The Molecular Organization of Self-awareness: Paralimbic Dopamine-GABA Interaction.

The electrophysiology of the paralimbic network ("default mode") for self-awareness has drawn much attention in the past couple of decades. In contrast, knowledge of the molecular organization of conscious experience has only lately come into focus. We here review newer data on dopaminergic control of awareness in humans, particularly in self-awareness. These results implicate mainly dopaminergic neurotransmission and the control of GABAergic function directly in the paralimbic network. The findings are important for understanding addiction, developmental disorders, and dysfunctional consciousness.

Attenuation of dopamine-induced GABA release in problem gamblers.

INTRODUCTION: We have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self-awareness via synchronizing oscillations in the gamma range. The synchronization of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA-ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self-awareness. METHODS: [11 C]Ro15-4513 PET, a marker of benzodiazepine α1/α5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L-dopa in a double-blind controlled study of male problem gamblers (N = 10) and age-matched healthy male controls (N = 10). RESULTS: The mean reduction of cortical gray matter GABA/BDZ receptor availability induced by L-dopa was significantly attenuated in the problem gambling group compared to the healthy control group (p = 0.0377). CONCLUSIONS: Our findings demonstrate that: (a) Exogenous dopamine can induce synaptic GABA release in healthy controls. (b) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.

Exogenous dopamine reduces GABA receptor availability in the human brain.

BACKGROUND: While it has recently been shown that dopamine release stimulates conscious self-monitoring through the generation of gamma oscillations in medial prefrontal/anterior cingulate cortex, and that the GABAergic system is effective in producing such oscillations, interaction of the two transmitter systems has not been demonstrated in humans. We here hypothesize that dopamine challenge stimulates the GABA system directly in the medial prefrontal/anterior cingulate region in the human brain. METHODS: Positron emission tomography (PET) with the GABA receptor α1/α5 subtype ligand [(11)C] Ro15-4513 was used to detect changes in GABA receptor availability after clinical oral doses of levodopa in a double blind controlled study. RESULTS: We here provide the first direct evidence for such coupling in the cerebral cortex, in particular in the medial prefrontal anterior cingulate region, by showing that exogenous dopamine decreases [(11)C] Ro15-4513 binding widely in the human brain compatible with a fall in α1 subtype availability in GABA complexes due to increased GABA activity.

Making sense: Dopamine activates conscious self-monitoring through medial prefrontal cortex.

When experiences become meaningful to the self, they are linked to synchronous activity in a paralimbic network of self-awareness and dopaminergic activity. This network includes medial prefrontal and medial parietal/posterior cingulate cortices, where transcranial magnetic stimulation may transiently impair self-awareness. Conversely, we hypothesize that dopaminergic stimulation may improve self-awareness and metacognition (i.e., the ability of the brain to consciously monitor its own cognitive processes). Here, we demonstrate improved noetic (conscious) metacognition by oral administration of 100 mg dopamine in minimal self-awareness. In a separate experiment with extended self-awareness dopamine improved the retrieval accuracy of memories of self-judgment (autonoetic, i.e., explicitly self-conscious) metacognition. Concomitantly, magnetoencephalography (MEG) showed increased amplitudes of oscillations (power) preferentially in the medial prefrontal cortex. Given that electromagnetic activity in this region is instrumental in self-awareness, this explains the specific effect of dopamine on explicit self-awareness and autonoetic metacognition.

Applying incentive sensitization models to behavioral addiction.

The incentive sensitization theory is a promising model for understanding the mechanisms underlying drug addiction, and has received support in animal and human studies. So far the theory has not been applied to the case of behavioral addictions like Gambling Disorder, despite sharing clinical symptoms and underlying neurobiology. We examine the relevance of this theory for Gambling Disorder and point to predictions for future studies. The theory promises a significant contribution to the understanding of behavioral addiction and opens new avenues for treatment.

Altered paralimbic interaction in behavioral addiction.

The introduction of magnetoencephalography has made it possible to study electromagnetic signaling in deeper, paralimbic cortical structures such as the medial prefrontal/anterior cingulate (ACC) and medial parietal/posterior cingulate (PCC) cortices. Self-awareness and self-control have been attributed to these regions. To test the hypothesis that they are dysfunctional in pathological gambling with poor self-control, we studied gamblers with and without previous stimulant abuse and age- and sex-matched controls. We found that pathological gamblers were more impulsive than controls in a stop-signal task and attributed this to changes in the activity of the paralimbic network: Pathological gamblers had reduced synchronization at rest in the high gamma range (55-100 Hz) compared with controls and failed to show an increase in gamma synchronization during rest compared with the task, as observed in controls. Subgroup analysis revealed that pathological gamblers without a history of stimulant abuse had lower PCC power during the stop-signal task compared with controls and gamblers with previous stimulant abuse. Furthermore, gamblers with a history of stimulant abuse had up to four times higher power at the ACC site during rest and the task compared with controls. In conclusion, pathological gamblers had higher impulsivity and functional paralimbic abnormalities, which could not be explained by a history of stimulant abuse. In addition, previous stimulant abuse had a marked effect on the amplitude of oscillatory brain activity in the ACC and PCC, suggesting long-term deleterious effects of repeated dopaminergic drug exposure. These consequences should be investigated in more detail in longitudinal studies.

Self-enhancement processing in the default network: a single-pulse TMS study.

Much research has been done on positive self-evaluation and its relationship to mental health. However, little is known about its neural underpinnings. Imaging studies have suggested that the brain's default network is involved with self-related processing and that one portion of the default network, medial prefrontal cortex (MPFC), is particularly involved with self-evaluation. Here, we used transcranial magnetic stimulation (TMS) to causally demonstrate that this network, and particularly MPFC, is involved with self-evaluative processing. In a first experiment, 27 healthy volunteers judged whether adjectives, evenly divided between desirable and undesirable traits, described themselves or their best friends, and a robust self-enhancement bias effect was found. In a second experiment, single-pulse TMS was applied targeting three locations (MPFC and left and right parietal cortex) in a different group of healthy volunteers while they performed the adjective task. In each trial, TMS was applied at one of five different times relative to onset of the adjective ranging from 0 to 480 ms. TMS affected self-enhancement bias in a site- and latency-specific manner: at MPFC, the self-enhancement bias actually reversed at 160 ms, with subjects favoring their best friend over themselves. TMS may thus be of use in investigating areas of mental illness in which self-evaluation is abnormal, potentially as a diagnostic tool. In addition, the present study, combined with our previous reports (Lou et al., Proc Natl Acad Sci USA 101(17):6827-6832, 2004, Exp Brain Res 207:27-38, 2010), causally demonstrates two kinds of self-related processing within the default network, one centered in parietal cortex and concerned with retrieval of self-related associations, and the other MPFC-centered and involved in self-evaluative processing.

Cerebral autoregulation in the first day after preterm birth: no evidence of association with systemic inflammation.

INTRODUCTION: Both systemic inflammation and impaired cerebral autoregulation (CA) have been associated with brain injury in preterm infants. We hypothesized that impaired CA represents a hemodynamic link between inflammation and brain injury. RESULTS: Neither fetal vasculitis nor interleukin-6 (IL-6) affected CA significantly. A high level of IL-6 was associated with hypotension (P = 0.03) irrespective of dopamine therapy. The magnitude of impairment in CA increased with decreasing mean arterial blood pressure (MAP) (P = 0.02). No significant associations were found between these parameters and either intraventricular hemorrhage (IVH) (n = 10) or neonatal mortality (n = 8). DISCUSSION: In conclusion, postnatal inflammation was weakly associated with arterial hypotension, and hypotension was weakly associated with impaired autoregulation. There was no direct association, however, between autoregulation and antenatal or postnatal signs of inflammation. METHODS: In our study, 60 infants (mean (±SD) of gestational age (GA) 27 (±1.3) wk) underwent continuous recording of MAP and cerebral oxygenation index (OI) by means of near-infrared spectroscopy (NIRS) for 2.3 ± 0.5 h, starting 18 ± 9 h after birth. Coherence and transfer function gain between MAP and OI represented the presence and degree of impairment of CA, respectively. We considered fetal vasculitis (placenta histology) to be an antenatal marker of inflammation, and used the level of IL-6 in blood, measured at 18 ± 10 h after birth, as a postnatal marker of inflammation. Definition of hypotension was MAP (mm Hg) ≤ GA (wk).

Paradigm shift in consciousness research: the child's self-awareness and abnormalities in autism, ADHD and schizophrenia.

UNLABELLED: Self-awareness is a pivotal component of any conscious experience and conscious self-regulation of behaviour. A paralimbic network is active, specific and causal in self-awareness. Its regions interact by gamma synchrony. Gamma synchrony develops throughout infancy, childhood and adolescence into adulthood and is regulated by dopamine and other neurotransmitters via GABA interneurons. Major derailments of this network and self-awareness occur in developmental disorders of conscious self-regulation like autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia. CONCLUSION: Recent research on conscious experience is no longer limited to the study of neural 'correlations' but is increasingly lending itself to the study of causality. This paradigm shift opens new perspectives for understanding the neural mechanisms of the developing self and the causal effects of their disturbance in developmental disorders.

Yoga lessons for consciousness research: a paralimbic network balancing brain resource allocation.

Consciousness has been proposed to play a key role in shaping flexible learning and as such is thought to confer an evolutionary advantage. Attention and awareness are the perhaps most important underlying processes, yet their precise relationship is presently unclear. Both of these processes must, however, serve the evolutionary imperatives of survival and procreation. They are thus intimately bound by reward and emotion to help to prioritize efficient brain resource allocation in order to predict and optimize behavior. Here we show how this process is served by a paralimbic network consisting primarily of regions located on the midline of the human brain. Using many different techniques, experiments have demonstrated that this network is effective and specific for self-awareness and contributes to the sense of unity of consciousness by acting as a common neural path for a wide variety of conscious experiences. Interestingly, hemodynamic activity in the network decreases with focusing on external stimuli, which has led to the idea of a default mode network. This network is one of many networks that wax and vane as resources are allocated to accommodate the different cyclical needs of the organism primarily related to the fundamental pleasures afforded by evolution: food, sex, and conspecifics. Here we hypothesize, however, that the paralimbic network serves a crucial role in balancing and regulating brain resource allocation, and discuss how it can be thought of as a link between current theories of so-called "default mode," "resting state networks," and "global workspace." We show how major developmental disorders of self-awareness and self-control can arise from problems in the paralimbic network as demonstrated here by the example of Asperger syndrome. We conclude that attention, awareness, and emotion are integrated by a paralimbic network that helps to efficiently allocate brain resources to optimize behavior and help survival.

Recurrent activity in higher order, modality non-specific brain regions: a Granger causality analysis of autobiographic memory retrieval.

It has been proposed that the workings of the brain are mainly intrinsically generated recurrent neuronal activity, with sensory inputs as modifiers of such activity in both sensory and higher order modality non-specific regions. This is supported by the demonstration of recurrent neuronal activity in the visual system as a response to visual stimulation. In contrast recurrent activity has never been demonstrated before in higher order modality non-specific regions. Using magneto-encephalography and Granger causality analysis, we tested in a paralimbic network the hypothesis that stimulation may enhance causal recurrent interaction between higher-order, modality non-specific regions. The network includes anterior cingulate/medial prefrontal and posterior cingulate/medial parietal cortices together with pulvinar thalami, a network known to be effective in autobiographic memory retrieval and self-awareness. Autobiographic memory retrieval of previous personal judgments of visually presented words was used as stimuli. It is demonstrated that the prestimulus condition is characterized by causal, recurrent oscillations which are maximal in the lower gamma range. When retrieving previous judgments of visually presented adjectives, this activity is dramatically increased during the stimulus task as ascertained by Granger causality analysis. Our results confirm the hypothesis that stimulation may enhance causal interaction between higher order, modality non-specific brain regions, exemplified in a network of autobiographical memory retrieval.

Emergent pharmacology of conscious experience: new perspectives in substance addiction.

We here review experimental findings relevant for the pharmacology of conscious experience, an issue largely neglected in pharmacological research. First, we focus on self-awareness, a pivotal component of conscious experience and its integration within the global neuronal network (GNW), a theoretical concept that unifies convergent approaches on the neural bases of conscious processing. We report recent evidence to show that self-awareness mobilizes a paralimbic circuitry of γ synchrony, and that such synchrony is, in particular, regulated by GABA interneurons under the control of acetylcholine and dopamine. Recent data illustrate that these neurotransmitters establish a causal relationship with the control of self-awareness. The hypothesis is presented that not only is self-awareness chemically regulated, but the reverse may be true. Long-term deficit in self-control of drug intake would result in compulsive substance use, accompanied, in particular, with lesions of the paralimbic circuitry of self-awareness, leading to aggravation of substance abuse, resulting in addiction in a vicious circle. Finally, we propose that the emergent pharmacology of conscious experience may provide new perspectives, not only in substance addiction but also in the many other pathological conditions with deficient self-awareness.

Impact of emotion on consciousness: positive stimuli enhance conscious reportability.

Emotion and reward have been proposed to be closely linked to conscious experience, but empirical data are lacking. The anterior cingulate cortex (ACC) plays a central role in the hedonic dimension of conscious experience; thus potentially a key region in interactions between emotion and consciousness. Here we tested the impact of emotion on conscious experience, and directly investigated the role of the ACC. We used a masked paradigm that measures conscious reportability in terms of subjective confidence and objective accuracy in identifying the briefly presented stimulus in a forced-choice test. By manipulating the emotional valence (positive, neutral, negative) and the presentation time (16 ms, 32 ms, 80 ms) we measured the impact of these variables on conscious and subliminal (i.e. below threshold) processing. First, we tested normal participants using face and word stimuli. Results showed that participants were more confident and accurate when consciously seeing happy versus sad/neutral faces and words. When stimuli were presented subliminally, we found no effect of emotion. To investigate the neural basis of this impact of emotion, we recorded local field potentials (LFPs) directly in the ACC in a chronic pain patient. Behavioural findings were replicated: the patient was more confident and accurate when (consciously) seeing happy versus sad faces, while no effect was seen in subliminal trials. Mirroring behavioural findings, we found significant differences in the LFPs after around 500 ms (lasting 30 ms) in conscious trials between happy and sad faces, while no effect was found in subliminal trials. We thus demonstrate a striking impact of emotion on conscious experience, with positive emotional stimuli enhancing conscious reportability. In line with previous studies, the data indicate a key role of the ACC, but goes beyond earlier work by providing the first direct evidence of interaction between emotion and conscious experience in the human ACC.

Dopaminergic stimulation enhances confidence and accuracy in seeing rapidly presented words.

Liberal acceptance, overconfidence, and increased activity of the neurotransmitter dopamine have been proposed to account for abnormal sensory experiences, for instance, hallucinations in schizophrenia. In normal subjects, increased sensory experience in Yoga Nidra meditation is linked to striatal dopamine release. We therefore hypothesize that the neurotransmitter dopamine may function as a regulator of subjective confidence of visual perception in the normal brain. Although much is known about the effect of stimulation by neurotransmitters on cognitive functions, their effect on subjective confidence of perception has never been recorded experimentally before. In a controlled study of 24 normal, healthy female university students with the dopamine agonist pergolide given orally, we show that dopaminergic activation increases confidence in seeing rapidly presented words. It also improves performance in a forced-choice word recognition task. These results demonstrate neurotransmitter regulation of subjective conscious experience of perception and provide evidence for a crucial role of dopamine.

Self-specific processing in the default network: a single-pulse TMS study.

In examining neural processing specific to the self, primarily by contrasting self-related stimuli with non-self-related stimuli (i.e., self vs. other), neuroimaging studies have activated a consistent set of regions, including medial prefrontal cortex (MPFC), precuneus, and right and left inferior parietal cortex. However, criticism has arisen that this network may not be specific to self-related processing, but instead reflects a more general aspect of cortical processing. For example, it is almost identical to the active network of the resting state, the "default" mode, when the subject is free to think about anything at all. We tested the self-specificity of this network by using transcranial magnetic stimulation (TMS) to briefly disrupt local cortical processing while subjects rated adjectives as like or unlike themselves or their best friend. Healthy volunteers show a self-reference effect (SRE) in this task, in which performance with self-related items is superior to that with other-related items. As individual adjectives appeared on a monitor, single-pulse TMS was applied at five different times relative to stimulus onset (SOA: stimulus onset asynchrony) ranging from 0 to 480 ms. In 18 subjects, TMS to left parietal cortex suppressed the SRE from 160 to 480 ms. SRE suppression occurred at later SOA with TMS to the right parietal cortex. In contrast, no effects were seen with TMS to MPFC. Together with our previous work, these results provide evidence for a self-specific processing system in which midline and lateral inferior parietal cortices, as elements of the default network, play a role in ongoing self-awareness.

Cerebral white matter blood flow and arterial blood pressure in preterm infants.

UNLABELLED: It is generally assumed that one reason why white matter injury is common in preterm infants is the relatively poor vascular supply. AIM: To examine whether blood flow to the white matter is relatively more reduced at low blood pressure than is blood flow to the brain as a whole. METHODS: Thirteen normoxic preterm infants had blood flow imaging on 16 occasions with single-photon emission computed tomography (SPECT) using 99Tc labelled hexa-methylpropylenamide oxime (HMPAO) as the tracer. Gestational age was 26-32 weeks. Transcutaneous carbon dioxide was between 4.7 and 8.5 kPa and mean arterial blood pressure between 22 and 55 mmHg. RESULTS: There was no statistically significant direct relation between white matter blood flow percentage and any of the variables. Using non-linear regression, however, assuming a plateau over a certain blood pressure threshold and a positive slope below this threshold, the relation to white matter flow percentage was statistically significant (p = 0.02). The threshold was 29 mmHg (95% confidence limits 26-33). CONCLUSION: Our analysis supports the concept of periventricular white matter as selectively vulnerable to ischaemia during episodes of low blood pressure.

Coherence in consciousness: paralimbic gamma synchrony of self-reference links conscious experiences.

A coherent and meaningful percept of the world is essential for human nature. Consequently, much speculation has focused on how this is achieved in the brain. It is thought that all conscious experiences have reference to the self. Self-reference may either be minimal or extended, i.e., autonoetic. In minimal self-reference subjective experiences are self-aware in the weak sense that there is something it feels like for the subject to experience something. In autonoetic consciousness, consciousness emerges, by definition, by retrieval of memories of personally experienced events (episodic memory). It has been shown with transcranial magnetic stimulation (TMS) that a medial paralimbic circuitry is critical for self-reference. This circuitry includes anterior cingulate/medial prefrontal and posterior cingulate/medial parietal cortices, connected directly and via thalamus. We here hypothesized that interaction in the circuitry may bind conscious experiences with widely different degrees of self-reference through synchrony of high frequency oscillations as a common neural event. This hypothesis was confirmed with magneto-encephalography (MEG). The observed coupling between the neural events in conscious experience may explain the sense of unity of consciousness and the severe symptoms associated with paralimbic dysfunction.

Neonatal cerebral oxygenation is not linked to foetal vasculitis and predicts intraventricular haemorrhage in preterm infants.

AIM: The aim of the study was to compare the cerebral tissue oxygenation index (c-TOI) measured by near infrared spectroscopy (NIRS) in infants with and without foetal vasculitis. METHODS: Twenty-four infants with placental signs of a foetal inflammatory response (FIR), foetal vasculitis, were compared with 39 controls. NIRS examination was done within the first 24 h. RESULTS: Infants with FIR had a significant lower gestational age (26.8 +/- 2.4 vs. 29.8 +/- 2.4 weeks' gestation; p < 0.01), Hb (9.4 +/- 1.2 vs. 10.9 +/- 1.5 mM; p < 0.01) and blood P(CO2) (5.5 +/- 0.8 vs. 6.3 +/- 1.1 kPa, p < 0.01) compared to controls. There was no significant difference in arterial blood pressure, inspiratory oxygen content, needs of mechanical ventilation or c-TOI (73.6 +/- 8.1% vs. 73.9 +/- 8.1% (p = 0.9)). The effect of FIR on c-TOI was -0.3% (95% CI -3.9 to 4.5%). This result was not affected by inclusion of potential confounders in the analysis. Eight infants subsequently developed intra/periventricular haemorrhage: four with minor lesions and four with severe lesions. There was a significant negative correlation between the severity of the intraventricular haemorrhage and the cerebral oxygenation (p = 0.002). CONCLUSION: Cerebral oxygenation was not affected in the first day of life in preterm infants born with foetal vasculitis, while cerebral oxygenation in infants that later developed intraventricular haemorrhage was impaired.