggesting that there may be no simple cause and effect. Patients exist in a more anxious state and therefore have a tendency to interpret faces as more threatening than they are. This tendency is especially seen in abused children. In addition, patients with anxiety disorders display cognitive "scripts" that regulate subsequent emotion. This is of course the basis for cognitive therapy, i.e., using cognition to regulate emotions.

This discussion prompted Steve Grant to surmise that the brain is not a linear system. Rather, he imagines that it is an improvisational system more akin to a jazz band with different participants (i.e., regions) having a constant dialogue. Such an analogy implies that there is no leader but different regions establishing dominance that changes over time. Still, the brain as a whole produces a gestalt that is perceived by sensory systems and executed by motor systems. Steve Henriksen said that physiological recordings of brain activity essentially offer evidence consistent with this idea and that it is more true than people would want to admit. Bita Moghaddam speculated that the PFC might be at the center of this ensemble. However, Steve Grant felt that there would be no conductor in the brain-as-improvisational-system concept. In this regard, he made the analogy to the jazz musician, Miles Davis. In his early days, Davis did act more as a conductor. But in his later years, he surrounded himself with musicians who played rather independently and each of whom was capable of being the leader at any time. Davis would then play only a few notes at intervals, causing the music to establish a new expression each time. Steve Grant imagined that the PFC functions in a manner similar to this. Susan Sesack wondered how, according to this scheme, the motor system might be improvisational without leading to motor incoordination. Steve Grant indicated that the motor system is probably neither fully improvised nor fully random. Instead, the motor system has many pre-planned "sets" to select from.

Steve Henriksen noted that lesions of the PFC generally produce neither sensory nor motor deficits but rather subtle behavioral deficits instead. Steve Grant indicated that this was consistent with the improvisational system concept. Dorsolateral lesions disrupt work performance, whereas orbitofrontal damage produces problems in the social/interpersonal domain. Essentially, PFC lesions produce problems with adaptation. (Note added by Sesack after the fact: The important role of the PFC in switching sounds like the manner in which Miles Davis worked his band. Consequently, lesions to the PFC would be expected to produce ensemble activity that became redundant after time, with no new expressions being elicited, i.e., perseveration).

Ron Dahl wished to push the analogy of an improvisational system further by asking how a system of shifting leaders and followers would develop. It was suggested that the unique vulnerability of the PFC to mental disorders might derive from the fact that it is continuously developing, in addition to its greater need for plasticity in order to accomplish its improvisational functions, i.e., breaking and reforming patterns extensively. The protracted development of the PFC was then noted in this regard. Such late development may be necessary because of the need for extensive practice. Like a jazz band, individual components cannot come on-line until they are experienced and capable of independent function.

It was also noted that the rhythm of the improvisational brain might be provided by monoamines, the hippocampus or the thalamus. Suzanne Haber noted that the reticular thalamus provides oscillatory patterns that could control rhythm and that this is under the control of cholinergic inputs. In addition, the thalamus might serve to provide emotional binding (i.e., binding emotions to stimuli) similar to the concept of perceptual binding in sensory systems. Nicola Mercuri noted that abnormal levels of activity in dopamine systems and the amygdala in schizophrenia might adversely affect the ensemble functions of the brain.

With regard to thalamocortical interactions, Ron Dahl asked about the importance of sleep deprivation. In his experience with troubled children, sleep deprivation caused far more serious consequences for emotional regulation than for cognitive processes. Someone noted that there was 20 years of data to support this that was funded by the US armed forces. Interestingly, imaging studies suggest that the PFC is shut off during REM sleep, whereas the amygdala is activated.

Workshop II: What is the Contribution of the Amygdala in Processing Emotion?
Chair: J. McGinty; Scribe: G. Meredith; Spokesperson; B. Everitt

There were four suggested questions for this workshop session, all of which were considered during the discussion. The discussion began with the statement that "the amygdala is very complex and our understanding of its structure and function is in flux". The question arose as to how the amygdala controls appetitive and aversive behaviors. In order to embark on this discussion, we need a more complete understanding of amygdalar organization. Martin Cassells produced conceptual diagrams of the amygdala on the board. Several different schemes were offered. The 'historical' or 'standard' scheme is illustrated below (PIR, piriform cortex; BL, basolateral complex; BM, basal medial nucleus; CeA, central nucleus; Med, medial nucleus of the amygdala in two divisions: the PD - posterodorsal, and the PV - posteroventral; op tr - optic tract).

The various schemes include those in which the amygdala is (1) an endocrine extension of the striatum (Swanson), (2) separated into medial and central extended amygdalae and cortical areas, which include the cortical nucleus and lateral and basolateral nuclei (Alheid and Heimer), or (3) simplified into an extension of the ventral striatal "shell"/olfactory tubercle and cortical divisions (Cassells), e.g. the intercalated islands resemble the islands of Calleja at the border of the shell of nucleus accumbens and the olfactory tubercle and the central nucleus is continuous with the shell proper; the medial part of the central nucleus (CeM) is pallidal in appearance. The amygdala should be studied in horizontal and sagittal views to appreciate its contiguous nature with the ventral striatum. Moreover, evidence from Tony Grace's lab shows that BL stimulation excites the GABAergic neurons in the intercalated islands and these in turn inhibit the central nucleus (similar to the cortical-accumbal-pallidal pathway).

Questions therefore arise as to whether the amygdala subserves 1) striatal or extended amygdala functions, or 2) visceral and/or emotional behavior? To answer these, we need an understanding of amygdalar connections (see below).

How and when does the amygdala interact with other brain regions to regulate emotions?
Amygdalar connections (DMN X, dorsal motor nucleus of the vagus; Hippo, hippocampus; IL, infralimbic area of the prefrontal cortex; NTS, nucleus of the tractus solitarius; PL, prelimbic area of the prefrontal cortex):

An important feature of the connectional scheme is that the primate wiring (grey) differs from that in the rat (black). The primate has a strong outflow from the lateral nucleus to the orbital prefrontal cortex and a major projection directly to the CeM, whereas the rat appears to require a connection with the CeL, which in turn projects to CeM. The question still arises as to the roles of these connections in visceral/emotional behavior. Certainly, a visceral sensation that elicits emotion is a component of that emotion. Therefore, the affective value of the stimulus must have a visceral representation and the regions important for both should be related.

To what degree is the amygdala involved in the regulation of positive or negative affect?
The amygdala clearly plays a role in fear conditioning: 1) conditioned stimuli are associated with aversive events; and 2) a conditioned stimulus takes on an affective value, especially if the stimulus is phobic. Connections through the brainstem, e.g. PAG, are required for freezing behavior. Moreover, 3) the amygdala seems to contribute to the 'feeling state' of "being afraid".

But what about positive events? Are these represented in the amygdala? Changes in the endocrine response and heart rate appear to be dependent on the central nucleus. However, it remains unclear how the amygdala responds to positive stimuli, primarily because most work has been done with aversive stimuli. There is very little analysis of the endocrine reaction to positive stimuli. We do know however that the lateral/BL complex must be intact to place an affective value on an outside stimulus. Nevertheless, both avoiding a punishing act and placing a "positive" value on a stimulus survive amygdalar lesions. So what is the amygdalar role in these events?

What are the cellular and synaptic events/interactions that contribute to the amygdalar role in the elaboration of 'emotion'?
There seems to be an interaction of the amygdala with the orbital cortex for the environmental relevance of a stimulus to be appreciated. The amygdala is also involved in conditioned associations and plasticity. BL neurons respond to shock, and chronic stress leads to a prolonged activation of BL neurons. If a dopamine stimulus is paired with foot shock, neurons in BL are activated. Conditioned place preference seems to require the amygdala. Moreover, positive place conditioning cannot be carried out without the amygdala. However, little is known about plasticity in amygdalar connections. Excitation of BL neurons via cortical inputs gives rise to activation of GABAergic neurons (thought to be in the intercalated islands) that inevitably depress activity in the central nucleus. Although the PFC is required to give value to a stimulus, its associative value lies in the amygdala.