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Aberrant activity in caudal subcallosal anterior cingulate cortex (scACC) is implicated in depression and anxiety symptomatology, with its normalisation a putative biomarker of successful treatment response. The function of scACC in emotion processing and mental health is not fully understood despite its known influence on stress-mediated processes through its rich expression of mineralocorticoid and glucocorticoid receptors. Here we examine the causal interaction between area 25 within scACC (scACC-25) and the stress hormone, cortisol, in the context of anhedonia and anxiety-like behaviour. In addition, the overall role of scACC-25 in hedonic capacity and motivation is investigated under transient pharmacological inactivation and overactivation. The results suggest that a local increase of cortisol in scACC-25 shows a rapid induction of anticipatory anhedonia and increased responsiveness to uncertain threat. Separate inactivation and overactivation of scACC-25 increased and decreased motivation and hedonic capacity, respectively, likely through different underlying mechanisms. Together, these data show that area scACC-25 has a causal role in consummatory and motivational behaviour and produces rapid responses to the stress hormone cortisol, that mediates anhedonia and anxiety-like behaviour.

• The use of MFB DBS for depression can be efficacious even in those patients who fail DBS at a separate target. • Having both MFB and SCC DBS seems to augment the treatment response in terms of patient-reported HAM-D score. • The increased efficacy of both systems together is likely due to combinatorial targeting of underlying disease networks. [ABSTRACT FROM AUTHOR]

Aberrant activity in caudal subcallosal anterior cingulate cortex (scACC) is implicated in depression and anxiety symptomatology, with its normalisation a putative biomarker of successful treatment response. The function of scACC in emotion processing and mental health is not fully understood despite its known influence on stress-mediated processes through its rich expression of mineralocorticoid and glucocorticoid receptors. Here we examine the causal interaction between area 25 within scACC (scACC-25) and the stress hormone, cortisol, in the context of anhedonia and anxiety-like behaviour. In addition, the overall role of scACC-25 in hedonic capacity and motivation is investigated under transient pharmacological inactivation and overactivation. The results suggest that a local increase of cortisol in scACC-25 shows a rapid induction of anticipatory anhedonia and increased responsiveness to uncertain threat. Separate inactivation and overactivation of scACC-25 increased and decreased motivation and hedonic capacity, respectively, likely through different underlying mechanisms. Together, these data show that area scACC-25 has a causal role in consummatory and motivational behaviour and produces rapid responses to the stress hormone cortisol, that mediates anhedonia and anxiety-like behaviour., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

High-trait anxiety is a risk factor for the development of affective disorders and has been associated with decreased cardiovascular and behavioral responsivity to acute stressors in humans that may increase the risk of developing cardiovascular disease. Although human neuroimaging studies of high-trait anxiety reveals dysregulation in primate cingulate areas 25 and 32 and the anterior hippocampus (aHipp) and rodent studies reveal the importance of aHipp glutamatergic hypofunction, the causal involvement of aHipp glutamate and its interaction with these areas in the primate brain is unknown. Accordingly, we correlated marmoset trait anxiety scores to their postmortem aHipp glutamate levels and showed that low glutamate in the right aHipp is associated with high-trait anxiety in marmosets. Moreover, pharmacologically increasing aHipp glutamate reduced anxiety levels in highly anxious marmosets in two uncertainty-based tests of anxiety: exposure to a human intruder with uncertain intent and unpredictable loud noise. In the human intruder test, increasing aHipp glutamate decreased anxiety by increasing approach to the intruder. In the unpredictable threat test, animals showed blunted behavioral and cardiovascular responsivity after control infusions, which was normalized by increasing aHipp glutamate. However, this aHipp-mediated anxiolytic effect was blocked by simultaneous pharmacological inactivation of area 25, but not area 32, areas which when inactivated independently reduced and had no effect on anxiety, respectively. These findings provide causal evidence in male and female primates that aHipp glutamatergic hypofunction and its regulation by area 25 contribute to the behavioral and cardiovascular symptoms of endogenous high-trait anxiety. [ABSTRACT FROM AUTHOR]

Subcallosal area 25 is one of the least understood regions of the anterior cingulate cortex, but activity in this area is emerging as a crucial correlate of mood and affective disorder symptomatology. The cortical and subcortical connectivity of area 25 suggests it may act as an interface between the bioregulatory and emotional states that are aberrant in disorders such as depression. However, evidence for such a role is limited because of uncertainty over the functional homologue of area 25 in rodents, which hinders cross-species translation. This emphasizes the need for causal manipulations in monkeys in which area 25, and the prefrontal and cingulate regions in which it is embedded, resemble those of humans more than rodents. In this review, we consider physiological and behavioral evidence from non-pathological and pathological studies in humans and from manipulations of area 25 in monkeys and its putative homologue, the infralimbic cortex (IL), in rodents. We highlight the similarities between area 25 function in monkeys and IL function in rodents with respect to the regulation of reward-driven responses, but also the apparent inconsistencies in the regulation of threat responses, not only between the rodent and monkey literatures, but also within the rodent literature. Overall, we provide evidence for a causal role of area 25 in both the enhanced negative affect and decreased positive affect that is characteristic of affective disorders, and the cardiovascular and endocrine perturbations that accompany these mood changes. We end with a brief consideration of how future studies should be tailored to best translate these findings into the clinic.

The medial prefrontal areas 32, 24, 14, and 25 (mPFC) form part of the limbic memory system, but little is known about their functional specialization in humans. To add anatomical precision to structural and functional magnetic resonance imaging (MRI) data, we aimed to identify these mPFC subareas in histological preparations of human brain tissue, determine sulci most consistently related with mPFC areal boundaries, and use these sulci to delineate mPFC areas in MRIs. To achieve this, we obtained three-dimensional MRI data from 11 ex vivo hemispheres and processed them for cyto- and myelo-architectonic analysis. The architectonic boundaries of mPFC areas were identified in histology and cortical surface length and volumes were measured. Unfolded maps of histologically determined boundaries were generated to identify the association of mPFC areal boundaries with sulci across cases. This analysis showed that cingulate and superior rostral were the sulci most consistently related to mPFC areal boundaries. Based on presence/absence and anastomosis between such sulci, 6 sulci patterns in the 11 hemispheres were found. A further analysis of 102 hemispheres of in vivo MRI scans ( N = 51 males, mean ± SD 24.1 ± 3.1 years of age) showed similar sulci patterns, which allowed us to delineate the mFPC areas in them. The volumes of mPFC areas across histological, ex vivo and in vivo MRI delineations were comparable and probabilistic maps generated from the MRIs of the102 hemispheres. Probabilistic maps of mPFC areas were registered to MNI space and are available for regional analysis of functional magnetic resonance imaging data. [ABSTRACT FROM AUTHOR]

Fronto-limbic circuits in the primate brain are responsible for executive function, learning and memory, and emotions, including fear. Consequently, changes in gene expression in cortical and subcortical brain regions housing these circuits are associated with many important psychiatric and neurological disorders. While high quality gene expression profiles can be identified in brains from model organisms, primate brains have unique features such as Brodmann Area 25, which is absent in rodents, yet profoundly important in primates, including humans. The potential insights to be gained from studying the human brain are complicated by the fact that the post-mortem interval (PMI) is variable, and most repositories keep solid tissue in the deep frozen state. Consequently, sampling the important medial and internal regions of these brains is difficult. Here we describe a novel method for obtaining discrete regions from the fronto-limbic circuits of a 4 year old and a 5 year old, male, intact, frozen non-human primate (NHP) brain, for which the PMI is exactly known. The method also preserves high quality RNA, from which we use transcriptional profiling and a new algorithm to identify region-exclusive RNA signatures for Area 25 (NFκB and dopamine receptor signaling), the anterior cingulate cortex (LXR/RXR signaling), the amygdala (semaphorin signaling), and the hippocampus (Ca ++ and retinoic acid signaling). The RNA signatures not only reflect function of the different regions, but also include highly expressed RNAs for which function is either poorly understood, or which generate proteins presently lacking annotated functions. We suggest that this new approach will provide a useful strategy for identifying changes in fronto-limbic system biology underlying normal development, aging and disease in the human brain. [ABSTRACT FROM AUTHOR]

The subgenual anterior cingulate cortex (subgenual ACC) plays an important role in regulating emotion, and degeneration in this area correlates with depressed mood and anhedonia. Despite this understanding, it remains unknown how this part of the prefrontal cortex causally contributes to emotion, especially positive emotions. Using Pavlovian conditioning procedures in macaque monkeys, we examined the contribution of the subgenual ACC to autonomic arousal associated with positive emotional events. After such conditioning, autonomic arousal increases in response to cues that predict rewards, and monkeys maintain this heightened state of arousal during an interval before reward delivery. Here we show that although monkeys with lesions of the subgenual ACC show the initial, cue-evoked arousal, they fail to sustain a high level of arousal until the anticipated reward is delivered. Control procedures showed that this impairment did not result from differences in autonomic responses to reward delivery alone, an inability to learn the association between cues and rewards, or to alterations in the light reflex. Our data indicate that the subgenual ACC may contribute to positive affect by sustaining arousal in anticipation of positive emotional events. A failure to maintain positive affect for expected pleasurable events could provide insight into the pathophysiology of psychological disorders in which negative emotions dominate a patient's affective experience. [ABSTRACT FROM AUTHOR]

The infralimbic cortex (ILc) in cat is the ventralmost part of the anterior cingulate gyrus. The ILc, together with the amygdala, bed nucleus of the stria terminalis and lateral hypothalamus, is involved in the regulation of fear behavior. The latter three structures are thought to take part in triggering the fear response by means of their projections to the pontine and medullary lateral tegmental field (LTF). The LTF is a large region extending from the parabrachial nuclei rostrally to the spinal cord caudally. It contains almost all the premotor interneurons for the brainstem and for some upper spinal cord motoneurons innervating the muscles of face, head and throat. The question is whether ILc also projects to the LTF. Such a pathway would allow the ILc to influence the fear response by acting directly on these premotor interneurons. Anterograde tracer injections were made in the medial surface of the cortex in four cats. Only when the injection sites involved ILc were anterogradely labeled fibers observed throughout the rostrocaudal extent of the LTF. To verify whether these projections indeed originated from ILc, in two other cases retrograde tracer injections were made in the pontomedullary LTF. The results showed many retrogradely labeled neurons in ILc, but none in adjacent cortical regions. These results show that the ILc projects to the LTF in cat and can possibly modulate the fear response not only via indirect but also via direct routes to the premotor interneurons in the brainstem. [ABSTRACT FROM AUTHOR]

Summary Anhedonia is a core symptom of depression, but the underlying neurobiological mechanisms are unknown. Correlative neuroimaging studies implicate dysfunction within ventromedial prefrontal cortex, but the causal roles of specific subregions remain unidentified. We addressed these issues by combining intracerebral microinfusions with cardiovascular and behavioral monitoring in marmoset monkeys to show that over-activation of primate subgenual anterior cingulate cortex (sgACC, area 25) blunts appetitive anticipatory, but not consummatory, arousal, whereas manipulations of adjacent perigenual ACC (pgACC, area 32) have no effect. sgACC/25 over-activation also reduces the willingness to work for reward. 18F-FDG PET imaging reveals over-activation induced metabolic changes in circuits involved in reward processing and interoception. Ketamine treatment ameliorates the blunted anticipatory arousal and reverses associated metabolic changes. These results demonstrate a causal role for primate sgACC/25 over-activity in selective aspects of impaired reward processing translationally relevant to anhedonia, and ketamine's modulation of an affective network to exert its action. Highlights • Primate sgACC/25 over-activation blunts reward anticipation, but not consumption • Over-activation of sgACC/25 also blunts willingness to work for reward • Anticipatory blunting involves metabolic changes in reward-related circuits • Acute ketamine reverses blunted anticipatory arousal and metabolic changes Using intracerebral microinfusions in marmosets, Alexander et al. demonstrate a causal role for sgACC/25 over-activity in specific aspects of impaired reward processing associated with anhedonia. Ketamine successfully ameliorates related impairments by modulating activity within a dysfunctional neural circuit involved in reward processing and interoception. [ABSTRACT FROM AUTHOR]

Subcallosal area 25 is one of the least understood regions of the anterior cingulate cortex, but activity in this area is emerging as a crucial correlate of mood and affective disorder symptomatology. The cortical and subcortical connectivity of area 25 suggests it may act as an interface between the bioregulatory and emotional states that are aberrant in disorders such as depression. However, evidence for such a role is limited because of uncertainty over the functional homologue of area 25 in rodents, which hinders cross-species translation. This emphasizes the need for causal manipulations in monkeys in which area 25, and the prefrontal and cingulate regions in which it is embedded, resemble those of humans more than rodents. In this review, we consider physiological and behavioral evidence from non-pathological and pathological studies in humans and from manipulations of area 25 in monkeys and its putative homologue, the infralimbic cortex (IL), in rodents. We highlight the similarities between area 25 function in monkeys and IL function in rodents with respect to the regulation of reward-driven responses, but also the apparent inconsistencies in the regulation of threat responses, not only between the rodent and monkey literatures, but also within the rodent literature. Overall, we provide evidence for a causal role of area 25 in both the enhanced negative affect and decreased positive affect that is characteristic of affective disorders, and the cardiovascular and endocrine perturbations that accompany these mood changes. We end with a brief consideration of how future studies should be tailored to best translate these findings into the clinic.

This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

Gene therapy has become of increasing interest in clinical neurosurgery with the completion of numerous clinical trials for Parkinson disease, Alzheimer disease, and pediatric genetic disorders. With improved understanding of the dysfunctional circuitry mediating various psychiatric disorders, deep brain stimulation for refractory psychiatric diseases is being increasingly explored in human patients. These factors are likely to facilitate development of gene therapy for psychiatric diseases. Because delivery of gene therapy agents would require the same surgical techniques currently being employed for deep brain stimulation, neurosurgeons are likely to lead the development of this field, as has occurred in other areas of clinical gene therapy for neurologic disorders. We review the current state of gene therapy for psychiatric disorders and focus specifically on particular areas of promising research that may translate into human trials for depression, drug addiction, obsessive-compulsive disorder, and schizophrenia. Issues that are relatively unique to psychiatric gene therapy are also discussed. [Copyright &y& Elsevier]

Neuromodulation using deep brain stimulation (DBS) has become an established therapy for the treatment of certain disorders such as Parkinson's disease and tremors. Recent advances in surgical and imaging techniques further decrease the surgical risk associated with these procedures. Symptoms such as tremor, bradykinesia, rigidity and gait disturbances can be significantly controlled with DBS. This results in an opportunity to decrease anti-parkinsonism medications, and their dyskinetic side-effects. Following the success of DBS in the management of movement disorders, the role of this therapy is being extensively studied in more complex disorders that involve cognition and behavior. The inherent complexity in cognitive circuitry makes neuromodulation using DBS more difficult than in movement disorders. The goal of DBS surgery in these diseases is not only to slow the cognitive decline, but also restoration of function and ultimately improvement in the quality of life. DBS as a treatment for patients with advanced dementia holds significant promise in delaying or reversing the progressive cognitive decline by enhancing connectivity in the memory networks. In appropriately selected patients this potentially reversible surgical therapy can lead to a significant improvement in the quality of life and reduce the burden on patients, families and the healthcare system. This review focuses on the recent and future studies involving neuromodulation for cognitive disorders such as Alzheimer's disease and Huntington's disease., (Copyright © 2014 Elsevier Ltd. All rights reserved.)