The ventro-medial prefrontal cortex: a major link between the autonomic nervous system, regulation of emotion, and stress reactivity?

ABSTRACT: Recent progress in neuroscience revealed diverse regions of the CNS which moderate autonomic and affective responses. The ventro-medial prefrontal cortex (vmPFC) plays a key role in these regulations. There is evidence that vmPFC activity is associated with cardiovascular changes during a motor task that are mediated by parasympathetic activity. Moreover, vmPFC activity makes important contributions to regulations of affective and stressful situations.This review selectively summarizes literature in which vmPFC activation was studied in healthy subjects as well as in patients with affective disorders. The reviewed literature suggests that vmPFC activity plays a pivotal role in biopsychosocial processes of disease. Activity in the vmPFC might link affective disorders, stressful environmental conditions, and immune function.

Impaired verbal memory in Parkinson disease: relationship to prefrontal dysfunction and somatosensory discrimination

OBJECTIVE: To study the neurocognitive profile and its relationship to prefrontal dysfunction in non-demented Parkinson's disease (PD) with deficient haptic perception. METHODS: Twelve right-handed patients with PD and 12 healthy control subjects underwent thorough neuropsychological testing including Rey complex figure, Rey auditory verbal and figural learning test, figural and verbal fluency, and Stroop test. Test scores reflecting significant differences between patients and healthy subjects were correlated with the individual expression coefficients of one principal component, obtained in a principal component analysis of an oxygen-15-labeled water PET study exploring somatosensory discrimination that differentiated between the two groups and involved prefrontal cortices. RESULTS: We found significantly decreased total scores for the verbal learning trials and verbal delayed free recall in PD patients compared with normal volunteers. Further analysis of these parameters using Spearman's ranking correlation showed a significantly negative correlation of deficient verbal recall with expression coefficients of the principal component whose image showed a subcortical-cortical network, including right dorsolateral-prefrontal cortex, in PD patients. CONCLUSION: PD patients with disrupted right dorsolateral prefrontal cortex function and associated diminished somatosensory discrimination are impaired also in verbal memory functions. A negative correlation between delayed verbal free recall and PET activation in a network including the prefrontal cortices suggests that verbal cues and accordingly declarative memory processes may be operative in PD during activities that demand sustained attention such as somatosensory discrimination. Verbal cues may be compensatory in nature and help to non-specifically enhance focused attention in the presence of a functionally disrupted prefrontal cortex.

Diminished prefrontal brain function in adults with psychopathology in childhood related to attention deficit hyperactivity disorder

The aim of the present study was to investigate prefrontal brain function and cognitive response control in patients with personality disorders who either suffered or did not suffer from psychopathology related to attention deficit hyperactivity disorder (ADHD) during childhood. For this purpose, 36 psychiatric out-patients with personality disorders--24 of whom showed ADHD-related psychopathology during childhood assessed by the German short form of the Wender Utah Rating Scale--and 24 healthy controls were investigated electrophysiologically by means of a cued Go-NoGo task (Continuous Performance Test). Topographical analyses were conducted to individually quantify the NoGo anteriorisation (NGA), a neurophysiological correlate of prefrontal response control that has been suggested to reflect activation of the anterior cingulate cortex. ADHD patients exhibited a significantly reduced mean NGA and diminished amplitudes of the Global Field Power, as well as a reduced increase of fronto-central P300 amplitudes, in NoGo-trials compared with the healthy controls, whereas patients with personality disorders alone did not differ from the control group in any of the electrophysiological parameters. The results indicate that ADHD-related psychopathology is associated with prefrontal brain dysfunction, probably related to processes of response inhibition and/or cognitive response control.

Testing the involvement of the prefrontal cortex in lucid dreaming: A tDCS study

Recent studies suggest that lucid dreaming (awareness of dreaming while dreaming) might be associated with increased brain activity over frontal regions during rapid eye movement (REM) sleep. By applying transcranial direct current stimulation (tDCS), we aimed to manipulate the activation of the dorsolateral prefrontal cortex (DLPFC) during REM sleep to induce lucid dreaming. Nineteen participants spent three consecutive nights in a sleep laboratory. On the second and third nights they randomly received either 1 mA tDCS for 10 min or sham stimulation during each REM period starting with the second one. According to the participants' self-ratings, tDCS over the DLPFC during REM sleep increased lucidity in dreams. The effects, however, were not strong and found only in frequent lucid dreamers. While this indicates some preliminary support for the involvement of the DLPFC in lucid dreaming, further research, controlling for indirect effects of stimulation and including other brain regions, is needed.

Mood effects of repetitive transcranial magnetic stimulation of left prefrontal cortex in healthy volunteers.

This study investigated the effect of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) of the left prefrontal cortex (LPFC) on mood in a sham-controlled crossover design. Twenty-five healthy male subjects received HF-rTMS of the LPFC in real and sham conditions. Forty trains (frequency 20 Hz, stimulation intensity 100% of individual motor threshold, train duration 2 s, intertrain interval 28 s) were applied in each session. Mood change from baseline was measured with five visual analog scales (VAS) for sadness, anxiety, happiness, tiredness and pain/discomfort. We were unable to demonstrate significant mood changes from baseline on visual analog scales after either sham or real stimulation of LPFC. There is insufficient evidence to support the general conclusion that HF-rTMS of LPFC has mood effects in healthy volunteers. Future studies should be sham-controlled, have larger sample sizes, and strictly stimulate one single region per session in order to exclude interaction effects with the previous stimulation.

Associations between prefrontal γ-aminobutyric acid concentration and the tryptophan hydroxylase isoform 2 gene, a panic disorder risk allele in women

Associations between the central serotonergic and γ-aminobutyric acid (GABA) systems play key roles in the prefrontal cortical regulation of emotion and cognition and in the pathophysiology and pharmacotherapy of highly prevalent psychiatric disorders. The goal of this study was to test the effects of common variants of the tryptophan hydroxylase isoform 2 (TPH2) gene on GABA concentration in the prefrontal cortex (PFC) using magnetic resonance spectroscopy. In this study involving 64 individuals, we examined the associations between prefrontal cortical GABA concentration and 12 single nucleotide polymorphisms (SNPs) spanning the TPH2 gene, including rs4570625 (−703 G/T SNP), a potentially functional TPH2 polymorphism that has been associated with decreased TPH2 mRNA expression and panic disorder. Our results revealed a significant association between increased GABA concentration in the PFC and the T-allele frequencies of two TPH2 SNPs, namely rs4570625 (−703 G/T) and rs2129575 (p≤0.0004) and the C-allele frequency of one TPH2 SNP, namely rs1386491 (p = 0.0003) in female subjects. We concluded that rs4570625 (−703 G/T), rs2129575 and rs1386491 play a significant role in GABAergic neurotransmission and may contribute to the sex-specific dysfunction of the GABAergic system in the PFC.

Low single dose gabapentin does not affect prefrontal and occipital gamma-aminobutyric acid concentrations

The γ-aminobutyric acid (GABA) system has been proposed as a target for novel antidepressant and anxiolytic treatments. Emerging evidence suggests that gabapentin (GBP), an anticonvulsant drug that significantly increases brain GABA levels, is effective in the treatment of anxiety disorders. The current study was designed to measure prefrontal and occipital GABA levels in medication-free healthy subjects after taking 0 mg, 150 mg and 300 mg GBP. Subjects were scanned on a 3T scanner using a transmit-receive head coil that provided a relatively homogenous radiofrequency field to obtain spectroscopy measurement in the medial prefrontal (MPFC) and occipital cortex (OCC). There was no dose-dependent effect of GBP on GABA levels in the OCC or MPFC. There was also no effect on Glx, choline or N-acetyl-aspartate concentrations. The previously reported finding of increased GABA levels after GBP treatment is not evident for healthy subjects at the dose of 150 and 300 mg. As a result, if subjects are scanned on a 3T scanner, low dose GPB is not useful as an experimental challenge agent on the GABA system.

Probabilistic contingency learning with limbic or prefrontal damage

AB A fundamental capacity of the human brain is to learn relations (contingencies) between environmental stimuli and the consequences of their occurrence. Some contingencies are probabilistic; that is, they predict an event in some situations but not in all. Animal studies suggest that damage to limbic structures or the prefrontal cortex may disturb probabilistic learning. The authors studied the learning of probabilistic contingencies in amnesic patients with limbic lesions, patients with prefrontal cortex damage, and healthy controls. Across 120 trials, participants learned contingent relations between spatial sequences and a button press. Amnesic patients had learning comparable to that of control subjects but failed to indicate what they had learned. Across the last 60 trials, amnesic patients and control subjects learned to avoid a noncontingent choice better than frontal patients. These results indicate that probabilistic learning does not depend on the brain structures supporting declarative memory.

Norepinephrine drives persistent activity in prefrontal cortex via synergistic α1 and α2 adrenoceptors

Optimal norepinephrine levels in the prefrontal cortex (PFC) increase delay-related firing and enhance working memory, whereas stress-related or pathologically high levels of norepinephrine are believed to inhibit working memory via α1 adrenoceptors. However, it has been shown that activation of Gq-coupled and phospholipase C-linked receptors can induce persistent firing, a cellular correlate of working memory, in cortical pyramidal neurons. Therefore, despite its importance in stress and cognition, the exact role of norepinephrine in modulating PFC activity remains elusive. Using electrophysiology and optogenetics, we report here that norepinephrine induces persistent firing in pyramidal neurons of the PFC independent of recurrent fast synaptic excitation. This persistent excitatory effect involves presynaptic α1 adrenoceptors facilitating glutamate release and subsequent activation of postsynaptic mGluR5 receptors, and is enhanced by postsynaptic α2 adrenoceptors inhibiting HCN channel activity. Activation of α2 adrenoceptors or inhibition of HCN channels also enhances cholinergic persistent responses in pyramidal neurons, providing a mechanism of crosstalk between noradrenergic and cholinergic inputs. The present study describes a novel cellular basis for the noradrenergic control of cortical information processing and supports a synergistic combination of intrinsic and network mechanisms for the expression of mnemonic properties in pyramidal neurons.

Impairments in an early stage of the decision-making process in patients with ventromedial prefrontal damage: preliminary results

Lesions of the ventromedial prefrontal cortex can result in a deficient decision-making behavior. So far, most experimental results in the neuropsychological decision-making research have been obtained with gambling tasks. Due to their high complexity, it is difficult to evaluate the underlying processes of the decision-making deficits. The aim of this study was to assess if patients with ventromedial prefrontal damage compared to patients with dorsolateral prefrontal damage and controls show a deficit in an early stage of the decision-making process. Nine patients with ventromedial prefrontal damage, three with dorsolateral prefrontal damage, and eleven healthy controls were tested with a newly developed decision task in which they had to search actively for the information they needed for their decisions. Our results show that patients with ventromedial prefrontal damage compared to the brain-lesioned dorsolateral prefrontal control group and healthy controls searched less for information with regard to risk defusing operators or consequences of their decisions indicating impairment already in the early stage of the decision-making process.

Impartiality in humans is predicted by brain structure of dorsomedial prefrontal cortex.

The moral force of impartiality (i.e. the equal treatment of all human beings) is imperative for providing justice and fairness. Yet, in reality many people become partial during intergroup interactions; they demonstrate a preferential treatment of ingroup members and a discriminatory treatment of outgroup members. Some people, however, do not show this intergroup bias. The underlying sources of these inter-individual differences are poorly understood. Here we demonstrate that the larger the gray matter volume and thickness of the dorsomedial prefrontal cortex (DMPFC), the more individuals in the role of an uninvolved third-party impartially punish outgroup and ingroup perpetrators. Moreover, we show evidence for a possible mechanism that explains the impact of DMPFC's gray matter volume on impartiality, namely perspective-taking. Large gray matter volume of DMPFC seems to facilitate equal perspective-taking of all sides, which in turn leads to impartial behavior. This is the first evidence demonstrating that brain structure of the DMPFC constitutes an important source underlying an individual's propensity for impartiality.

Dorsolateral and ventromedial prefrontal cortex orchestrate normative choice.

Humans are noted for their capacity to over-ride self-interest in favor of normatively valued goals. We examined the neural circuitry that is causally involved in normative, fairness-related decisions by generating a temporarily diminished capacity for costly normative behavior, a 'deviant' case, through non-invasive brain stimulation (repetitive transcranial magnetic stimulation) and compared normal subjects' functional magnetic resonance imaging signals with those of the deviant subjects. When fairness and economic self-interest were in conflict, normal subjects (who make costly normative decisions at a much higher frequency) displayed significantly higher activity in, and connectivity between, the right dorsolateral prefrontal cortex (DLPFC) and the posterior ventromedial prefrontal cortex (pVMPFC). In contrast, when there was no conflict between fairness and economic self-interest, both types of subjects displayed identical neural patterns and behaved identically. These findings suggest that a parsimonious prefrontal network, the activation of right DLPFC and pVMPFC, and the connectivity between them, facilitates subjects' willingness to incur the cost of normative decisions.

Feeling present in arousing virtual reality worlds: prefrontal brain regions differentially orchestrate presence experience in adults and children

Virtual reality (VR) is a powerful tool for simulating aspects of the real world. The success of VR is thought to depend on its ability to evoke a sense of "being there", that is, the feeling of "Presence". In view of the rapid progress in the development of increasingly more sophisticated virtual environments (VE), the importance of understanding the neural underpinnings of presence is growing. To date however, the neural correlates of this phenomenon have received very scant attention. An fMRI-based study with 52 adults and 25 children was therefore conducted using a highly immersive VE. The experience of presence in adult subjects was found to be modulated by two major strategies involving two homologous prefrontal brain structures. Whereas the right DLPFC controlled the sense of presence by down-regulating the activation in the egocentric dorsal visual processing stream, the left DLPFC up-regulated widespread areas of the medial prefrontal cortex known to be involved in self-reflective and stimulus-independent thoughts. In contrast, there was no evidence of these two strategies in children. In fact, anatomical analyses showed that these two prefrontal areas have not yet reached full maturity in children. Taken together, this study presents the first findings that show activation of a highly specific neural network orchestrating the experience of presence in adult subjects, and that the absence of activity in this neural network might contribute to the generally increased susceptibility of children for the experience of presence in VEs.