Neuroimaging Abnormalities in the Subgenual Prefrontal Cortex: Implications for the Pathophysiology of Familial Mood Disorders ¨ ¨ WC Drevets1,2,Dongur3 and JL Price3

Home , Cingulate cortex, Infralimbic cortex, Prefrontal cortex

PERSPECTIVE Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders ¨ ¨ WC Drevets1,2,DOngur3 and JL Price3

1Department of Psychiatry; 2Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15238; 3Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA

The prefrontal cortex (PFC) ventral to the genu of the corpus callosum has been implicated in the modulation of visceral responses to stressful and emotionally provocative stimuli, based upon analysis of lesion effects involving this area in humans and experimental animals. In a recent magnetic resonance imaging (MRI) study of familial mood disorders, we demonstrated that the mean grey matter volume of this cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of their treatment status or current mood state. Moreover, in preliminary histopathological assessments of subgenual PFC tissue taken post mortem from subjects with MDD and bipolar disorder we obtained results suggesting that this decrement in grey matter volume is associated with a reduction in glia without an equivalent loss of neurons. The potential functional signiﬁcance of these neuroimaging and microscopic abnormalities is discussed with respect to evidence that subgenual PFC dysfunction may disturb stress-related autonomic and neuroendocrine responses and reward-related mesolimbic dopamine function. These data may thus hold important implications for the development of neural models of mood disorders that can account for the abnormal hedonic, motivational, neuroendocrine, and autonomic manifestations evident in these idiopathic conditions. Keywords: anterior cingulate; glia; MRI; PET; major depression; bipolar disorder; emotion

In a recent neuroimaging study of mood disorders we difference persisted during treatment and was present reported that the grey matter volume of the prefrontal in various mood states, suggesting that it reflected a cortex (PFC) ventral to the genu of the corpus callosum trait-like abnormality.1 is reduced in familial bipolar disorder and familial In pursuing the nature of these neuroimaging abnor- ¨ ¨ major depressive disorder (MDD).1 The magnetic res- malities, D Ongur and JL Price initiated post mortem onance imaging (MRI)-based neuromorphometric mea- histopathological assessments of brain tissue taken sures acquired to demonstrate this abnormality in the from the left subgenual PFC of subjects who had been ‘subgenual’ PFC were guided by positron emission clinically diagnosed as having bipolar disorder, MDD, tomographic (PET) images that showed an abnormal or no psychiatric disorder (courtesy of the Harvard reduction of cerebral blood flow (BF) and glucose Brain Bank and the Washington University Department metabolism in this area in depression.2–4 Because anti- of Pathology). The neuroimaging data had specifically depressant treatment did not reverse these physiologi- implicated the cortex situated on the anterior cingulate cal abnormalities, the MRI measures of grey matter vol- gyrus ventral to the anteroventral border of the corpus ume were obtained to determine whether the callosum, which in the human is comprised predomi- decrements in regional BF and metabolism were at nantly of area 24b and, to a lesser extent, 24a (Figure least partly explained by a corresponding reduction in 1; in contrast, in the Macaque area 24b is situated cortex.5 This hypothesis was confirmed, as the mean anterior to the genu of the corpus callosum).1,6 The grey matter volume of the left subgenual PFC was initial histopathological assessments thus targeted the reduced by 39% and 48% in the bipolar disordered section of area 24a and 24b (microscopically defined and unipolar depressed samples, respectively, relative by its agranularity) located ventral and caudal to the to the controls (F = 9.8; P Ͻ 0.0002, after covarying for genu of the corpus callosum (Figure 2). age, gender and whole brain volume).1 This volumetric Preliminary post mortem measures from four subjects with a history of MDD, three with bipolar disorder and four with no history of psychiatric disorders were Correspondence: WC Drevets, MD, B 938, Presbyterian University Hospital, University of Pittsburgh Medical Center, 200 Lothrop consistent with a reduction in the mean grey matter St, Pittsburgh, PA 15213, USA volume of the subgenual PFC in both mood-disordered Received and accepted 2 December 1997 groups (Figure 2). Cell counting studies suggested that Neuroimaging abnormalities in the subgenual PFC WC Drevets et al 221 the decrement in grey matter is associated with a reduction in glia without an equivalent loss of neurons. The glial cell counts of six of the seven mood-disordered subjects were less than the mean glial count of the controls, and three mood-disordered subjects had dramatically reduced glial numbers, with cell counts of only 3%, 13%, and 24% (in one bipolar and two unipolar subjects, respectively) of the mean value of the controls. In contrast, the neuronal number was not decreased and the neuronal density appeared increased, as would be expected in association with a reduction in cortical volume (five of the seven mood- disordered subjects had neuronal densities which exceeded the upper range of neuronal density in the controls). Consistent with the expectation that mood disorders are heterogenous with respect to etiology,7 the variability of these glial counts and of our previous MRI measures in the subgenual PFC are high across mood- disordered subjects and the ranges of values in the ill and normative groups partly overlap. Such variability Figure 1 Drawings of coronal sections through the genu of the corpus callosum (CC) and the subgenual and posterior is typical of psychobiological data acquired from orbital PFC of a human brain at levels 26 and 30 mm rostral mood-disordered samples, which generally show that to the anterior commissure. Agranular (Agran), dysgranular subsets, rather than entire samples, of subjects meeting (Dysgran) and granular (Gran) cortical regions are marked. criteria for MDD and bipolar disorder manifest biologi- The subgenual PFC consists of agranular cortex on the cal markers for affective disease.7 In our neuroimaging anterior cingulate gyrus ventral to the genu of the corpus cal- study, we enhanced the likelihood of identifying bio- 1,6 1 losum. Modified from Drevets et al. logical markers by selecting subjects who had first- degree relatives with the same mood disorder diagnosis.1,7,8 The extent to which the neuroimaging abnormalities in the subgenual PFC also extend to non-fam-

Figure 2 Post mortem measures of grey matter volume (left ordinate) and absolute cell number (right ordinate) obtained from the left subgenual PFC in controls (n = 4), unipolar depressives (n = 4), and bipolar disordered subjects (n = 3). The subject groups did not significantly differ in mean age, post mortem interval, or gender composition. The mean duration of formal- dehyde fixation was longer for the mood-disordered subjects than for the controls, although this would not be expected to selectively alter glial counts or profiles in Nissl-stained tissue. The subgenual PFC measures were obtained from area 24, as defined in Nissl-stained tissue as the agranular cortex dorsal to granular area 10 (Figure 1),6 in evenly spaced coronal sections spanning from the slice immediately caudal to the genu of the corpus callosum through the slice 8 mm caudal to the genu. Area 24 comprised most of the first full gyrus ventral to the anteroventral border of the corpus callosum (Figure 1; the MRI- based neuromorphometric measures discussed in the text were acquired by segmenting the grey matter on this gyrus1). The cortical volume of area 24 was measured using stereological techniques (Cavalieri estimator) and the cell number and density were measured using an optical dissector. Both the absolute glial number and the glial density were reduced (P Ͻ 0.05) in the combined mood disorder group relative to the control group. Neuroimaging abnormalities in the subgenual PFC WC Drevets et al 222 ilial cases thus remains unclear. Nevertheless, in PFC, neuromorphometric abnormalities have been contrast to depressive samples with familial pure reported in structures that are anatomically related to depressive disease or familial bipolar disorder, who the subgenual PFC.10 In an MRI-based morphometric both showed abnormally reduced metabolism in this study of bipolar disorder, Pearlson et al11 found that of area, we observed that subjects who met criteria for several temporal lobe structures examined, only the depression spectrum disease (MDD subjects with first- left amygdala was abnormally reduced in volume. degree relatives who have alcoholism or sociopathy, Since the amygdala and the subgenual PFC share sub- and not mania),8 did not significantly differ from con- stantial, predominantly ipsilateral anatomical connec- trols with respect to the mean subgenual PFC glucose tions, it is possible that the left-lateralized volumetric metabolism.9 Moreover, a recent MRI study found that reductions in these two structures are related.12 the mean subgenual PFC grey matter volume (defined The caudate nucleus has also been found to be using the anatomical landmarks we used1) was signifi- abnormally reduced in volume in MDD, although this cantly reduced with respect to controls in bipolar sub- finding was not replicated in bipolar disorder.10,13 The jects with mood-disordered first-degree relatives subgenual PFC and the amygdala specifically project (consistent with our data1), but not in bipolar subjects to the ‘limbic’ striatum, comprised of the ventromedial without mood-disordered first-degree relatives (Y caudate and the nucleus accumbens.12 Post mortem Hirayasu, personal communication). Post mortem stud- studies that more specifically examine these striatal ies of subjects with well-characterized personal and areas may thus have greater sensitivity for identifying family history will ultimately be needed to establish histopathological changes common to both MDD and whether the histopathological changes in the subgen- bipolar disorder. ual PFC are specific to familial subtypes of mood dis- Finally, third ventricle enlargement is consistently orders. found in studies of bipolar disorder, although the spe- While these microscopic findings require confir- cific tissue where volume loss resulted in ex vaccuo mation in larger subject samples, characterization by changes in third ventricle size has remained specific stains, and replication across laboratories, unclear.10,11 The subgenual PFC shares extensive their potential impact upon elucidating the pathophy- reciprocal connections with the periventricular and siology of familial mood disorders may be substantial. mediodorsal nuclei of the thalamus that line the third In contrast to the nonspecific glial proliferation seen ventricle wall.12 Post mortem assessments of these in neurodegenerative disorders, reductions in glia have nuclei in bipolar disorder may thus clarify the nature generally not been reported in other conditions. It is of the third ventricle enlargement in this condition. nevertheless critical to establish that reductions in glial Taken together, these data suggest that mood dis- numbers are not simply associated with nonspecific orders may be associated with a neuropathological pro- factors such as exposure to psychotropic drugs or alco- cess affecting an anatomical circuit involving the hol. If such changes prove specific to mood disorders, subgenual PFC and related parts of the amygdala, the determining whether they reflect a neurodevelopmen- striatum and the thalamus. If the volumetric abnor- tal defect (eg, associated with genetic factors regulating malities in the abovementioned structures are related, glial genesis or proliferation) or an acquired effect of microscopic inspection of the changes in each struc- recurrent illness may provide clues regarding the etiol- ture may nevertheless reflect distinct changes from ogy of familial mood disorders. those identified in the subgenual PFC. For example, if Future studies must also characterize the anatomical familial mood disorders are associated with a specificity of these microscopic changes. In our neuro- reduction in glia substantial enough to impair gluta- imaging study, we did not identify significant differ- mate uptake in the subgenual PFC, then neural trans- ences between the bipolar and control groups in the mission from this structure to its efferent projection volume of other portions of the anterior cingulate cor- fields may pathologically increase.14 Since these pro- tex or of the whole brain.1 Nevertheless, the methods jections involve excitatory amino acid transmitters, it we employed were insensitive to potential, regional might be hypothesized that the volume loss in the anatomical differences in other structures. We thus amygdala, the striatum, and the thalamus may reflect selected the less specific term ‘subgenual PFC’ in lieu neuronal loss resulting from excitotoxicity. of more specific designations (eg, ‘subcallosal anterior cingulate’) to reflect the uncertainty involved in defin- Comparison with other functional imaging studies ing the anatomical extent of an abnormality using neuroimaging techniques. The preliminary microscopic The subgenual PFC was not specifically assessed in assessments of the subgenual PFC tissue described earlier PET studies of mood disorders, which generally above may justify this approach, since the reduction in obtained measures from large preselected regions-of- glia appears to also extend ventrally beyond area 24 interest (ROI) that precluded restricted localization into the remainder of the ventromedial prefrontal within the very large human PFC.15 In contrast, more cortical wall. recent PET studies that used statistical mapping or ROI analysis of images of sufficiently high spatial resol- Comparison with other structural neuroimaging ution to identify physiological differences in the studies subgenual PFC have confirmed and extended our neur- While previous MRI and post mortem studies of mood ophysiological finding in depression. Buchsbaum et disorders have not specifically examined the subgenual al16 reported decreased metabolism in unmedicated, Neuroimaging abnormalities in the subgenual PFC WC Drevets et al 223 unipolar depressives relative to controls in ventromed- PFC.14 In monkeys and other experimental animals the ial prefrontal ROI that included the ventral-most seg- subgenual PFC has extensive connections with the ment of the anterior cingulate cortex and appeared to amygdala, the lateral hypothalamus, the nucleus comprise the area we referred to as the subgenual PFC accumbens, the ventral tegmental area (VTA), the sub- (localization in this study involved direct comparisons stantia nigra, the raphe, the locus ceruleus, the peri- of PET image slices to an atlas, so neither MRI-based aqueductal grey, and brainstem autonomic nuclei.12,19–22 anatomical landmarks nor stereotaxic coordinates for Since these structures have been implicated in various the intergroup difference were available for compari- aspects of emotional behavior, it is conceivable that son with our results). More recently, Mayberg et al17 abnormal synaptic interactions involving the proje- reported that subjects with a history of MDD scanned ctions between these areas and the subgenual PFC may in remission showed a blunted hemodynamic response underlie the disturbances of emotional processing, during sadness induction in the subgenual PFC monoaminergic neurotransmitter release, neuroendo- (Mayberg et al referred to this area as Brodmann Area crine function, and autonomic regulation seen in 25, although in the human brain the cingulate cortex depression. in this position corresponds primarily to Area 24b, and Humans with lesions that include the subgenual PFC Area 25 (ie, infralimbic cortex) instead lies more demonstrate abnormal autonomic responses to caudal). This sadness induction task, which involves emotional experiences, inability to experience emotion contemplation of sad autobiographical material, has related to concepts that ordinarily evoke emotion, and 17 18 been shown by both Mayberg et al and George et al inability to use information regarding the likelihood of to increase BF in the subgenual PFC in healthy controls punishment vs reward in guiding social behavior.23,24 (eg, George et al reported that the peak BF increase in Based partly upon these observations, Damasio et the left ventral anterior cingulate had coordinates: al23,25 proposed that the ability to evaluate the conse- =− = = x 14, y 30, z 0 (interpreted as in Image section quences of social behavior depends upon visceral feed- legend), located about 1 cm from the sterotaxic center back mediated through interactions between the ven- of mass of the abnormality in depression shown in the tromedial PFC, the hypothalamic autonomic centers, Image section). In contrast, the remitted MDD subjects and the brainstem monoaminergic neurotransmitter studied by Mayberg et al did not show an increase in systems. If so, disordered interactions between the the subgenual PFC blood flow as they performed this subgenual PFC and these latter structures may poten- task, as would be expected if a trait-like reduction in tially result in the impairments of evaluative pro- grey matter exists in this area in MDD. cessing seen in mood disorders. For example, such Functional imaging studies of depression have ident- pathological modulation of evaluative processing may ified BF and metabolic abnormalities in a variety of conceivably underlie the heightened sensitivity to fail- other structures as well in MDD, consistent with the ure, pathological guilt, and exaggerated self-criticism hypothesis that the subgenual PFC participates in an seen in depression, as well as the swings toward inap- extended functional anatomical network involving propriate elation, emotional lability, and insensitivity multiple structures to mediate the emotional, neuro- to the negative outcome of pleasurable or violent psychological, neurochemical, and behavioral manifes- 7,26,27 tations of depression.2,15 For example, the depressive behavior in mania. samples in which we found reduced subgenual PFC Compatible with this hypothesis, rats with lesions glucose metabolism were later shown to also have involving the ventromedial PFC that appear to include abnormally increased metabolism in the amygdala, the the area homologous to the subgenual PFC (ie, approxi- lateral and posterior orbital cortex, the medial thala- mately prelimbic cortex) demonstrate alterations in mus, and the posterior cingulate cortex, and decreased neuroendocrine, autonomic and behavioral responses metabolism in the dorsomedial PFC, the dorsal antero- to stress that resemble changes in these systems in 19 lateral PFC and the caudate.15 These findings have been humans with mood disorders. For example, Diorio et 28 consistently reported in previous studies of unmedi- al showed that medial PFC lesions of the prelimbic cated depressives with primary MDD.15 and infralimbic portions of the anterior cingulate cortex increased the plasma ACTH and corticosterone (CORT) responses to restraint stress, while implants of Potential implications of subgenual PFC crystalline CORT in the same cortical areas decreased dysfunction the ACTH and CORT responses to restraint stress. The functional significance of the neuroimaging and Diorio et al28 concluded that the glucocorticoid recep- microscopic abnormalities in the subgenual PFC in tors demonstrated in these ventromedial PFC areas are mood disorders is unclear. If a reduction of cortical glia involved in the negative feedback effect of glucocort- in this area is confirmed, the importance of these cells icoids on stress-related hypothalamic-pituitary-adrenal (eg, astrocytes) in providing trophic factors and energy (HPA) axis activity. Since major depression is associa- substrates to neurons, maintaining potassium homeo- ted with elevated basal cortisol levels, increased cen- stasis in the extracellular fluid, and removing gluta- tral drive on cortisol release at the circadian nadir, mate from the neuropil to end synaptic transmission abnormal delayed glucocorticoid negative feedback, suggest mechanisms by which glial hypofunction and dysregulation of cortisol responses to stressors, the could disturb synaptic activity within the subgenual relationship between subgenual PFC dysfunction and Neuroimaging abnormalities in the subgenual PFC WC Drevets et al 224 HPA axis activity in mood disorders warrants further lesions on sympathetic and parasympathetic function investigation.29,30 in rats, it is noteworthy that depressed humans have In addition to demonstrating neuroendocrine been shown to have reduced HRV, elevated resting changes, rats with bilateral lesions of the dorsal prelim- heart rate, and increased sympathetic nervous system bic and anterior cingulate cortices also show exagger- activity relative to controls.35,38 The imbalance in sym- ated freezing behavior and heart rate increases during pathetic-to-parasympathetic tone reflected by these exposure to fear-conditioned sensory and/or contextual autonomic abnormalities is hypothesized to account stimuli.31,32 In contrast, bilateral lesions involving both for the elevated risks for developing ventricular tachy- the infralimbic and the ventral prelimbic cortices result cardia, myocardial infarction and sudden death seen in reduced HR responses to fear-conditioned stimuli.32 in depressed patients with cardiovascular disease.39–41 Taken together, these findings led Frysztak and Neaf- Given the role of the subgenual PFC in modulating sey32 to propose that the ventral prelimbic and infra- autonomic nervous system function, investigations of limbic cortices normally act to increase heart rate dur- the relationship between neuroimaging abnormalities ing stress. in the subgenual PFC and this pattern of reduced para- This drive on increasing sympathetic autonomic sympathetic and increased sympathetic function in arousal and CORT release in response to stress were MDD are warranted. more specifically linked to the function of the right In addition to modulating autonomic and neuroen- ventromedial PFC by Sullivan and Grattan.33 They docrine responses to behaviorally significant stimuli, reported that rats with lesions involving the left infra- the subgenual PFC may also participate in evaluative limbic, prelimbic, and anterior cingulate cortices dem- processing via modulation of monoaminergic neuro- onstrated heightened sympathetic autonomic arousal transmitter function. The midbrain connections of the and exaggerated CORT responses to restraint stress subgenual PFC include projections to neurons in the relative both to control animals and to animals with VTA, the substantia nigra, the raphe, and the locus right-sided lesions of the same areas. In contrast, right- ceruleus.19–21,42 Although the functional significance of lesioned animals showed attenuation of the CORT rise these anatomical connections remains unclear, the and the autonomically-mediated gastric stress pathol- extant data regarding the ventromedial PFC and its ogy associated with restraint stress. From these data relationship to the mesolimbic dopamine (DA) system Sullivan and Grattan33 concluded that left ventromed- merit comment. ial PFC lesions disinhibit the function of the right ven- Of the PFC areas that receive dopaminergic inputs, tromedial PFC, which mediates the heightened sym- Area 24 of the anterior cingulate gyrus (part of which pathetic autonomic, affective, and HPA-axis arousal is comprised by the subgenual PFC) receives the most seen in the left-lesioned animals. (Specialization of dense DA innervation, principally from the VTA.43 In functions based upon laterality may also account for rats, electrical or glutamatergic stimulation of medial the observations that while bilateral lesions of the pre- PFC areas that appear to include the subgenual PFC limbic and infralimbic cortices increase the plasma elicits burst firing patterns of dopaminergic cells in the CORT responses to restraint stress,28 nevertheless elec- VTA and increases DA release in the nucleus.44–48 The trical stimulation of the prelimbic cortex also increases burst firing of DA cell activity elicits more terminal DA circulating CORT.34 Given the left-lateralization of our release per action potential than the non-bursting, neuroimaging findings in the subgenual PFC,1 these pacemaker firing pattern.46 The phasic, burst firing of lesion analyses suggest the hypothesis that dysfunction DA neurons and accompanying rise in DA release nor- of the left subgenual PFC in mood disorders specifi- mally occur in response to primary rewards (until they cally results in the heightened affective, neuroendoc- become fully predicted) and reward-predicting stim- rine and sympathetic autonomic arousal seen in uli.49 In contrast, once a fully predicted reward sud- depression.26,29,30,35 denly fails to occur, the DA neurons are depressed in Lesions of the ventromedial PFC also alter parasym- their activity at precisely the time when the reward had pathetic autonomic function in rats in a manner that previously been expected to occur. Thus DA neurons shows an intriguing parallel with autonomic abnor- appear to participate in encoding information regard- malities reported in humans with MDD. Frysztak and ing the stimuli that predict reward and the deviation Neafsey32 found that rats with lesions of the prelimbic between this prediction and the actual occurrence of and infralimbic cortex show reduced beat-to-beat varia- reward.49 The evidence that the subgenual PFC may bility of the heart rate both at rest and during exposure modulate the electrophysiological responses of VTA to fear-conditioned stimuli. Heart rate variability DA neurons suggests that this cortex also participates (HRV) putatively reflects parasympathetic control of in evaluating the reward-related significance of stimuli. the sinus node via vagal nerve transmission.36,37 Since Such a role would provide a neural mechanism by the area corresponding to the subgenual PFC contains which subgenual PFC dysfunction could alter hedonic neurons that project to the nucleus tractus solitarius perceptions and motivated behavior in mood dis- (NTS) of the vagus nerve,22 it is possible that ventro- orders. The PET imaging evidence that glucose metab- medial PFC lesions which disrupt these projections olism in the subgenual PFC is abnormally decreased in reduce parasympathetic tone, resulting in blunted the depressed but increased in the manic phase of HRV. bipolar disorder1 suggests the following hypothesis. In In considering the effects of ventromedial PFC depression reduced subgenual PFC activity is associa- Neuroimaging abnormalities in the subgenual PFC WC Drevets et al 225 ted with diminished stimulation of mesolimbic DA and the mechanisms of antidepressant or antimanic release, resulting in the absence of behavioral incen- treatments. Finally, while the available analyses of tive, apathy and anhedonia, whereas in mania lesions that encompassed the subgenual PFC in rats increased subgenual PFC activity results in excessive and humans examined lesions that would have also stimulation of mesolimbic DA release, manifested by affected the surrounding cortex, their results neverthe- exaggerated hedonic responses and press of occu- less implicate this region as a site where dysfunction pation.50,51 This hypothesis is compatible with pharma- could conceivably result in the emotional, autonomic, cological evidence that antidepressant drugs enhance neuroendocrine, and behavioral manifestations of mesolimbic dopamine receptor sensitivity and increase depression and mania. interstitial DA concentrations in the medial PFC, that DA receptor antagonists and DA synthesis inhibitors References have antimanic effects, and that mania can be precipi- tated (in euthymic or depressed bipolar patients) by DA 1 Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M 50,52,53 et al. 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