Richard C. Wolf

Ventromedial Prefrontal Cortex Is Critical for the Regulation of Amygdala Activity in Humans

BACKGROUND Dysfunction in the ventromedial prefrontal cortex (vmPFC) is believed to play a pivotal role in the pathogenesis of mood and anxiety disorders. Leading neurocircuitry models of these disorders propose that hypoactivity in the vmPFC engenders disinhibited activity of the amygdala and, consequently, pathologically elevated levels of negative affect. This model predicts that a selective loss or diminution of function of the vmPFC would result in heightened activity of the amygdala. Although this prediction has been borne out in rodent lesion and electrophysiologic studies using fear conditioning and extinction paradigms, there has not yet been a definitive test of this prediction in humans. METHODS We tested this prediction through a novel use of functional magnetic resonance imaging in four neurosurgical patients with focal, bilateral vmPFC damage. RESULTS Relative to neurologically healthy comparison subjects, the patients with vmPFC lesions exhibited potentiated amygdala responses to aversive images and elevated resting-state amygdala functional connectivity. No comparable group differences were observed for activity in other brain regions. CONCLUSIONS These results provide unique evidence for the critical role of the vmPFC in regulating activity of the amygdala in humans and help elucidate the causal neural interactions that underlie mental illness.

Interpersonal Traits of Psychopathy Linked to Reduced Integrity of the Uncinate Fasciculus

Psychopathy is a personality disorder characterized by callous lack of empathy, impulsive antisocial behavior, and criminal recidivism. Here, we performed the largest diffusion tensor imaging (DTI) study of incarcerated criminal offenders to date (N = 147) to determine whether psychopathy severity is linked to the microstructural integrity of major white matter tracts in the brain. Consistent with the results of previous studies in smaller samples, we found that psychopathy was associated with reduced fractional anisotropy in the right uncinate fasciculus (UF; the major white matter tract connecting ventral frontal and anterior temporal cortices). We found no such association in the left UF or in adjacent frontal or temporal white matter tracts. Moreover, the right UF finding was specifically related to the interpersonal features of psychopathy (glib superficial charm, grandiose sense of self‐worth, pathological lying, manipulativeness), rather than the affective, antisocial, or lifestyle features. These results indicate a neural marker for this key dimension of psychopathic symptomatology. Hum Brain Mapp 36:4202–4209, 2015.

Ventromedial prefrontal cortex mediates visual attention during facial emotion recognition

The ventromedial prefrontal cortex is known to play a crucial role in regulating human social and emotional behaviour, yet the precise mechanisms by which it subserves this broad function remain unclear. Whereas previous neuropsychological studies have largely focused on the role of the ventromedial prefrontal cortex in higher-order deliberative processes related to valuation and decision-making, here we test whether ventromedial prefrontal cortex may also be critical for more basic aspects of orienting attention to socially and emotionally meaningful stimuli. Using eye tracking during a test of facial emotion recognition in a sample of lesion patients, we show that bilateral ventromedial prefrontal cortex damage impairs visual attention to the eye regions of faces, particularly for fearful faces. This finding demonstrates a heretofore unrecognized function of the ventromedial prefrontal cortex-the basic attentional process of controlling eye movements to faces expressing emotion.

Ventromedial Prefrontal Cortex Lesions Alter Neural and Physiological Correlates of Anticipation

Uncertainty is a ubiquitous feature of our daily lives. Although previous studies have identified a number of neural and peripheral physiological changes associated with uncertainty, there are limited data on the causal mechanisms underlying these responses in humans. In this study, we address this empirical gap through a novel application of fMRI in neurosurgical patients with focal, bilateral ventromedial prefrontal cortex (vmPFC) damage. The fMRI task involved cued anticipation of aversive and neutral picture stimuli; “certain” cues unambiguously indicated the upcoming picture valence, whereas “ambiguous” cues could precede either picture type. Healthy subjects exhibited robust bilateral insula responses to ambiguous cues, and this cue-related insula activity significantly correlated with heart rate variability during the task. By contrast, the vmPFC lesion patients exhibited altered cue-related insula activity and reduced heart rate variability. These findings suggest a role for vmPFC in coordinating neural and physiological responses during anticipation.

Urinary Excretion of Progesterone Metabolites in Pregnant Rhesus Monkeys

Summary Ten different steroids were detected in the nonphenolic fraction of pregnant monkey urine. Of these 5β-pregnane-3α-20α-diol, androsterone, DHEA, etiocholanolone, 5β-pregnane-3α-ol,20-one, and 5α-pregnane-3β-ol,20-one were identified. Corroborating evidence that these steroids represent urinary metabolites of progesterone was obtained by analyzing the urine of ovariectomized progesterone-treated rhesus. Both pregnant and injected animals excreted the same metabolites with the exception of one, which was present only in pregnant monkey urine. The excretion of 8 of the 10 steroids increased during the last weeks of pregnancy; however, at no time did 5β-pregnane-3α, 20α-diol represent the major progesterone metabolite. Although the individual pregnanediol levels in eight monkeys were different, the peak value in each monkey was reached 72 to 24 hr before parturition (100 to 900 μg/24 hr), then decreased to trace or nondetectable amounts on the day of parturition, and remained low thereafter.

Circadian Rhythms of Plasma 17-Hydroxycorticosteroids in the Infant Monkey

Summary Plasma 17-hydroxycorticosteroids (17-OHCS) exhibited a significant circadian rhythm in rhesus monkeys (M. mulatta) in the first week of life. In two experiments, plasma 17-OHCS levels averaged 35 μg/100 ml at 8-9:00 am, and declined to levels of 29 μg/100 ml at 9:00 pm (Expt. I) and 24 μg/100 ml at 12:00 midnight (Expt. II). These changes were about half the magnitude reported by others in the adult monkey. Correlated with this steroid rhythm, the infant monkey, although having a polyphasic 24-hr sleep pattern, also exhibited a tendency to sleep more at 1:00 and 3:00 am than at other times of the day. This suggested a relationship between sleep–activity cycles and steroid cycles in the infant monkey similar to that in the adult monkey.

Plasma Cholesterol in Pregnant Rhesus Monkeys.

Summary Plasma concentration of total cholesterol is decreased during pregnancy in rhesus monkeys. The decline is observed within one month following conception and continues until the 12th week of gestation. Plasma cholesterol does not change until one week following parturition when a return to nonpregnant levels is observed. At 3 weeks postpartum cholesterol concentrations are the same as those found prior to conception.

Serum progesterone and corpus luteum function in pregnant pigtailed monkeys (Macaca nemestrina)

Corpus luteum (CL) function and control during pregnancy and early lactation in the pigtailed macaque was investigated. Peripheral concentrations of progesterone (P) on day 10 of pregnancy were 12.98 +/- 2.21 ng/ml and decreased progressively to 7.96 +/- 1.27 ng/ml by day 21 of pregnancy. The concentration of P increased around day 27 of gestation and reached peak levels of 18.48 +/- 2.45 ng/ml on day 37, thereafter gradually decreasing to a nadir at about midgestation. Ten days before parturition P concentrations increased again (P < 0.05). Concentrations of P decreased from 6.62 +/- 1.48 ng/ml on the day of delivery to 2.16 +/- 0.43 ng/ml on day 2 of lactation and remained low thereafter. Ovariectomy on day 35 did not affect the normal course of gestation or the patterns of P secretion during pregnancy. However, in these ovariectomized animals, in spite of suckling, P was not detectable after parturition. In intact monkeys, serum concentrations of P in the utero-ovarian vein at days 80 and 159 of pregnancy were higher relative to the uterine vein. Incubation studies utilizing 3H-cholesterol as a substrate revealed that the CL were capable of synthesizing P on days 35 and 159 of gestation. Histologically, the CL contained active luteal cells at late pregnancy. Low serum concentrations of chorionic gonadotropin were detected on day 10 of gestation; concentrations of this hormone reached high levels between days 18 and 24 and the titers were nondetectable after day 40 of pregnancy. Luteinizing hormone was present in constant amounts in the circulation during pregnancy and lactation. These data suggest that the CL of pregnancy in the pigtailed monkey is functional or capable of functioning during various stages of pregnancy. However, the fetoplacental unit is the primary source of P during the latter 4.5 months of gestation. As in other primates, a functional CL is not required for maintenance of pregnancy after implantation nor for lactation. Thus, the physiological significance of CL function during pregnancy is unclear.

Quantification of 20α- and 20β-dihydroprogesterone in plasma of the pregnant rhesus monkey

Abstract A competitive protein binding assay for 20α- and 20β-dihydroprogesterone is described which involves an initial chemical or enzymatic oxidation of these two isomers to progesterone. The assay can distinguish between 20α- and 20β-dihydroprogesterone and is sensitive to pg amounts of these two steroids. Venous steroid concentrations were measured in the pregnant rhesus monkey employing this assay. In this species the corpus luteum (CL) at days 22 and 157 of gestation is the primary ovarian source of 20α-dihydroprogesterone as indicated by a higher plasma concentration of this steroid in the ovarian vein draining the ovary containing the CL (+CL) than in the contralateral vein (−CL) (9.34 ng/ml versus 1.72 ng/ml, day 22; 7.52 ng/ml versus 1.96 ng/ml, day 157). By contrast the CL at day 50 appeared to secrete no 20α-dihydroprogesterone as evidenced by the essentially equal steroid levels in both ovarian veins. The CL synthesizes 20β-dihydroprogesterone only during early gestation (21–22 days) when the concentration of this steroid was 6.46 ng/ml and 0.87 ng/ml in the ovarian (+CL) and ovarian (−CL) veins, respectively. Synthesis of both 20α- and 20β-dihydroprogesterone occurs in the fetoplacental unit throughout pregnancy. This is indicated by higher steroid concentrations in the uterine vein than in the femoral vein. The results suggest both a qualitative and quantitative alteration in the luteal synthesis of 20α- and 20β-dihydroprogesterone with the advancement of gestation. The data also provide additional evidence that the steroidogenic activity of the CL is enhanced before parturition.

Plasma 17-OHCS Response of the Infant Rhesus Monkey to a Noninjurious, Noxious Stimulus.∗

Summary Two-day-old rhesus monkeys, restrained and rotated for one hour, exhibited elevations of 25.8 ± 3.3 (S.E.) μg% in plasma nonconjugated 17-OHCS. This sizable and consistent increase was 44% as great as the one hour increase in plasma nonconjugated 17-OHCS following ACTH, suggesting either that the restraint and rotation was not sufficiently stressful or that the infant CNS-hypophyseal axis was not sufficiently developed to stimulate fully the adrenal cortex.