Selective Pharmacological Activation of Limbic Structures in Human Volunteers

Papez¹ and MacLean² proposed the idea of a limbic system consisting of phylogenetically older brain structures arranged in a network at the center of the brain. These were presumed to be responsible for the subjective and physiological correlates of emotions. The concept has been widely—and often uncritically—adopted by psychiatrists, neurologists, and basic neuroscientists, probably because of its remarkable face validity. Indeed, the split between “cortical” and “limbic” provides an anatomical metaphor for the universal human experience of a distinction between “cognition” and “emotion,” and between “conscious” and “unconscious.” It also seems to explain many puzzling dissociations between preserved cognitive functioning, on the one hand, and impaired emotional or social functioning, on the other, as in patients who suffer from selective damage to the amygdalae/parahippocampal regions³ or to orbitofrontal cortex.^4,5

However, it has been pointed out that the concept of a limbic “system” is poorly defined and that evidence for a role in emotions is often circular.^6–8 For example, whether a brain area is assumed to be part of the so-called system often depends on whether it is found to be associated with emotions. In addition, some areas, such as the hippocampus, that are clearly “limbic” on anatomical grounds have been found to be primarily related to cognitive rather than emotional functions. Furthermore, the empirical evidence relating limbic structures to emotions in humans remains indirect. The most convincing studies involve direct electrical stimulation using depth electrodes chronically implanted in patients with severe intractable epilepsy.^9–11 However, experiences reported by such patients may be related to changes in neural circuitry that are secondary to epilepsy. These experiences may also result primarily from the activation of neocortical efferents rather than from activation that remains intrinsic to limbic circuits, as local recordings cannot rule out this possibility. Finally, functional neuroimaging studies using patients with pathological emotional conditions (such as depression) or emotion-arousing stimuli have not supported the idea of an integrated limbic system responsible for all emotional phenomena. Neocortical areas are typically found to be activated as well.^12,13

To go beyond the simplistic idea of “emotions” being the expression of a monolithic “limbic system,” it is necessary to determine 1) what responses—emotional or not—are associated with the selective activation of limbic structures in the normal human brain; and 2) what associations exist between particular structures (or groups of co-activated structures) and specific components of the subjective, autonomic, and endocrine aspects of emotional responses.

Following the method described in Ketter et al.,¹⁴ we began to address these issues in healthy human volunteers by using a noninvasive (pharmacological) limbic activation procedure coupled with positron emission tomography (PET) for identification of activated structures. Using this procedure, we can correlate subjective reports with confirmed activation of anterior limbic and paralimbic structures. By capitalizing on the variability of responses between consecutive activations in the same subjects, and between different subjects, the procedure can also identify correlations between specific patterns of regional cerebral blood flow (rCBF) changes and specific subjective and physiological responses to the drug challenge.

We used the local anesthetic procaine hydrochloride as a pharmacological probe. In animals, intravenous administration of procaine induces electrical activity in limbic structures while suppressing activity in neocortical structures.^15–17 In humans, procaine induces emotional, autonomic, and endocrine responses comparable to those of direct electrical stimulation of the amygdala.^17,18 The mechanism through which procaine selectively activates limbic structures is not known, but it may be related to the particular distribution of mu-opiate and acetylcholine receptors⁶ or corticotropin-releasing hormone receptors¹⁸ in limbic and paralimbic structures. It may also be related to the specific histological characteristics of limbic structures (which, for example, make them a specific target of the herpes virus in the central nervous system⁶).

Limbic stimulation with intravenous procaine is well suited for PET studies because it is a safe procedure in healthy volunteers, produces peak effects within 2 minutes, and is of short duration (about 5 minutes). In the present study, we recorded subjective and physiological responses to procaine HCl in healthy volunteers while simultaneously measuring changes in rCBF using PET imaging of oxygen-15 water.

METHODS

Subjects

Ten healthy volunteers (mean age 20.4 years, SD=3.66; 5 female, 5 male) participated in the study, which was approved by our institutional review board. All participants were screened for absence of a history of seizures or any psychiatric disorder—including substance abuse—by the Structured Clinical Interview for DSM-III-R, nonpatient version.¹⁹ Subjects were informed that the purpose of the study was to establish the effects of systemic administration of a local anesthetic on the central and peripheral nervous system, and to record subjective responses. They were informed that they could withdraw from the study at any time, and all subjects provided informed consent.

Procedures

Prior to PET scanning, subjects received two nonblind injections of procaine (first: 0.96 mg/kg; second: 1.84 mg/kg) at our clinical research center to reduce anticipatory anxiety about the drug. This session also served to familiarize subjects with the postinjection interview (described below) and with the types of experiences about which they were to be questioned during the scanning session. Although this procedure compromises the subsequent single-blinding of injections, the effects of procaine are so discriminable that it seemed more important to reduce anxiety—which may have contaminated the experiment—rather than attempt to preserve an illusory blind.

During scanning, each subject received two single-blind injections of placebo (A) and procaine (B; 1.84 mg/kg) at 20-minute intervals in the PET scanner, in ABBA order to control for the effect of time in the scanner. Anticipatory anxiety was kept as constant as possible by keeping subjects blind to the number and order of procaine and placebo injections.

Regional Cerebral Blood Flow:

Preparation for scanning included application of a thermally molded facial mask to minimize head movements in the ECAT 951r/31 scanner; an intravenous catheter in both antecubital fossa to administer the tracer, placebo (saline), and procaine HCl; leads on the index fingers and chest to record electrodermal and heart rate activity, respectively; and a blood pressure cuff on the left arm. A 10-minute transmission scan using three rotating “pin” sources of germanium-68/gallium-68 for the purpose of calculating attenuation factors preceded the blood flow studies. During each scan, subjects rested quietly in the supine position with eyes open and without any sensory stimulation.

Qualitative rCBF was measured by using the bolus H₂¹⁵O technique²⁰ with a 60-second scan begun 20 seconds after an injection of 50 mCi of H₂¹⁵O diluted in approximately 5–7 ml of saline. Each rCBF measure began 2 minutes after injections of procaine or placebo (corresponding to the peak CNS effects of procaine as determined through pilot studies with a different group of subjects). All images were reconstructed to a resolution of 8 mm full width half maximum (FWHM).

Subjective Phenomena:

Five minutes after each procaine or placebo injection, subjects were extensively interviewed to obtain information about affective, cognitive, somatovisceral, and perceptual experiences. Subjective responses were recorded during a 10-minute structured interview after each injection by using a modified version of the Kellner questionnaire.²¹ Subjects rated their responses on a 6-point scale, where 6 was anchored as “very intense” or, in the case of common experiences such as anxiety, “the most you ever felt like this in your life.” Subjects were explicitly instructed to rate the magnitude of their experiences following each injection and relative to the preinjection period. During this interview, subjects were also asked to describe in detail more qualitative aspects of their experience.

Psychophysiological and Endocrine Measures:

Heart rate and electrodermal activity were recorded continuously, beginning 1 minute prior to drug or placebo injection. Because of technical problems with the recording equipment, electrodermal activity was not analyzed. Blood samples for beta-endorphin and cortisol levels were obtained 5 and 15 minutes, respectively, after the first two injections.

Data Analysis

Regional Cerebral Blood Flow:

PET images were analyzed by using statistical parametric mapping software.²² Images were registered with the use of an algorithm to correct for small head movements.²³ Images were then transformed to a stereotactic coordinate system and were standardized to an atlas brain to facilitate intersubject pooling.^24,25 Mean rCBF equivalents (normalized to 50 ml·100 ml^–1·min^–1) were derived per voxel for each condition and adjusted for the confounding effects of whole-brain differences in blood flow within and between subjects by using analysis of covariance.²² Resulting images were smoothed with a three-dimensional Gaussian filter (20 mm FWHM) to reduce high-frequency noise and reduce the effect of individual differences in gyral anatomy. To identify significant rCBF variance across scans, an omnibus F-test was conducted on a pixel-by-pixel basis. Only pixels with significant variance across the four scans were subjected to further analyses. Planned contrasts (t-statistic) were then conducted on a pixel-by-pixel basis, using the mean rCBF value for each scan to evaluate condition effects (activation=procaine−placebo; deactivation=placebo−procaine). Finally, the resulting pixel-by-pixel distribution of t-values was then transformed to z-scores to allow the associated displays to be independent of degrees of freedom. The critical value for alpha was set at P<0.0001.

Subjective Phenomena:

For the purpose of comparing subjective ratings after procaine and after placebo, ratings were collapsed into experiential domains of emotion, cognition, somatic sensation, and perceptual sensations. These data were then pooled across each of the two placebo and procaine conditions and analyzed by using paired t-tests.

Relations Between rCBF and Subjective Phenomena:

To explore correlations between specific subjective ratings and blood flow changes in particular regions of interest (ROIs), subjects' MRIs were first all coregistered to a common reference MRI. ROIs of a fixed circular size (637 square pixels) were then drawn on the common MRI for the amygdala, anterior cingulate gyrus, insular cortex, inferior frontal cortex, and extrastriate visual cortex, bilaterally (10 ROIs in total). The radioactive counts for each scan of each subject were then derived for each of these ROIs ([10 ROIs]×[9 subjects]×[4 scans]=360 individual values). The mean counts from the two occipital ROIs of a given subject served as a denominator to normalize the count from each ROI. Spearman rank correlations could then be calculated between normalized ROI counts and subjective ratings over the 36 scans available.

RESULTS

Regional Blood Flow Changes

Procaine had highly selective effects on anterior limbic and paralimbic structures (Figure 1). It induced bilateral activation (left panel, Figure 1A) of the entire extent of the anterior cingulate gyrus, of insular cortex, and of the region of the amygdalae/parahippocampal gyri. Notably, no neocortical area was significantly activated. There were several areas of “deactivation” (Figure 1A, right panel): left inferior parietal lobule, right thalamus, and bilateral cerebellum. The locations and magnitudes of these changes are listed in Table 1. Using a less restrictive statistical threshold (P<0.01), we observed rCBF changes in other neocortical areas, but all were also areas of deactivation rather than activation (right medial prefrontal cortex, superior occipital gyrus, precentral and postcentral gyri).

In an additional analysis, PET data for 9 of the 10 subjects were mathematically registered to their own structural MRI (one subject refused to participate in the MRI procedure) by using the algorithm and software described by Woods et al.²³ One subject's MR image was selected as a reference MR for the group, and each of the other subjects' MR data sets were then registered to this image. After conversion to this common MR, PET data were then analyzed to create pixel-by-pixel maps of the mean differences in blood flow between procaine and placebo conditions, divided by the standard deviation of the changes; in other words, a mapping of effect sizes (Figure 1B). Regions of interest superimposed on these MRIs further confirmed consistent activation of all anterior limbic and paralimbic structures identified in Figure 1A. (Each of these structures was activated in at least 8 of the 9 subjects.) The image resulting from this analysis is displayed in Figure 1B; regions of activation were determined by setting the visible threshold to z≥3.0.

Subjective Experiences

Activation of this anterior limbic/paralimbic network was associated with brief but distinctive and intense subjective experiences. These experiences cut across psychiatric disease entities and are best described as a powerful and overwhelming feeling that something of direct personal meaning is happening to the subject without specific content. Figure 2 displays the subjects' magnitude ratings of subjective experiences in the placebo and procaine conditions across four categories of reports: emotion, cognition, sensory perception, and somatic sensations. The t-tests indicated that procaine significantly increased subjective effects in all four domains (all t>5.90, df=9, P<0.0005). In the affective domain, subjects reported euphoria, anxiety, depression, and fear. Subjects also typically experienced cognitive phenomena such as derealization and inability to concentrate, as well as a variety of sensory and somatic sensations often accompanying anxiety and psychotic states or the aura of partial complex seizures, such as unformed auditory and visual hallucinations.

Across all subjects, all 13 DSM-IV²⁶ panic symptoms were noted in the spontaneous reports following procaine injections. In contrast, only 3 such symptoms were reported following placebo (chills or hot flushes, paresthesias, and derealization; all rated as “mild intensity” or less). Notably, 4 of 10 subjects reported symptoms consistent with panic anxiety that were clinically indistinguishable from a classic panic attack as defined by DSM-IV criteria. These subjects experienced sudden and intense anxiety (“the worst I've ever felt in my life”; “It was a horrible experience”) without a specific object (“I can't say I was afraid of anything in particular. It was like I was going to die”), accompanied by smothering (“like a huge weight on my chest”; “I felt I couldn't breathe”), intense derealization (“Everything seemed like it was far away”; “I felt spacy and dizzy”) and a variety of peripheral sensations (“My face felt very warm”; “My hands were numb”).

To examine if the experience of panic in our experiment was associated with a specific pattern of anterior limbic/paralimbic activation, we conducted an exploratory analysis using four scans from each of the 4 subjects who had a full-blown panic attack and comparing them with four scans from each of 4 other subjects who had no or very little anxiety (less than 2 on our scale ranging from 0 to 6, where 2 is anchored as “slight”). This analysis (Figure 3) showed that subjects who did not panic had greater rCBF change in the tip of the anterior cingulate cortex (bilaterally) as well as in a small area of left inferior frontal cortex (both P<0.0001) after the procaine injection. There were no other significant differences detected between the two groups.

Finally, we searched for a correlation between the subjective ratings of “anxiety,” “calmness,” and “euphoria” and changes in blood flow in four preselected regions bilaterally: anterior cingulate cortex, amygdala, insular cortex, and inferior frontal cortex. As previously reported by Ketter et al.,¹⁴ we found a reliable correlation between counts in the left amygdala and anxiety (r=0.41, P<0.02), but not between the right amygdala and anxiety (r=0.17, P<0.3). Similarly, there was a negative correlation between counts in the left amygdala and the self-rating of “calmness” (r=–0.37, P<0.03), but not between the left amygdala and “euphoria” (r=0.05, P=0.78). The right amygdala did not show such a negative correlation with “calmness.” None of the other ROIs tested showed a significant correlation with the subjective ratings.

Autonomic and Endocrine Changes

Although heart rate was increased at 1 minute following procaine injection, this increase was no longer significant at the time of the PET scan (mean increase at time of scan=3.8 beats per minute, SEM=2.8). As found in previous studies, plasma cortisol level was increased after the first procaine injection (mean increase=4.4 μg/dl, SEM=1.7, P<0.05), but the increase in beta-endorphin—a peptide co-released with adrenocorticotropic hormone—was not statistically significant (mean increase=5.8 pmol/l, SEM=4.0).

Functional Connectivity and Functional Specificity

To explore whether the limbic and paralimbic structures exhibiting significant procaine-related effects behaved as a functionally integrated circuit,²⁷ we conducted a varimax-rotated principal components analysis (PCA) on the regions of interest identified in Figure 1. This analysis describes the set of ROIs in terms of uncorrelated (i.e., orthogonal) components that account for a unique amount of variability in the ROIs. Resulting factor loadings reflect the correlations between each ROI and each identified factor. Data were entered into the PCA were the maximal rCBF pixel values from each significant ROI, for each subject, from each of the four scans. Maximal pixel values were taken from rostral and caudal anterior cingulate, given its wide extent and significant evidence of its differential structural and functional organization.^28,29 Three factors with eigenvalues ≥1 (the amount of variability accounted for by each component) accounted for 60.5%, 10.7%, and 9.6% of the total variance, respectively. This exploratory analysis revealed three orthogonal patterns of activity (Table 2): ROIs loading primarily on Factor 1 included anterior limbic and paralimbic structures: anterior cingulate, insular cortex, and amygdalae/parahippocampal regions. Factor 2 primarily comprised cerebellum, thalamus, and inferior parietal lobule. Factor 3 loaded most heavily on the caudal aspect of the anterior cingulate. The fact that activations of the anterior limbic/paralimbic structures were more highly correlated with each other than with the nonlimbic ROIs suggests that they behaved as if they were part of a functionally integrated ensemble.

Because there was significant variation in subjective responses between injections and between subjects, we attempted to determine whether specific subjective responses (anxiety, depression, euphoria, perceptual disturbances, derealization) were correlated with different patterns of activation in terms of rCBF. However, in our small sample, this analysis yielded only small and nonsignificant correlations. We suspect that such an analysis would require a larger sample or one in which subjects' mood is controlled experimentally (through mood induction,¹² for example) prior to procaine injections.

DISCUSSION

To summarize, the present study demonstrates that selective activation of an anterior limbic and paralimbic network, in the absence of significant neocortical activation, induces powerful emotional and visceral experiences in healthy subjects. Our results confirm the presumption, based on animal and clinical studies, that intense emotions and related somatic and visceral sensations are an important functional correlate of the activation of limbic and paralimbic areas in the normal human brain. Furthermore, the highly selective activation of anterior limbic/paralimbic structures with a pharmacological probe that is distributed diffusely demonstrates that such phylogenetically older brain circuits have distinctly different pharmacodynamics from those of neocortex and that they can be selectively targeted by particular drugs—a fact that has long been suspected from the selective effects of psychiatric medications.

The marked elicitation of somatovisceral phenomena is consistent with suggestions that these sensations are mediated by the insular cortex³⁰ and possibly by part of the cingulate cortex.²⁸ The insula in particular is a highly polymodal region, receiving visceral, olfactory, gustatory, and somatosensory inputs. Although poorly understood, it probably plays an important role in relating interoceptive signals to information from other modalities. Electrical stimulation of the insula has also been specifically associated with gastrointestinal sensations.^31,32 Functional imaging studies have only begun to address the function of insular cortex. Activation has been observed in studies of phobic patients stimulated with phobic stimuli^13,33 as well as during practice of a cognitive task.³⁴ On the basis of our results, we suspect that insular cortex activation in these other studies reflects the presence of somatovisceral symptoms—either associated with anxious anticipation or with a long, protracted PET scanning session.

We believe that robust activation of the anterior cingulate cortex in our study is related to the motivational and attentional function often attributed to this structure.^28,35,36 The anterior cingulate cortex has been implicated in tasks that demand attention (such as the Stroop task) and in the response to motivational states (for example, spontaneous vocalizations as opposed to evoked vocalizations). It is clear that the strong effects of procaine on mood, sensory perception, and somatovisceral sensation powerfully mobilized subjects' attention and could therefore be expected to activate anterior cingulate cortex. (Indeed, one subject graphically described this combined state of attention and somatovisceral sensations as “being grabbed by the balls.”)

Finally, the amygdala has been implicated in emotional responses in general³⁷ and in the fear response in particular.^38–40 Given the significant number of subjects who experienced anxiety or fear in response to procaine, it may not be surprising that we observed activation in the amygdalae/parahippocampal region bilaterally. Yet, surprisingly few functional imaging studies have documented amygdala activation in relation to emotional states.

It is important to note that several PET studies of induced emotions have failed to document limbic or paralimbic activation in the presence of very strong emotional responses, including cocaine-induced euphoria and panic anxiety.^41–44 These results suggest that limbic or paralimbic activity may be sufficient but not necessary for certain emotional experiences to occur (see, for example, Lane et al.⁴⁵) or that some emotional experiences do induce activity in such structures, but below the threshold detectable with PET. Such a failure to document limbic or paralimbic activity in studies of induced emotion or of emotional disorders might also reflect a number of methodological problems.⁴⁶ However, our results significantly overlap with the pattern of rCBF evoked in normal subjects following infusion of the panic-inducing agent cholecystokinin tetrapeptide (CCK₄), reported by Benkelfat et al.⁴⁷ In that study, activation of left anterior cingulate, and of insular cortex and amygdala bilaterally, was observed in the absence of cortical activation.

Both the nature and the variability of the subjective experiences we observed are perhaps easiest to describe in comparison to the clinical manifestations of partial complex seizures (PCS), as previously noted by Stark-Adamec et al.⁴⁸ These phenomena are also comparable to the responses observed with depth electrode stimulation of limbic structures, such as the amygdala and parahippocampal gyri. Fear is the most common experiential phenomenon described during such experiments.^10,11Figure 4 illustrates the similar distribution of subjective experiences in PCS and those following procaine injections in our study. Experiential phenomena during the aura phase of PCS are taken from King and Marsan.⁴⁹ Only PCS phenomena that were reported in that study and were directly inquired about in our questionnaire were included for comparison. As in that report, emotions refers to subjective feeling of an unexpected and self-limiting emotional state, and visceral sensation refers to localized warmth, pressure, or a rising or sinking feeling experienced inside the chest or abdomen. Cephalic sensations observed were pressure, warmth, tingling, or numbness localized to the head or face. Derealization refers to a feeling of unreality of immediate surroundings. Somatosensory sensations included primarily tingling and numbness but also increased acuity of touch sensations. Visual phenomena were illusions such as changes in light, color vision, or object shadows. Auditory phenomena were unformed hallucinations, typically described as a loud buzzing or ringing heard equally in both ears and an enhancement of auditory acuity. Olfactory symptoms consisted of a hallucination of unpleasant smell (“acrid pungent smell”). Gustatory symptoms consisted of hallucinations of a bitter or metallic taste. The qualitative and quantitative similarity to experiences of epileptic patients was most impressive with respect to emotional and viscerosomatic phenomena. In contrast, procaine may have induced primary sensory illusions and hallucinations more frequently than is typically reported in temporal lobe epilepsy.

The striking similarity of the subjective experiences we recorded and the phenomenology of epileptic auras demonstrates that many of the symptoms experienced by patients with PCS can be a direct consequence of the activation of normal anterior limbic and paralimbic structures, in the absence of an epileptic disease process. We observed these phenomena in almost all of our healthy subjects, none of whom had a history of seizure disorder or psychiatric disorder. Furthermore, the comparable frequency of different subjective phenomena after procaine injection and during PCS auras suggests that anterior limbic stimulation tends to elicit particular symptoms with a comparable frequency independently of the nature of the stimulus (chemical or electrical).

We should note, however, that the emotional phenomena induced by procaine did not include the elicitation of vivid memories often reported by epileptic patients following limbic stimulation. Bancaud et al.⁹ have suggested that such experiences are related to temporal neocortical activation, which was not observed in our blood-flow maps following procaine injections. Our study therefore tends to support their conclusions about the anatomical origin of vivid memory phenomena in PCS.

The elicitation of panic by intravenous procaine has not been reported previously (except by Ketter et al.¹⁴) and has likely been underestimated in the present study, since these symptoms were not directly probed by our questionnaire. Notably, there have been several reports of an association of panic with temporal lobe abnormalities^50–52 and with PCS.^53–55 There are also reports of successful treatment of panic disorder with limbic anticonvulsants.⁵⁶ As in Ketter et al.,¹⁴ we found a positive correlation between anxiety and blood flow in the left amygdala but not the right. This unilateral finding confirms that, in humans in particular, there may be a lateralization of function between the two amygdalae. Our exploratory analysis of panic versus no-anxiety scans also suggests that subjects who did not experience anxiety may have activated areas of the frontal lobes (tip of the anterior cingulate and left inferior frontal cortex) that could be relevant to inhibiting an anxiety response. Several authors^57–59 have proposed that inferior frontal regions contribute to the modulation of emotional responses and that the left frontal cortex in particular is associated with positive affect or inhibition of negative affect.⁵⁸

A possible concern with our results is that procaine may have a direct vasoconstricting or vasodilating effect on CNS vasculature that could alter activity in the vascular tree directly rather than modify neural activity. Indeed, the areas of activation observed in our study overlap in part with the course of the anterior and middle cerebral arteries. However, there are a number of reasons to believe that the blood flow changes we observed are related to changes in neural activity rather than to vascular effects. First, the impact of an initial bolus of arterial activity on the PET image has been considerably lessened in our study by using the minor modifications in the technique described by Raichle et al.²⁰ The original approach initiates scanning when tracer activity first enters the head (approximately 14–16 seconds after injection), which maximizes the imaging of high arterial activity. Our approach, in contrast, delays onset of scanning until 20 seconds, thus avoiding this initial arterial phase. Also, the scan has been lengthened to 60 seconds from the original 40 seconds, which further dilutes any remaining vascular effect by about 50%. Second, procaine is known to induce electrical activity in limbic structures, as recorded from intracranial electrodes in animals and from intracranial^10,11,53 and scalp electrodes in humans.⁶⁰ Third, the subjective reports of patients were almost identical to those of patients experiencing epileptic activity in limbic structures, and did not include complaints of headaches or nausea as seen in patients with vascular CNS changes.

Our PET deactivation results could suggest that emotional experiences are related to a relative bilateral deactivation of the cerebellum. Cerebellar deactivation has not, however, been implicated previously in emotional experiences, either in healthy volunteers or in psychiatric patients. Our exploratory PCA did not aid in interpreting this cerebellar deactivation, since both the first (anterior limbic and paralimbic structures) and second (cerebellum, inferior parietal lobule and thalamus) factors were correlated with emotional and somatosensory changes associated with procaine (data not shown). However, it is possible that cerebellar deactivation contributed significantly to the marked sense of derealization reported by our subjects following procaine injections. Parietal cortex has been associated with perception of extrapersonal space, and the thalamus is critical to the integration of sensory signals.⁶ Deactivation of these structures may thus be directly related to the experience of derealization. An alternative hypothesis is that cerebellar deactivation reflects a “steal phenomenon” without any true relationship to derealization. It is also possible that the relative cerebellar deactivation is an artifact of the global normalization process used prior to analysis, which removes the robust increase in whole-brain absolute blood flow seen with procaine.¹⁴ Investigation of depersonalization and derealization has received little attention in biological psychiatry, however, and the possibility of a relationship between these symptoms and parietal, thalamic, and cerebellar function may warrant further research.

CONCLUSION

The fact that some anterior limbic and paralimbic structures can be selectively and reliably activated with a pharmacological challenge demonstrates vividly the relative independence of these regions from neocortical circuits. This selectivity can be used to advance the study of how these heretofore poorly understood circuits contribute to behavior and emotional experiences, both normal and abnormal. In particular, it may lead to new diagnostic procedures in neuropsychiatry.⁶¹ A combination of functional neuroimaging and a pharmacological limbic “challenge“—whether with procaine or with some other agent—may provide a specific diagnostic procedure for the evaluation of patients with anxiety, mood, or seizure disorders comparable to the thallium “stress test” commonly used to evaluate function in patients suffering from cardiac disease.

ACKNOWLEDGMENTS

The authors thank Drs. J. R. Jennings and C. Gautier for their assistance with the autonomic measures and their helpful comments on this manuscript. This research was supported by funds received from the NIMH Center for Functional Brain Imaging and NIH/NCRR General Clinical Research Center of the University of Pittsburgh (Grant 5M01 RR00056) and an NIMH Research Scientist Development Award and NARSAD Young Investigators Award to the first author, as well as an NIMH Clinical Training in Psychiatry Research Fellowship, a NARSAD Young Investigators Award, and a Scottish Rite Schizophrenia Research Program award to the second author.

TABLE 1.

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TABLE 2.

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