Paul J. Whalen Bio

Most work to date has assessed amygdala function within the framework of its role in fear conditioning. This is an excellent starting point drawing much support from the pioneering efforts of scientists such as Ursin & Kaada, Blanchard & Blanchard, Weiskrantz, Heimer, Kapp, McGaugh, LeDoux, & Davis. Our work is designed to demonstrate that a circuitry originally designed for fear and fear-related learning (in an evolutionary sense), might now support more subtle fluctuations in state more appropriately referred to as vigilance. These fluctuations, observed in response to stimuli that predict biologically relevant outcomes, then give rise to a host of central and peripheral responses that facilitate the processing of biologically relevant information.

To elaborate, when confronted with the appropriate stimuli — ok, let's say a bear — this system will call for extreme states such as fear. But the bulk of the human amygdala's day is likely spent assessing more subtle stimuli — I mean, when was the last time you ran into a bear? Expressions on the faces of others, for example, need not produce a strong emotional state, but they produce robust activation of the amygdala. We suggest that this activation is related to the fact that facial expressions are, in essence, conditioned stimuli; that is, they have predicted biologically relevant outcomes for you in the past, thus, upon their presentation in an experimental study, they will command the respect of this system (at least initially). While these signals will often be comparable across a group of subjects, we can also find evidence of individual differences between subjects. (See 'Research Projects' Link above)

In addition to facial expressions, we also find that we need to exert greater control over the stimuli that we use to activate the amygdala. Thus, in parallel to our studies of facial expression, we also conduct more traditional Pavlovian conditioning studies. This work allows us to more rigorously test some of our hypotheses concerning amygdala function as well as better interpret our facial expression data.

Finally, a useful way to test hypotheses about the function of normal neural circuitry is to apply similar tests to subject samples whose circuitry may be compromised. To this end, we study both subjects with anxiety disorders as well as normal variations in anxiety in healthy control subjects. Given that our work is based upon the notion that the amygdala functions to modulate moment-to-moment levels of vigilance, we are interested in documenting that some symptoms of the anxiety disorders may be related to dysfunction in this circuitry. While others might conceptualize anxiety as exaggerated fear, we would suggest that it is more usefully conceptualized as hypervigilance. That is, it is not the detection of potential threat that is exaggerated (this works pretty well in both normal and abnormal systems), it is the degree to which this system necessarily involves the rest of the brain & body upon the detection of potential threat, that forms the basis for higher levels of anxiety and the anxiety disorders. To date, we have focused on the study of generalized anxiety disorder (GAD) as a model disorder for the assessment of a hypothesized aberration in this vigilance system.

Directions to the lab

Work in our laboratory has been aimed at better understanding regional differences in BOLD (blood oxygen level dependent) fMRI responses within the amygdaloid region observed across numerous fMRI reports. One way to begin to address this issue as it relates to human BOLD signal response is to invoke a dorsal/ventral distinction across the human amygdala.

Amygdaloid Complex - The Whalen Lab

ac: ant. comm., r/l, right/left; s/i, superior-inferior;
a/p, anterior-posterior (other abbreviations defined in text).

This figure depicts the left amygdaloid complex within the temporal lobe. Subnuclei of the human amygdala located within the dorsal amygdala include the central nucleus (Ce), medial nucleus (Me) and anterior amygdala area (AAA). The ventral amygdala is comprised of the basolateral complex (BLC) and cortical nucleus (Co). The BLC consists of the lateral nucleus and the basal nuclei. Note that this dorsal/ventral distinction will be less meaningful in non-primate subjects since the sub-nuclei of the amygdala are rotated in differing positions across different animal groups. This human dorsal vs. ventral designation provides a means for incorporating numerous results from the animal literature offering compelling evidence that the BLC (located ventrally in the human) can be dissociated behaviorally from the Ce (located dorsally in the human).

For example, a model that has proven useful presents the BLC as a sensory input and convergent processing region, and the Ce as an output source affecting autonomic and somatomotor responsivity. The BLC receives the heaviest feedback projections from sensory and prefrontal cortical regions. This design allows for the convergence of multi-modal cortically-processed information in the BLC with the latest sensory stimuli being detected. In turn, the BLC projects to the Ce. The Ce is known to project to hypothalamic and brainstem target areas and it is these projections that can drive appropriate autonomic and motor responsivity. But the Ce also projects to all major neuromodulatory centers [e.g., cholinergic, dopaminergic, serotonergic and noradrenergic source neurons] and it is these connections that may more globally modulate an appropriate level of vigilance.

Note that the Ce within the dorsal amygdala extends into the substantia innominata (SI) region within the immediately superior and adjacent ventral basal forebrain. The SI comprises numerous intermingled neuronal groups including sublenticular extended amygdala neurons (SLEA) that represent an extension of the Ce and Me. These neurons extend in a superior and medial direction from the Ce and Me reaching past the anterior commissure, even being found in the nucleus accumbens shell division (NAs). The bed nucleus of the stria terminalis (BNST) is a nucleus that comprises a congregation of SLEA neurons.

More recently, it has been shown that there exists a group of cell masses between the ventral BLC and the more dorsal Ce that mediates communication between these two regions. These neurons are referred to as the intercalated cell masses (ICMs; see the work of Pare and colleagues). These cell masses represent a sort of 'moat' that controls communication between what the BLC detects and what the Ce responds to. They provide the answer to a long standing conundrum concerning amygdala function. How can a detection system effectively continue to represent the present value of a predictive stimulus (e.g., in terms of valence) without necessarily calling the action system (e.g., dorsal amygdala/SI) into action? The answer lies in the ICMs. By providing an inhibitory barrier between the BLC and the Ce, the BLC can continue to recognize potential threats (actually the lateral nucleus in particular, see the work of LeDoux and colleagues), while the ICMs inhibit the Ce, thereby inhibiting overt responses to potentially threatening stimuli that have proven to pose no threat in the present context (i.e. habituation). Thus, habituation of responsivity of the amygdaloid complex to repeated presentation of biologically relevant stimuli is an active process. It does not necessitate a time-limited role for the amygdala, but instead represents the conservation of resources (e.g., responsivity of the dorsal amygdala/SI), while the ventral amygdala continues to represent the significance of these stimuli's potential or future importance.

An additional SI neuronal group we highlight here is the nucleus basalis of Meynert (NBM). NBM neurons receive a projection from the Ce and provide a primary source of acetylcholine for the entire cortex. Acetylcholine serves to potentiate neuronal responsivity (i.e., decrease thresholds) and thereby facilitate information processing throughout cortical systems. Thus, driven by inputs from the BLC signaling the detection of relevant sensory stimuli, the Ce provides an important direct connection to the NBM that functions to augment sensory information processing by increasing acetylcholine release throughout the entire cortex. An organism in this state would be a more efficient processor of information. This new information can then be communicated back to the BLC via cortical feedback projections. Such feedback would serve to update information stored in the BLC, which would impact the response of the animal the next time a similar activating stimulus is encountered.

In terms of BOLD signal within the dorsal amygdala/SI region, the close proximity and intermingled nature of the Ce, SLEA and NBM makes them impossible to discern. Indeed, since these systems appear to interact towards a similar functional goal, namely, alerting the rest of the brain and body to be more vigilant, trying to discern their respective contributions may not be our first objective.

Given these points, we use the term dorsal amygdaloid/SI region to designate the dorsal amygdala/SI border region where fMRI activations could involve the activity of Ce, SLEA and/or NBM neurons. We hypothesize that ventral amygdala signal is related to the detection and discrimination of presented stimuli based upon their past predictive nature. Dorsal amygdala/SI activation, on the other hand, will be greatest when the predictive nature of presented stimuli is presently unclear. This vigilance system would be especially important to consider in relation to response to stimuli with unclear predictive value, especially within the realm of the anxiety disorders.

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