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Psychosomatic Medicine 62:549-559 (2000)
© 2000 American Psychosomatic Society

ORIGINAL ARTICLES

Effects of Yohimbine on Cerebral Blood Flow, Symptoms, and Physiological Functions in Humans

Oliver G. Cameron, MD, PhD, Jon Kar Zubieta, MD, PhD, Leon Grunhaus, MD and Satoshi Minoshima, MD, PhD

From the Department of Psychiatry (O.G.C., J.K.Z.) and Department of Internal Medicine, Section of Nuclear Medicine and PET Center (J.K.Z., S.M.), University of Michigan Medical Center, Ann Arbor, MI; and Department of Psychiatry (L.G.), Sackler Medical School, Tel Aviv, Israel.

Address reprint requests to: Oliver G. Cameron, MD, PhD, Department of Psychiatry, UH-D9814, University of Michigan Medical Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0118. Email: ocameron{at}umich.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 
OBJECTIVE: Increases in adrenergic activity are associated with stress, anxiety, and other psychiatric, neurological, and medical disorders. To improve understanding of normal CNS adrenergic function, CBF responses to adrenergic stimulation were determined.

METHODS: Using PET, the CBF changes after intravenous yohimbine, an {alpha}2-adrenoreceptor antagonist that produces adrenergic activation, were compared with placebo in nine healthy humans. Heart rate, blood pressure, PaCO2, plasma catecholamines, and symptom responses were also determined.

RESULTS: Among nonscan variables, yohimbine produced significant symptom increases (including a panic attack in one subject), a decrease in PaCO2 due to hyperventilation, increases in systolic and diastolic blood pressure, and a trend toward a significant norepinephrine increase. Among scan results, yohimbine produced a significant decrease in whole-brain absolute CBF; regional decreases were greatest in cortical areas. Medial frontal cortex, thalamus, insular cortex, and cerebellum showed significant increases after normalization to whole brain. Medial frontal CBF change was correlated with increases in anxiety. A panic attack produced an increase instead of a decrease in whole-brain CBF. Factors potentially contributing to the observed CBF changes were critically reviewed. Specific regional increases were most likely due in large part to activation produced by adrenergically induced anxiety and visceral symptoms.

CONCLUSIONS: This study supports the relationship of anxiety and interoceptive processes with medial frontal, insular, and thalamic activation and provides a baseline for comparison of normal yohimbine-induced CNS adrenergic activation, adrenergically-based symptoms, and other markers of adrenergic function to stress, emotion, and the adrenergic pathophysiologies of various CNS-related disorders.

Key Words: yohimbine • cerebral bloodflow • positron emission tomography • interoception • anxiety • human

Abbreviations: CBF = cerebral blood flow; CNS = central nervous system; PET = positron emission tomography; PaCO2 = arterial partial pressure ofCO2.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 
Adrenergic and noradrenergic changes have been observed in the periphery and in the CNS in association with stress and a number of psychiatric and psychosomatic, as well as medical and neurological, disorders (1–4). (Subsequently, "adrenergic" will refer to noradrenergic as well as adrenergic function.) One way to assess potential adrenergic abnormalities is by administration of substances that modify adrenergic function. Yohimbine, an {alpha}2-adrenoreceptor antagonist that produces adrenergic activation at least to a large extent through its antagonism of inhibitory neuronal autoreceptors (5–7), is one of the substances that has been used. For example, yohimbine has been used to induce anxiety symptoms and study the associated pathophysiological changes, mainly in people with panic disorder (6, 8–11).

One method of evaluating CNS adrenergic function is with functional imaging techniques. Two general methods are available. First, ligands specific for adrenergic receptors could be developed. Second, because coupling exists among neuronal activity, cerebral glucose metabolism (CMRglu), and CBF (12–14), adrenergic function can be assessed by measuring CMRglu or CBF responses to administration of pharmacological agents that act specifically on adrenergic receptor systems. A prior single-photon emission tomography (SPECT) study found that people with panic disorder demonstrated a decrease in the CBF response to yohimbine in the frontal lobe region in comparison to normal subjects (15, 16). A PET study demonstrated that people with posttraumatic stress disorder had decreases in CMRglu in response to yohimbine in several cortical brain regions that showed increases in healthy subjects (17).

In the present study PET was used to determine CBF changes in healthy humans in response to administration of yohimbine. Because effects on CBF are coupled to CNS neuronal activity (12–14), the pattern of CBF response to yohimbine should permit inferences about whole-brain and regional CNS adrenergic function (5–7). Understanding the CBF response in normal subjects should provide a basis for identifying presumptive adrenergic abnormalities in various disorders in subsequent studies, as well as providing information about pharmacologic mechanisms of adrenergic functioning (1, 18). Prior results (15–17, 19) support the hypotheses that a) yohimbine will decrease whole-brain CBF, b) regional differences in brain CBF response will be observed, especially in cortical areas, c) there will be a significant association between CBF changes and anxiety symptoms in the frontal CNS regions, and d) yohimbine will produce activation in brain regions associated with visceral sensory perceptive processes (20–24).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 
Subjects
Each subject participated in one experimental session of 3 to 4 hours duration. All were free of psychiatric and medical disorders at the time of study, based on a medical history inventory and interview by one of the investigators, and all denied ever having experienced any panic attacks. All denied known history of psychiatric disorders in any first-degree relatives. None were hypertensive, based on sitting blood pressure measurement, and all had normal 12-lead electrocardiograms. All subjects were at least 18 years of age and not older than 40, and all were drug free including avoidance of caffeine for at least 24 hours before study (25). Nine subjects (six women and three men) were studied; mean age was 30.7 years and mean weight was 69.3 kg. All subjects gave written informed consent.

Procedure
Nonscan Procedure.
At the beginning of imaging sessions, subjects had two catheters placed, one in an antecubital vein for injection of [15O]H2O and for obtaining venous blood specimens for measurement of plasma catecholamines (epinephrine and norepinephrine), and the other in the radial artery of the opposite arm at the wrist for measurement of time course of distribution of [15O]H2O and for obtaining arterial blood for measurement of PaCO2 A blood pressure cuff was positioned on the same arm as the venous catheter. Heart rate was determined by radial artery palpation in the same arm as the blood pressure was measured. Drug and placebo were administered intravenously over 3 minutes as a 10-ml bolus. Yohimbine was given in a dose of 0.15 mg/kg, up to a maximum dose of 10 mg, a dose that gave robust effects in prior studies (26, 27). The half-life of intravenous yohimbine is approximately 45 minutes (26), and the peak adrenergic effect at this dose as indicated by plasma norepinephrine changes is within 10 minutes after infusion (27).

Arterial blood for PaCO2 was obtained at 2 minutes after the start of the scan. Heart rate and blood pressure were determined immediately after the end of the scan, followed by obtaining a 5-ml venous blood sample for catecholamine determinations. Analog symptom ratings were done immediately after the heart rate and blood pressure measurements and blood sampling. Symptoms, which were rated (0–10, with 0 = "none" and 10 = "most ever"), are listed in Table 1. Subjects were instructed to give an average symptom rating for the duration of the scan. These postscan procedures took approximately 3 minutes to complete.


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  		Table 1. Mean (SD) of Nonscan Results
 
Blood for catecholamine determinations was collected into tubes containing an antioxidant and anticoagulant. Specimens were stored on ice immediately. Plasma was separated and frozen at -80°C until assay. Assays were performed with HPLC and electrochemical detection (28).

Scans.
After catheter insertions and blood pressure cuff positioning, subjects were placed supine in the gantry of the scanner. CBF images were obtained using a Siemens 931/08–12 PET scanner (CTI Inc., Knoxville, TN), which acquires 15 simultaneous, contiguous slices with 6.75-mm slice intervals. Quantitative CBF measurement was performed as follows. After intravenous administration of 80 mCi of [15O]H2O, nine dynamic PET image sets were obtained over 6 minutes and subsequently combined into one set of images representing the aggregate CBF over the 6 minutes. Each image was reconstructed using a filter with a cutoff frequency of 0.45 cycles per projection, giving reconstructed in-plane resolution of 8.0 mm full-width-at-half-maximum (FWHM) and axial resolution of 8.0 mm FWHM. The arterial blood radionuclide concentration was measured continuously (except when the arterial sample for PaCO2 was being drawn) from a radial artery using a peristalsis pump and a NE-102 plastic scintillation detector during image acquisition. CBF was calculated by a weighted integral method (29), omitting the first 30 seconds of data, as described previously (30, 31). A two-compartment CBF model with the [15O]H2O method was used (32). Attenuation correction was performed with a 10 to 15 minute transmission scan using a 68Ge source.

Drug or placebo was administered immediately before the start of each scan. The scan data acquisition started immediately on completion of the infusion. To study each subject in one experimental session and to avoid residual effects of yohimbine during the placebo scan, all subjects received the two PET scans in a single-blind fixed-order design, the first scan after a saline placebo administration and the second after yohimbine. The second scan was always at least 15 minutes after the first, which represents approximately seven half-lives for decay of [15O].

Data Analysis
Using the arterial blood radionuclide time-activity curve, quantitative CBF images were generated. Comparisons of absolute (ie, nonnormalized) CBF after drug vs. after placebo scans were done for whole brain. Absolute CBF values were also used in the region of interest (ROI) and pixel-by-pixel regional analyses (see below).

In addition to absolute CBF analyses, analyses of normalized data were done for both types of regional analyses (33). Normalization to whole brain was used to remove the mean yohimbine or placebo effect on whole-brain CBF. This allows a) comparisons of relative effects on different brain regions to each other after removal of any effects on whole brain, and b) combining data across subjects after removal of expected whole-brain differences in CBF among subjects, thereby reducing variability.

Absolute and normalized regional scan data were analyzed with two methods: a) ROIs drawn in an automated fashion for seven cortical and six subcortical predetermined brain areas and b) with a computer program that determines, on a pixel-by-pixel basis, regions of statistically significant differences between two conditions.

Before both types of analyses, each PET image set was standardized anatomically to a stereotactic atlas brain (34) using a linear scaling edge detection and nonlinear deformation method (35). The spatial location of the ROIs was standardized using a predefined ROI template that followed the same stereotactic orientation and the regional definitions of the atlas. These were irregular ROIs drawn following the contour of the gray matter (one ROI each side) of a stereotactically aligned PET study from a healthy subject by one of the investigators. Cortical areas, except for the cerebellum, thalamus, and putamen, were sampled in this manner at the mid-caudate level, mid-thalamic level. ROIs were then transferred to the study images by the same investigator, blind to subject and scan order. The regions chosen for the ROI analysis, with their corresponding Brodmann areas (BA) are listed in Table 2. The frontal and insular cortical ROIs were of particular interest because of results from the prior studies of the effects of yohimbine on frontal CBF (6,15) and CMRglu (17) and because of the putative involvement of the insular cortex in visceral somatosensory processes (see Discussion).


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  		Table 2. Mean (SD) of Absolute CBF Scan Results
 
The method for computerized pixel-by-pixel analysis was described previously (36, 37). After reconstruction, all images were realigned to the intercommisural (AC-PC) line. A pixel-by-pixel statistical subtraction analysis between the two scan conditions was performed by estimating the smoothness of the images (38) after three-dimensional Gaussian filtering (FWHM = 9 mm) to enhance the signal-to-noise ratio and compensate for small anatomic variance in the standard stereotactic coordinate system (39). Z-score images were generated using a pooled variance over the cerebral cortex (40). A statistically significant threshold with adjustment for multiple comparisons controlling a Type I error rate at p = .05 was estimated on the above Z-score images using a statistical model based on a Euler characteristic (40).

Differences for the ROI analyses were evaluated with paired t tests. For the ROI analysis, Spearman rank correlation coefficients were determined for the ROIs with the results of the nonscan variables. For the ROI and correlational analyses, significance levels were defined as p <= .05. For the ROI method, data were analyzed with and without inclusion of the one subject who had the panic attack vs. the other eight subjects (see Results).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 
Nonscan Results
Results for the nonscan variables are presented in Table 1. Subjective symptom ratings were all significantly changed during the yohimbine scan. One subject, although having no prior history of an anxiety disorder, had a panic attack in response to yohimbine, but was able to lie still to complete the scan. In comparison to the mean for the other subjects, this subject’s change in symptoms were "mental anxiety": 10 vs. 4.25; "physical anxiety": 8 vs. 4.62; "restless": 9 vs. 3.38; "irritability": 7 vs. 1.75; "change in concentration": 8 vs. 3.38; and "relaxed": -6 vs. -7.12 (negative result for "relaxed" because subjects became less relaxed after yohimbine). Because there was no a priori justification for excluding this subject (ie, she had no psychiatric diagnosis before study), she was included in the data analyses. However, to assess the effects of the data from this subject on overall results, the results with the ROI analysis were also analyzed after exclusion of this subject (Tables 1 and 2).

Physiological variables also showed significant effects. PaCO2 was significantly decreased after yohimbine. Including all subjects, systolic and diastolic blood pressures both increased significantly, whereas heart rate increased nonsignificantly. Norepinephrine showed a trend toward being increased; epinephrine was minimally increased.

Unlike the other subjects, the subject with the panic attack showed a very large increase in heart rate (56 beats per minute). The overall heart rate increase for all subjects was almost completely due to this subject (mean increase for the other eight subjects was only 1.12 beats per minute). The increase in blood pressure in the subject that panicked was also greater than the mean change for the other subjects (systolic: 30 vs. 6.62 mm Hg; diastolic: 15 vs. 10.1 mm Hg).

Scan Results
Results for the scan variables for the ROI analyses are presented in Table 2 and for the pixel-by-pixel analyses in Figures 1 and 2. Based on the ROI analyses, the eight subjects who did not have a panic attack showed decreases in whole-brain CBF after yohimbine (range of decrease 4%–29%); mean decrease for these eight subjects was approximately 14.5%. The subject who panicked, despite hyperventilating, had a CBF increase of approximately 23%; with inclusion of this subject the mean decrease for all nine subjects was approximately 11%.



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  		Fig. 1. Z-score significance map of absolute decreases in regional CBF in response to intravenous yohimbine (placebo scan minus yohimbine scan). Scan slices are horizontal at millimeter (mm) levels above (+) or below (-) the AC-PC line as indicated. Difference in each voxel is represented by color coding. Color coding bar indicating correspondence of color to Z-score appears on the Figure (maximum Z-score = 3.50). Right and left are reversed. Map is overlaid on a generic magnetic resonance imaging (MRI) template to provide anatomical orientation.

 


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  		Fig. 2. Z-score significance map of normalized increases in regional CBF in response to intravenous yohimbine (yohimbine scan minus placebo scan). Normalization was performed by dividing each voxel value by whole brain value. Scan slices are horizontal at millimeter (mm) levels above (+) or below (-) the AC-PC line as indicated. Difference in each voxel is represented by color coding. Color coding bar indicating correspondence of color to Z-score appears on the Figure (maximum Z-score = 5.50). Right and left are reversed. Map is overlaid on a generic MRI template to provide anatomical orientation.

 
For both the pixel-by-pixel and the ROI regional analyses, absolute changes and changes of normalized data were examined separately. With the pixel-by-pixel analysis, including all nine subjects, the greatest changes in absolute CBF were decreases in cortical areas (Figure 1); no regions showed significant absolute increases (not shown). After normalization, no areas were decreased significantly more than whole brain (not shown). There were relative increases in the thalamus, medial frontal area, insular cortices bilaterally, and the cerebellum (Figure 2). (Note that the frontal ROI includes both frontal and prefrontal areas and part of the anterior cingulate region.)

For the ROI analyses, with inclusion of all subjects, there were statistically significant decreases in absolute CBF in both right and left parietal cortices; all other analyzed regions also decreased, but not significantly, and the decreases in the insular cortices were very small (Table 2). After normalization, there were significant decreases (ie, significantly greater than whole brain) in the left frontal cortex and the right parietal cortex (both p < .03, not shown). For normalized data, the right and left insular cortices, the thalamus, and the cerebellum showed significant increases (ie, lesser decreases than whole brain, all p < .02, not shown). Thus, the pixel-by-pixel and ROI analyses were in agreement for both absolute and normalized data. The fact that with the ROI analysis frontal cortices were decreased more than whole brain, whereas with the pixel-by-pixel analysis medial frontal cortex specifically was decreased less than whole brain, reflects the fact that the medial frontal region is only a relatively small part of the whole frontal area, an area that had a different CBF response than the remainder of the overall frontal region.

With the ROI analysis, after exclusion of the subject who had the panic attack, for absolute values, five of the seven cortical regions (right and left frontal and parietal cortices and occipital cortex bilaterally) were significantly decreased in comparison to whole brain, and the pons and right cerebellum showed trends (Table 2). After normalization, with exclusion of the subject who panicked, left frontal and right parietal cortices again were significant (ie, decreased more than whole brain, both p < .04, not shown). Again, the right and left insular cortices, the thalamus, and the cerebellum showed significant increases (ie, a lesser decrease than whole brain, all p < .03, not shown).

The subject who panicked showed a qualitatively somewhat different CBF response from the other subjects; in this subject, the left frontal cortex, the pons, and the cerebellum were decreased less than whole brain, whereas in the other subjects, the decreases in these areas were larger than whole brain. These results for the subject who panicked represented Z-score values above the mean of 1.09 (pons), 1.18 (left cerebellum), 1.50 (left frontal cortex), and 1.62 (right cerebellum). Thus, although suggestive of a qualitatively different pattern, none were outside of the 95% confidence intervals.

Correlations were performed between the regions found to be significant in the ROI analysis (bilateral thalamus and medial frontal cortex, and right and left insulae and cerebellar cortices) with the hemodynamic, PaCO2, catecholamine, and symptom variables. Using normalized scan data, the relative increase in medial frontal cortical CBF was significantly positively correlated with change in heart rate (r = +0.81, two-tailed p < .05) and change in "mental anxiety" (r = +0.68, two-tailed p = .05); the magnitude of the correlation with change in heart rate was due mainly to the subject who had the panic attack, but was comparable for "mental anxiety" with or without inclusion of that subject. For absolute data, the correlation for medial frontal cortex with heart rate was +0.66 and with "mental anxiety" was +0.31; these correlations did not reach statistical significance. No other correlations for absolute or normalized data reached statistical significance.

Because of the small sample size, to reach significance the absolute value of an individual correlation was at least ±0.68. Looking for trends of correlations that did not reach statistical significance but were nonetheless suggestive of patterns of possible physiological importance, correlations more than +0.50 were assessed for each of the six brain regions found to be significant in the normalized data. For absolute scan data, each of the ROIs analyzed was positively correlated with PaCO2 and epinephrine. Additionally, thalamus, medial frontal cortex, and right insula were positively correlated with heart rate and irritability, whereas the two cerebellar cortices and the left insula were positively correlated with systolic blood pressure and negatively correlated with difficulty concentrating. For normalized scan data, medial frontal cortex was positively correlated with restlessness and PaCO2 (as well as heart rate and mental anxiety), and negatively correlated with feeling relaxed. The cerebellar cortices were negatively correlated with norepinephrine and PaCO2 and positively with feeling relaxed. A few other sporadic correlations exceeded ±0.50, but no pattern was suggested. Interpretation of these correlations must be done cautiously because of the small sample sizes and multiple tests performed.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 NOTES
 REFERENCES
 
The hypotheses presented in the Introduction based on previous research were supported. In response to CNS and systemic adrenergic activation by yohimbine, whole-brain CBF was decreased, with the greatest decreases in cortical regions. The correlational data demonstrated an association between anxiety and changes in medial frontal cortex. Brain regions associated with visceral sensory processes—thalamus and insular cortices, as well as medial frontal cortex region—were affected by yohimbine-induced adrenergic activation. Additionally, the correlational patterns suggest relationships among epinephrine and PaCO2 with absolute changes in yohimbine-induced CBF changes, as well as an overall responsivity of the medial frontal cortex to both physiological and symptom variables.

Potential Effects of Panic, Hypocapnia, Habituation, and Physiological Changes
There are several possible factors that could affect the results observed. Inclusion of the subject that panicked had only a minor effect. The decrease in absolute whole-brain CBF was more robust if this subject was not included, but for normalized data, the pattern of significant results was not changed. It is noteworthy that the occurrence of a panic attack increased whole-brain CBF despite the multiple other factors that tended to decrease it. For the correlational results, the significant relationship for medial frontal cortical CBF with anxiety was not affected by inclusion of the subject who panicked, whereas the relationship with heart rate was.

PaCO2 was reduced during the scans involving the active substance because the subjects hyperventilated. It is well documented that hypocapnia reduces CBF (41), including studies with functional imaging techniques (42–44). Thus, whole-brain CBF decreases seen in response to yohimbine were due at least in part to hyperventilation. However, effects of hypocapnia seem to be uniform throughout the brain gray matter (44, 45). Thus, significant effects seen in normalized data only in specific regions are unlikely to be due to hypocapnia.

Because the yohimbine scan for each subject was completed after the placebo scan (ie, fixed-order, single-blind design), another possible cause for the reduction in whole-brain CBF during the second scan is habituation. A number of studies have reported decreases in whole-brain CBF from the first to subsequent scans (46–51), although some studies did not report this (52–54). Based on these results, as with hypocapnia, habituation might have contributed to the whole-brain CBF decrease, but does not account for the specific regional increases seen after normalization.

Among other nonscan variables, potential causes of the CBF changes might include changes in heart rate, blood pressure, and norepinephrine. The heart rate and blood pressure changes could not account for the change, however, because they should be associated with CBF increases rather than decreases. It also seems unlikely that an increase in norepinephrine contributed to the CBF decrease. Brain norepinephrine has been associated with cerebral vasoconstriction (19), although not all data are consistent with this (55–58). Data on the effects of circulating norepinephrine on CBF are inconsistent (59); circulating norepinephrine does not cross the blood-brain barrier (60–62). CBF was not decreased by intracarotid injections of norepinephrine in humans (63).

Potential Vascular, Metabolic, and CNS {alpha}2-Adrenoreceptor Distribution Effects
The above factors could have accounted for some or all of the whole-brain CBF decrease, but are unlikely to account for the relative increases seen in medial frontal cortex, insular cortices, thalamus, and cerebellar cortices. Factors that could have produced these specific regional effects include vascular and other potential adrenoreceptor-mediated effects and symptoms including anxiety and visceral symptoms.

Although yohimbine could have vascular effects without entering the CNS, it does freely enter mammalian brain (64). Results from prior studies of the effects of yohimbine on CBF and cerebral vasculature (15, 16, 65, 66) are inconsistent, but suggest that yohimbine decreases CBF in some brain regions. In humans, yohimbine decreased frontal cortical CBF in people with panic disorder (15, 16); other areas studied—parietal, temporal, and visual cortices, striatum, thalamus, and cerebellum—did not show differences. This study, however, only assessed diagnosis-related differences, not absolute effects of yohimbine. The present study found yohimbine-induced CBF decreases in cortical regions. Prior studies of adrenergically activating agents on regional CBF (67–69) did not find CBF changes in frontal cortex or cerebellum different from other regions, although thalamus did seem less sensitive (insular cortex was not tested). Thus, direct adrenergic effects of yohimbine on cerebral vasculature does not explain the results observed.

The observation that clonidine, an {alpha}2-adrenoreceptor agonist, reduces whole-brain CBF (70–73), as did yohimbine, an antagonist, indicates that adrenoreceptor-mediated effects also cannot fully account for the observed results; if it did, clonidine should produce changes in CBF opposite from yohimbine. In a human PET study with clonidine (74), increased CBF was observed mainly in subcortical regions, whereas decreases occurred mainly in cortical regions. In conjunction with our results, these findings are inconsistent with a single reciprocal mechanism.

Effects of yohimbine on CMRglu have also been addressed (17, 75). In humans, yohimbine produced increases in whole-brain CMRglu and in cortical and subcortical structures (17). The fact that yohimbine increases CMRglu implies that it produces neuronal activation (12–14). Thus, regions found to be different from whole brain in this study were different due to neuronally-mediated activation, not just smaller CBF decreases. In other words, differences in regional pattern between the effects of yohimbine on CBF and CMRglu indicates that yohimbine had specific regional effects over and above direct effects on CBF.

As noted in the Introduction, it seems likely that effects of yohimbine observed in this study were due at least partly to direct activation of CNS {alpha}2 adrenoreceptors. Does the distribution of {alpha}2 adrenoreceptors in human brain parallel the pattern of effects seen in the present study? Previous studies showed highest levels of human brain {alpha}2 adrenoreceptors in neocortex, cingulate gyrus, hippocampus, and hypothalamus. Regions with very low levels included thalamus and white matter. Cerebellum, amygdala, midbrain, pons, medulla, and basal ganglia were intermediate (76–78). Comparison of receptor distribution to the pattern of regional CBF effects in this study indicates that CBF changes were not simply due to receptor activation by yohimbine. Although in the present study, yohimbine produced effects on several cortical areas, there were also effects on CBF in thalamus and possibly cerebellum, regions with only low or intermediate numbers of receptors. Thus, neither vascular nor CNS {alpha}2-adrenoreceptor-mediated effects can explain the pattern of regional increases observed.

Anxiety and Visceral Sensory Symptoms
Yohimbine produces symptoms associated with adrenergic activation, including subjective anxiety, especially in anxiety disorders. Although no completely consistent CNS abnormalities have been observed, in imaging studies of anxiety frontal cortical changes have been reported (15, 16, 79–84). The results of the present study, including correlational results, are consistent with this association of anxiety with frontal changes. These results are also consistent with prior findings that CBF and CMRglu changes in frontal (85–91) and other areas (87, 89, 92) are associated with emotional experiences in normal subjects. Production of subjective sensations probably played a significant role in the yohimbine-induced effects observed in this study.

A major issue in understanding the pathophysiologies of psychosomatic and psychiatric disorders and emotion is the relationship between visceral sensory experiences and CNS function. For example, what is the mechanism of awareness of heart action during a panic attack? Not a great deal is known about CNS mechanisms of visceral sensory awareness (interoception) (20–24), although studies have investigated afferent function of the autonomic nervous system (23, 93–95). Animal studies indicate that anatomic regions involved in visceral afferent function include brain stem structures, hypothalamus, amygdala, thalamus, and cortex—especially the insular cortex (93, 94).

The insula is strongly implicated in visceral (and somatic, Ref. 96) sensory function. The insular cortex is involved in affective components of visceral function: a) insula demonstrates extensive connections with limbic structures, including amygdala (97–100), b) functional connections between insula and viscera exist (94, 97, 100, 101), c) the insula is involved in cardiac control (102–104), "stress" (105), the "fight-or-flight" response (106), and "sudden death" (107), and d) insular activation occurred in CBF studies of panic disorder and phobias (80, 81, 108, 109) and with emotion in normal subjects (89). These observations are consistent with important insular involvement in normal and abnormal visceral awareness.

Other structures are implicated. The locus coeruleus, which is comprised of adrenergic cell bodies, is involved in visceral sensory processes (110), of special relevance because of the known activation of the locus coeruleus by yohimbine (5–7) and because of involvement of CNS adrenergic functioning in attentional processes—of essential importance in awareness, including visceral awareness, and in anxiety (111–112). Finally, the thalamus is involved in sensory processes, including visceral sensory processes (113–115).

Consistent with the above, in the present study yohimbine activated not only frontal cortex but also insular cortices and thalamus (Figure 2). Although vascular and receptor effects might have contributed to yohimbine-induced regional changes, it is likely that these frontal, insular, and thalamic changes were produced mainly by adrenergic activation leading to CNS-mediated anxiety-like reactions and sensations mediated through visceral sensory pathways. Thus, interoceptive processes probably played an important role in the effect observed. This study provides support for involvement of thalamus and insular and frontal cortices in visceral sensory-perceptual processes.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
NOTES
 REFERENCES
 
Symptoms and physiological effects of yohimbine observed here are consistent with results from prior studies. Scan data demonstrate that yohimbine produced decreases in whole-brain CBF, which was more prominent cortically than subcortically. Multiple mechanisms that could have contributed to these decreases are reviewed. Relative increases in CBF superimposed on the decreases were observed in medial frontal cortex, insular cortex, thalamus, and cerebellar hemispheres. The explanation for these increase most consistent with the pattern of activated regions observed is that these changes were produced by adrenergically induced increases in anxiety and visceral symptom perception. This study of yohimbine-induced CBF changes provides further support for the association of visceral sensations, anxiety, and emotion with the particular brain regions that were activated.

These results advance understanding of how adrenergic mechanisms control CBF and thus CNS function. It provides a baseline for studying how these processes might be dysfunctional in various disorders. Pharmacological activation can provide an experimental model to study normal and pathological interoceptive processes and improve understanding of the relationships among CNS adrenergic function, regional CBF and CMRglu, and brain mechanisms of emotion and visceral sensation.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
REFERENCES
 
Presented in abstract form at the American Psychosomatic Society and the Society of Biological Psychiatry.

Received for publication January 15, 1999.

Revision received December 16, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 

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