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In the latest edition of our series of neuroanatomical areas of importance for neuropsychiatry, Wayne Drevets, MD, and Jonathan Savitz, PhD, have outlined the clinical importance of the ventral anterior cingulate structures for the regulation of mood. This area was an early target for interventional neurosurgery for depression some half a century ago, and today has become one of the key sites of deep brain stimulation for affective disorders. The anterior cingulate cortex was a part of the initial circuit of Papez thought to be related to the regulation of emotion. However, since then, much experimental work has outlined different cingulate regions with differing anatomical connectivity and functions. Drevets and Savitz draw attention to the subgenual area and describe the local and distant anatomical connectivities that emphasize its relevance for several neuropsychiatric disorders.
The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this “subgenual” ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended “visceromotor network” of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.
The ventral anterior cingulate cortex (ACC) increasingly has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a neuroimaging study of mood disorders,1 it was discovered that this region’s gray matter volume was abnormally reduced in familial bipolar disorder and major depressive disorder (MDD). The magnetic resonance imaging- (MRI) based morphometric measures acquired to demonstrate this abnormality were guided by positron emission tomography (PET) images showing an abnormal reduction of cerebral blood flow (CBF) and glucose metabolism in the prefrontal cortex (PFC) ventral to the corpus callosum genu (ie, “subgenual”) in depression (Figure 1).1 Voxel-by-voxel analyses of neurophysiological data from independent depressed samples versus controls localized the peak difference in activity more specifically to the subgenual ACC (sgACC). Because antidepressant treatment did not reverse these physiological abnormalities, MRI measures of gray matter volume of the sgACC were obtained to determine whether the decrements in regional CBF and metabolism might be accounted for by a corresponding reduction in cortex.2 This hypothesis was confirmed, as the mean gray matter volume of the left sgACC was reduced in bipolar disorder and MDD compared with healthy control samples.1
In pursuing the nature of these neuroimaging abnormalities, Ongür and colleagues3 undertook postmortem assessments of brain tissue taken from the sgACC of subjects diagnosed as having bipolar disorder, MDD, schizophrenia, or no psychiatric disorder. The sgACC implicated by the neuroimaging data consisted of Brodmann area (BA) 24b and, to a lesser extent, BA 24a anteriorly, and area 25 posteriorly (Figure 2).4 Although the PET data showed that the posterior and anterior sgACC were affected, the peak difference between groups localized to the anterior sgACC. Thus, initial histopathological assessments targeted the section of BA 24 located ventral and posterior to the corpus callosum genu (Figure 3). These assessments confirmed the reduction in mean sgACC gray matter volume in bipolar disorder and MDD versus healthy controls, and associated this deficit with a reduction in glia and no equivalent loss of neurons.3 The neuronal density appeared increased, as would be expected in association with a reduction in neuropil (moss-like layer of gray matter containing axons and dendrites that occupies most of the cortex volume).
Other studies have shown that this volumetric reduction existed early in the illness course of MDD and bipolar disorder5,6 and was also evident in young adults at high familial risk for MDD7,8 Furthermore, this abnormality persisted during antidepressant treatment and was present in the manic and depressed phases of bipolar disorder.1 The volumetric deficit applied to males8,9 and females,5 to psychotic unipolar and bipolar depression,6,10,11 and to bipolar-spectrum illness.12
The variability of the volumetric measures of gray matter volume in the sgACC across subjects was high, the ranges of values in ill and normative groups overlapped substantially, and not all studies replicated these findings (Tables 1–4). Such variability is typical of neurobiological data acquired from mood disordered samples, partly because MDD and bipolar disorder appear heterogenous with respect to etiology, and studies generally find that subsets, rather than entire samples, of subjects meeting criteria for these disorders manifest biological markers for affective disease. For example, elderly MDD subjects with late-onset depression show an increased prevalence of neuroimaging correlates of cerebrovascular disease, including nonspecific signs of atrophy, but did not show evidence of focal reductions.7 Research by Drevets and colleagues13 limited the sample selection to early-onset MDD and bipolar disorder cases, who have shown volumetric abnormalities that are localized more specifically to some PFC and temporal lobe structures.
In unipolar depressives, to further enhance the sensitivity for identifying neurobiological markers for affective illness, Drevets and colleagues1 initially selected cases according to criteria for “familial pure depressive disease,” a condition defined by having an MDD subject with a first-degree relative with MDD, but no first-degree relative with mania, alcoholism, or sociopathy.21 In contrast to MDD samples with familial pure depressive disease or familial bipolar disorder, subjects who met criteria for depression spectrum disease (MDD subjects who have a first-degree relative with alcoholism or sociopathy21 did not differ significantly from healthy controls with respect to the mean sgACC glucose metabolism29 or volume) (J. Savitz, PhD, et al, unpublished data, 2008).
Drevets and colleagues1 also enhanced the likelihood of identifying biological markers in bipolar disorder by selecting subjects who had first-degree relatives with bipolar disorder. The extent to which the neuroimaging abnormalities in the sgACC also extend to non-familial cases, thus, remained unclear. An MRI study from an independent laboratory6 found that the mean sgACC gray matter volume (defined using the same anatomical landmarks we used) was reduced significantly versus controls in bipolar disorder subjects with mood disordered first-degree relatives, but not in bipolar disorder subjects without mood disordered first-degree relatives. Consistent with these data, McDonald and colleagues42 showed that reduced volume of a right “perigenual” ACC region that included both the sgACC and the ACC situated anterior to the corpus callosum genu (ie, “pregenual”; pgACC) was associated with increasing genetic risk for bipolar disorder (based upon the numbers of affected relatives). Boes and colleagues8 found that the left pgACC (sgACC plus pgACC) volume was smaller in boys with sub-clinical depressive symptoms, and that the negative correlation between left sgACC volume and depression symptoms was particularly robust in boys with a family history of depression.
In more recent research, morphometric MRI studies4 divided this region into anterior and posterior sgACC regions, which corresponded approximately to BAs 24 and 25, respectively (Figure 2). The posterior sgACC appears homologous with the infralimbic cortex (BA 25) of the rodent and monkey on the basis of cytoarchitectonic and connectional features.4 The posterior sgACC volume was reduced in MDD cases with psychotic features, but not in a psychiatric control group with schizophrenia.10 Only the MDD group showed an increase in posterior sgACC gray matter after a 2-year follow-up period (of naturalistic treatment). For the MDD subjects, but not for the subjects with schizophrenia, the Global Assessment Scale scores during follow-up correlated positively with cortical depth at baseline and with volume increases during follow-up. Thus, the volumetric abnormalities in this region may predict and reflect the course of depressive illness.
The finding that the posterior sgACC volume may increase in association with prolonged clinical improvement is noteworthy based upon cross-sectional studies (Neumeister et al, unpublished data, 2008) of MDD cases studied during long-term remission. Despite the finding that the sgACC volume deficit in MDD showed no significant change during antidepressant treatment for a mean of 4 months,36 subjects with a history of MDD who were selected for their capacity to remain in remission while unmedicated for at least 3 months (and a mean of several years) showed sgACC volumes that were significantly higher than those of controls. These cross-sectional data did not allow determination of whether such subjects had manifested reduced sgACC volume during depression that then had increased during prolonged remission, or whether these subjects were instead resilient to the pathophysiologcal process that led to the reduction in sgACC volume during MDD. Longitudinal studies are needed to elucidate this issue, but the possibility that such individuals possess (a) resilience factor(s) that allows them to recover from major depressive episodes without the development of chronic illness would hold great potential clinical importance in mood disorders research.
However, chronic lithium treatment, which exerts robust neurotrophic effects in animal models, has been associated with increasing gray matter volume toward normal in treatment responders in the sgACC and other PFC areas (Figure 3).50
Partly compatible with these data, Bearden and colleagues47 reported that the volumes of the left ACC, including of the sgACC, were greater in lithium-treated bipolar disorder subjects than both healthy controls and bipolar disorder subjects not receiving lithium. In magnetic resonance spectroscopy studies of bipolar disorder, chronic lithium treatment also was associated with increased concentrations of N-acetyl-aspartate (NAA), a marker of neuronal integrity.52
Most neuroimaging studies have not identified significant differences between mood disordered and healthy control groups in the volumes of the whole brain, although several groups have reported gray matter loss in other portions of anterior or posterior cingulate cortex.62 In the ACC, abnormalities in CBF/metabolism, tissue volume, and glial cells have been demonstrated in the ACC situated anterior to the corpus callosum genu (ie, pgACC}. This region includes portions of BAs 24 and 32, an area that also forms an integral part of the ventral “emotion” circuit implicated in affective illness.63
The sgACC shares similarities with the pgACC area situated immediately adjacent to the sgACC, such that distinctions of the cortex at the actual sgACC/pgACC interface seem arbitrary. The anterior sgACC and the adjacent ventral pgACC both are cytoarchitectonically BA 24 (Figure 4), and they share similar anatomical connectivity.4 Moreover, the abnormal reductions of glia in MDD extend to the pgACC (BA 24)64 as well as to the orbitofrontal and dorsal anterolateral PFC (BA 9)65–67 and the amygdala.68,69 Hence, the term “perigenual” ACC is often applied to the ACC near the genu, and for comparison we listed findings in the pgACC together with those in the adjacent sgACC in Tables 1–4.
Nevertheless, the functions of the anterior sgACC and more dorsal regions of the pgACC appear distinct with respect to some neuroimaging studies of emotional behavior. The tissue near the sgACC/pgACC junction shows increased hemodynamic activity during a variety of emotional-behavioral tasks, including tasks involving sadness induction70,71; exposure to traumatic reminders72; selecting sad or happy targets in an emotional go-no-go study73; monitoring of internal states in individuals with attachment avoidant personality styles74; and extinction learning to previously fear-conditioned stimuli.75 These findings suggest in humans roles the ACC in the automatic regulation of emotional behavior. In contrast, more dorsal regions of the pgACC show physiological responses to more diverse types of emotionally valenced or autonomically arousing stimuli.76–78 In mood disorders, the sgACC activity frequently has been shown to correlate positively with the severity of depressive symptoms,79 whereas the pgACC activity has more consistently been linked to treatment outcome.80
The reduction in resting sgACC CBF and metabolism that we initially observed in depressed bipolar disorder and MDD subjects has been replicated by other studies of MDD20,26,38 and bipolar disorder (Tables 1 and and22).24,37–39 These findings also were extended by data showing that metabolic reductions predate the onset of clinical symptoms, as Kumano and colleagues31 found that cancer patients who went on to develop depression had lower baseline metabolic rates of the sgACC compared with cancer controls who did not become depressed. However, other studies reported increased metabolic activity in the sgACC in primary15,16,19,28,30,41,45,81 or secondary depression.82
These apparently discrepant results may be explained by the interrelationships between deficits in gray matter volume and physiological imaging data. The reduction in sgACC volume is sufficiently prominent (ranging in magnitude from 15% to 50% across positive studies [Tables 3 and and4])4]) to produce partial volume effects in functional brain images due to their relatively low spatial resolution. Therefore, although relative to controls, the depressed MDD and bipolar disorder subjects showed metabolic activity that appeared reduced in the sgACC,1 when this volumetric deficit was taken into account by correcting the metabolic data for the partial volume averaging effect associated with the corresponding gray matter reduction, metabolism instead appeared increased in the sgACC in the unmedicated-depressed phase and normal in the medicated-remitted phase.83
Consistent with the conclusions of these partial volume corrections, researchers consistently show that the sgACC metabolism is elevated in the depressed phase relative to the remitted phase of the same MDD subjects. For example, in studies of remitted MDD subjects, the sgACC metabolism increases during depressive relapse induced during either tryptophan depletion84 or catecholamine depletion.85 Moreover, the sgACC metabolism decreases during effective antide-pressant treatment. For example, Drevets and colleagues,1 Drevets and colleagues,38 Holthoff and colleagues,25 and Mayberg and colleagues16 reported a remission-associated decrease in the activity of this region during antidepressant treatment, Nobler and colleagues86 obtained analogous results after ECT administration, and Mayberg and colleagues28 showed that CBF decreased in the sgACC and other ventromedial PFC regions during improvement associated with deep brain stimulation of the sgACC. Also consistent with these data, several studies have shown that in MDD the depression severity correlates positively with blood flow or metabolism in the sgACC79 compatible with evidence that blood flow increases in the sgACC in healthy humans during experimentally induced sadness.70,71
Finally, the abnormal elevation of sgACC metabolism that Mah and colleagues43 and others39 observed in depressed bipolar disorder subjects were limited to cases who were medicated chronically with lithium or divalproex. Chronic lithium treatment resulted in increased gray matter volume in the sgACC (Figure 3),3 consistent with evidence from preclinical studies87 indicating that lithium and divalproex exert neurotrophic and neuroprotective effects in the frontal cortex of experimental animals. If the increase in sgACC tissue is sufficient to reduce the partial volume averaging effect in PET images, then metabolic activity would be imaged as being elevated in such depressed subjects versus controls (Table 5), Longitudinal imaging studies acquired both pre- and post-mood stabilizer therapy are needed to characterize relationships between volume and metabolism.
Although it remains unclear whether they reflect a neurodevelopmental abnormality or an acquired effect of recurrent illness, it is noteworthy that in regions that appear homologous to areas where gray matter reductions are evident in depressed humans (ie, medial PFC, hippocampus), repeated stress results in dendritic atrophy and reductions in glial cells in rodents.88–92 Dendritic atrophy putatively would be reflected by a decrease the volume of the neuropil. These data suggest that impaired emotion regulation may contribute to the volumetric abnormalities found in these structures in MDD, by permitting stress responses that are exaggerated in magnitude or duration.92 Such changes could, in turn, exacerbate the emotion dysregulation associated with bipolar disorder, as in rodents dendritic atrophy arising in the medial PFC during repeated stress resulted in impaired modulation (ie, extinction) of behavioral responses to fear-conditioned stimuli.91 Notably, when rats were subjected to repeated stress, the dendritic atrophy could be reversed by lithium administration,90 resembling the effects of lithium on the gray matter reductions in bipolar disorder (Figure 3).
The stress-induced dendritic remodeling process depends upon interactions between the increased N/-methyl-D-aspartate receptor stimulation and glucocorticoid secretion associated with repeated stress.92 The depressive subtypes (eg, bipolar disorder, familial pure depressive disease) who show regional reductions in gray matter volume also show evidence of increased cortisol secretion during stress94 and glutamatergic transmission (eg, elevated glucose metabolism predominantly reflects corresponding increases in glutamatergic transmission.95 Notably, impaired sgACC function in mood disorders may conceivably contribute to cortisol hypersecretion in depression.96 Diorio and colleagues97 showed that glucocorticoid receptors expressed in the ventral ACC play a major role in the negative feedback effect of glucocorticoid secretion during stress, and that lesions of the prelimbic and infralimbic portions of the ACC increase the adrenocorticotropic hormone and corticosterone (CORT) responses to restraint stress. Conversely, CORT implants in these regions decreased the adrenocorticotropic hormone and CORT responses to restraint stress.
Another potential predisposition for undergoing excessive remodeling in the sgACC may be the “short” allele of the serotonin transporter promoter length polymorphism. This polymorphism was associated with reduced gray matter in the sgACC, reduced functional connectivity between the amygdala and the sgACC, and higher temperamental anxiety in otherwise healthy s-carriers.97 Conceivably, this effect may prove maladaptive under severe stress, potentially underlying the increased risk the s-allele confers for developing depression within the context of stress.98
The sgACC shares substantial, predominantly ipsilateral anatomical connections with the amygdala and subiculum, and it is possible that the left-lateralized volumetric reductions in these structures are related. In the amygdala, left-lateralized reductions in glia have been demonstrated in MDD,68,69 although the literature disagrees about the direction and existence of volumetric changes in mood disorders. In the hippocampus, MDD subjects showed greater decrements in volume following fixation (implying a deficit in the neuropil),99 while, more specifically, in the hippocampal subiculum/ventral CA1 region, bipolar disorder subjects had reductions in synapses and synaptic proteins100,101 and left-lateralized reductions in gray matter102 compared with controls.
The sgACC also projects to the ventromedial striatum and the accumbens area,4 which were reported to be abnormally small in a postmortem volumetric study of mood disorders,103 and to the periventricular and mediodorsal nuclei of the thalamus that line the third ventricle wall. Although, third ventricle enlargement is consistently found in bipolar disorder, the specific tissue where volume loss resulted in ex vaccuo changes in third ventricle size has remained unclear.7,13 Nevertheless, taken together, these data suggest that mood disorders are associated with a neuropathological process affecting circuits that involve the sgACC together with anatomically related parts of the orbitomedial PFC, amygdala, hippocampus, striatum, and thalamus.
In monkeys and other experimental animals, the putatively homologous cortex to the sgACC shares extensive anatomical connections with the amygdala; subiculum; hypothalamus; accumbens; ventral tegmental area (VTA); substantia nigra; raphe; locus ceruleus; periaqueductal gray and brainstem autonomic nuclei; and other areas of the orbitomedial PFC.4,76 These structures are implicated in the modulation of emotional behavior, raising the possibility that abnormal synaptic interactions between these areas and the sgACC may contribute to disturbances in emotional processing or regulation.3
Rats with bilateral lesions of the ACC and dorsal prelimbic cortex show exaggerated freezing behavior and heart rate increases during exposure to fear-conditioned sensory and/or contextual stimuli.104,105 In contrast, bilateral lesions involving the infralimbic and the ventral prelimbic cortices result in reduced heart rate responses to fear-conditioned stimuli.105 Sullivan and Gratton106 more specifically showed that rats with lesions involving the left infralimbic, prelimbic, and anterior cingulate cortices demonstrated heightened sympathetic autonomic arousal and exaggerated CORT responses to restraint stress relative both to control animals and to animals with right-sided lesions of the same areas. In contrast, right-lesioned animals showed attenuation of the CORT rise and the autonomically mediated gastric stress pathology associated with restraint stress. From these data, Sullivan and Grattan106 concluded that left ventromedial PFC lesions disinhibit the function of the right ventromedial PFC, which mediates the heightened sympathetic autonomic, affective, and hypothalamic-pituitary-adrenal axis arousal seen in the left-lesioned animals. In mood disorders, an altered balance between left and right sgACC function conceivably may contribute to the heightened affective, neuroendocrine, and sympathetic autonomic arousal seen in depression.
For example, depression has been associated with a reduction in the parasympathetic-to-sympathetic tone that is hypothesized to contribute to the elevated risks for developing ventricular tachycardia, myocardial infarction, and sudden death in depressed patients with cardiovascular disease.107 The extensive interconnections between the posterior sgACC (BA 25) and the nucleus tractus solitarious of the vagus nerve that mediate parasympathetic function led to this region initially being termed “visceromotor cortex.”105 The anterior sgACC and pgACC share more prominent projections with the PAG columns that mediate sympathetic autonomic expression.108 Lesions of the ventromedial PFC also alter parasympathetic autonomic function in rats in a manner that shows an intriguing parallel with autonomic abnormalities reported in humans with MDD.105 Together, these data suggest the hypothesis that dysfunction of the sgACC results in understimulation of parasympathetic tone in mood disorders.
Humans with lesions that include the sgACC demonstrate abnormal autonomic responses to emotional experiences, inability to experience emotion related to concepts that ordinarily evoke emotion, and inability to use information regarding the likelihood of punishment versus reward in guiding social behavior.109 Based partly upon these observations110 proposed that the ability to evaluate the consequences of social behavior depends upon visceral feedback mediated through interactions between the ventromedial PFC, hypothalamic autonomic centers, and brain-stem monoaminergic neurotransmitter systems. Although the ventromedial PFC lesions under consideration affected such a large region that it was not possible to draw specific conclusions regarding the sgACC from such cases, these observations, combined with the known connectivity of the sgACC, suggest the hypothesis that pathological modulation of visceral feedback may underlie the oversensitivity to failure and pathological guilt in depression and the insensitivity to the negative outcome of pleasurable or violent behavior in mania.
Finally, the role of the ventral ACC in modulating the electrophysiological responses of VTA dopamine neurons suggests this cortex may also participate in evaluating the salience of rewards. Of the PFC areas that receive dopaminergic inputs, BA 24 of the ACC receives the most dense dopamine innervation (principally from the VTA), and in rats, electrical or glutamatergic stimulation of ventral ACC elicits burst-firing patterns of dopaminergic cells in the VTA and dopamine release in the nucleus accumbens.76 The phasic, burst firing of dopamine neurons and accompanying rise in dopamine release normally occur in response to primary rewards and reward-predicting stimuli.111 The findings that glucose metabolism in the sgACC is abnormally decreased in the depressed but increased in the manic phases of bipolar disorder1 suggests the hypothesis that, in depression, reduced sgACC activity is associated with diminished stimulation of mesolimbic dopamine release, resulting in the absence of behavioral incentive, apathy, and anhedonia, whereas in mania increased sgACC activity results in excessive stimulation of mesolimbic dopamine release, manifested by exaggerated hedonic responses and elevated motivational drive.76
Neuroimaging, neuropathological, and lesion analysis data implicate an extended anatomical network formed by the neural projections of the sgACC and other areas of the orbitomedial PFC with the amygdala; hippocampus; superior and medial temporal gyri; ventral striatum; mid- and posterior cingulate cortex; thalamus; hypothalamus; periaqueductal gray; and habenula,4 in the regulation of the evaluative, expressive, and experiential aspects of emotion.55 Impaired function within this network could conceivably dys-regulate emotional expression and experience, conceivably giving rise to the clinical signs and symptoms of depression or mania.7 CNS
Disclosures: Drs. Drevets, Savitz, and Trimble do not have an affiliation with or financial interest in any organization that might pose a conflict of interest.