Role of the Primate Orbitofrontal Cortex in Mediating Anxious Temperament

Department of Psychiatry, University of Wisconsin Medical School, Madison, Wisconsin 53719-1176, USA.
Biological Psychiatry (Impact Factor: 10.26). 12/2007; 62(10):1134-9. DOI: 10.1016/j.biopsych.2007.04.004
Source: PubMed


Excessive behavioral inhibition during childhood marks anxious temperament and is a risk factor for the development of anxiety and affective disorders. Studies in nonhuman primates can provide important information related to the expression of this risk factor, since threat-induced freezing in rhesus monkeys is a trait-like characteristic analogous to human behavioral inhibition. The orbitofrontal cortex (OFC) and amygdala are part of a circuit involved in the processing of emotions and associated physiological responses. Earlier work demonstrated involvement of the primate central nucleus of the amygdala (CeA) in mediating anxious temperament. This study assessed the role of the primate OFC in mediating anxious temperament and its involvement in fear responses.
Twelve adolescent rhesus monkeys were studied (six lesion and six control monkeys). Lesions were targeted at regions of the OFC that are most interconnected with the amygdala. Behavior and physiological parameters were assessed before and after the lesions.
The OFC lesions significantly decreased threat-induced freezing and marginally decreased fearful responses to a snake. The lesions also resulted in a leftward shift in frontal brain electrical activity consistent with a reduction in anxiety. The lesions did not significantly decrease hypothalamic-pituitary-adrenal (HPA) activity or cerebrospinal fluid (CSF) concentrations of corticotrophin-releasing factor (CRF).
These findings demonstrate a role for the OFC in mediating anxious temperament and fear-related responses in adolescent primates. Because of the similarities between rhesus monkey threat-induced freezing and childhood behavioral inhibition, these findings are relevant to understanding mechanisms underlying anxious temperament in humans.

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    • "OFC receives direct reciprocal connections from the amygdala19 which has been revealed to play an important role in neuroanatomical pathways for panic disorder and so they may be working together to mediate anxiety. It has been demonstrated that OFC mediates anxiety behavior and perception in child and adolescent primates19 and is involved in emotional processing20 as much the most important clinical aspect of panic disorder, anxiety and fear are associated with the function of the amygdala and fear sensation is stored in the hippocampus itself. Given its association with anxiety modulating role both behaviorally and perceptionally of OFC itself, our finding demonstrating that panic patients had significantly smaller left and right OFC volumes compared with healthy controls may be related to the pathogenesis of panic disorder. "
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    ABSTRACT: Given the association between the pathophysiology of panic disorder and prefrontal cortex function, we aimed to perform a volumetric MRI study in patients with panic disorder and healthy controls focusing on the in vivo neuroanatomy of the OFC. Twenty right-handed patients with panic disorder and 20 right-handed healthy control subjects were studied. The volumes of whole brain, total white and gray matters, and OFC were measured by using T1-weighted coronal MRI images, with 1.5-mm-thick slices, at 1.5T. In addition, for psychological valuation, Hamilton Depression Rating (HDRS) and Panic Agoraphobia Scales (PAS) were administered. Unadjusted mean volumes of the whole brain volume, total white and gray matter were not different between the patients and healthy controls while the patient group had significantly smaller left (t=-6.70, p<0.0001) and right (t=-5.86, p<0.0001) OFC volumes compared with healthy controls. Our findings indicate an alteration of OFC morphology in the panic disorder and suggest that OFC abnormalities may be involved in the pathophysiology of panic disorder.
    Psychiatry investigation 12/2012; 9(4):408-12. DOI:10.4306/pi.2012.9.4.408 · 1.28 Impact Factor
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    • "The rhesus macaque has emerged as an excellent model for HPA axis dysregulation studies, owing to the similar neuroanatomical, behavioral and genetic features shared with humans (Geyer et al. 2000; Gibbs et al. 2007; Kalin et al. 2007; Schwandt et al. 2010). The rhesus macaque genome also includes common polymorphisms that are orthologous to human gene variants implicated in HPA axis regulation, including rh5-HTTLPR (Bennett et al. 2002), rhMAOA-LPR (Newman et al. 2005; Wendland et al. 2006), and rhOPRM1 C77G, which is functionally similar to the human OPRM1 A118G variant (Miller et al. 2004). "
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    ABSTRACT: Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis pathway is associated with several neuropsychiatric disorders, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia and alcohol abuse. Studies have demonstrated an association between HPA axis dysfunction and gene variants within the cortisol, serotonin and opioid signaling pathways. We characterized polymorphisms in genes linked to these three neurotransmitter pathways and tested their potential interactions with HPA axis activity, as measured by dexamethasone (DEX) suppression response. We determined the percent DEX suppression of adrenocorticotropic hormone (ACTH) and cortisol in 62 unrelated, male rhesus macaques. While DEX suppression of cortisol was robust amongst 87% of the subjects, ACTH suppression levels were broadly distributed from −21% to 66%. Thirty-seven monkeys from the high and low ends of the ACTH suppression distribution (18 ‘high’ and 19 ‘low’ animals) were genotyped at selected polymorphisms in five unlinked genes (rhCRH, rhTPH2, rhMAOA, rhSLC6A4 and rhOPRM). Associations were identified between three variants (rhCRH-2610C>T, rhTPH2 2051A>C and rh5-HTTLPR) and level of DEX suppression of ACTH. In addition, a significant additive effect of the ‘risk’ genotypes from these three loci was detected, with an increasing number of ‘risk’ genotypes associated with a blunted ACTH response (P = 0.0009). These findings suggest that assessment of multiple risk alleles in serotonin and cortisol signaling pathway genes may better predict risk for HPA axis dysregulation and associated psychiatric disorders than the evaluation of single gene variants alone.
    Genes Brain and Behavior 11/2012; 11(8). DOI:10.1111/j.1601-183X.2012.00856.x · 3.66 Impact Factor
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    • "Increased glucose metabolism in the OFC has been reported previously in rhesus monkeys using similar PET- FDG approaches in response to relocation and threat stress (Kalin et al., 2008). Moreover, lesions of the OFC in monkeys reduces fear-related behaviors (Kalin et al., 2007), supporting our interpretation that the greater OFC activation detected in our ELS monkeys may reflect elevated stress reactivity, although these physiological measures showed no overall group differences. "
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    ABSTRACT: Early life stress (ELS) is a risk factor for anxiety, mood disorders and alterations in stress responses. Less is known about the long-term neurobiological impact of ELS. We used [(18)F]-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) to assess neural responses to a moderate stress test in adult monkeys that experienced ELS as infants. Both groups of monkeys showed hypothalamic-pituitary-adrenal (HPA) axis stress-induced activations and cardiac arousal in response to the stressor. A whole brain analysis detected significantly greater regional cerebral glucose metabolism (rCGM) in superior temporal sulcus, putamen, thalamus, and inferotemporal cortex of ELS animals compared to controls. Region of interest (ROI) analyses performed in areas identified as vulnerable to ELS showed greater activity in the orbitofrontal cortex of ELS compared to control monkeys, but greater hippocampal activity in the control compared to ELS monkeys. Together, these results suggest hyperactivity in emotional and sensory processing regions of adult monkeys with ELS, and greater activity in stress-regulatory areas in the controls. Despite these neural responses, no group differences were detected in neuroendocrine, autonomic or behavioral responses, except for a trend towards increased stillness in the ELS monkeys. Together, these data suggest hypervigilance in the ELS monkeys in the absence of immediate danger.
    06/2012; 2(1):181-93. DOI:10.1016/j.dcn.2011.09.003
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