Quantum and Multidimensional Explanations in a Neurobiological Context of Mind.

This article examines the possible relevance of physical-mathematical multidimensional or quantum concepts aiming at understanding the (human) mind in a neurobiological context. Some typical features of the quantum and multidimensional concepts are briefly introduced, including entanglement, superposition, holonomic, and quantum field theories. Next, we consider neurobiological principles, such as the brain and its emerging (physical) mind, evolutionary and ontological origins, entropy, syntropy/neg-entropy, causation, and brain energy metabolism. In many biological processes, including biochemical conversions, protein folding, and sensory perception, the ubiquitous involvement of quantum mechanisms is well recognized. Quantum and multidimensional approaches might be expected to help describe and model both brain and mental processes, but an understanding of their direct involvement in mental activity, that is, without mediation by molecular processes, remains elusive. More work has to be done to bridge the gap between current neurobiological and physical-mathematical concepts with their associated quantum-mind theories.

Delayed mood transitions in major depressive disorder.

The hypothesis defended here is that the process of mood-normalizing transitions fails in a significant proportion of patients suffering from major depressive disorder. Such a failure is largely unrelated to the psychological content. Evidence for the hypothesis is provided by the highly variable and unpredictable time-courses of the depressive episodes. The main supporting observations are: (1) mood transitions within minutes or days have been reported during deep brain stimulation, naps after sleep deprivation and bipolar mood disorders; (2) sleep deprivation, electroconvulsive treatment and experimental drugs (e.g., ketamine) may facilitate mood transitions in major depressive disorder within hours or a few days; (3) epidemiological and clinical studies show that the time-to-recovery from major depressive disorder can be described with decay models implying very short depressive episodes; (4) lack of relationship between the length of depression and recovery episodes in recurrent depression; (5) mood fluctuations predict later therapeutic success in major depressive disorder. We discuss some recent models aimed to describe random mood transitions. The observations together suggest that the mood transitions have a wide variety of apparently unrelated causes. We suggest that the mechanism of mood transition is compromised in major depressive disorder, which has to be recognized in diagnostic systems.

Emergence Of Consciousness And Qualia From A Complex Brain.

Qualia are private conscious experiences of which the associated feelings can be reported to other people. Whether qualia are amenable to scientific exploration has often been questioned, which is challenged by the present article. The following arguments are given: 1. the configuration of the brain changes continuously and irreversibly, because of genetic and environmental influences and interhuman communication; 2. qualia and consciousness are processes, rather than states; 3. private feelings, including those associated with qualia, should be positioned in the context of a personal brain as being developed during life; 4. consciousness and qualia should be understood in the context of general system theory, thus concluding that isolated, in vitro, properties of neurons and other brain constituents might marginally contribute to the understanding of higher brain functions, mind or qualia; 5. current in vivo approaches have too little resolution power - in terms of space and time - to delineate individual and subjective brain processes. When subtle personalized properties of the nervous system can be assessed in vivo or in vitro, qualia can scientifically be investigated. We discuss some approaches to overcome these barriers.

The depressed patient in a biological world: on philosophical and diagnostic strategies.

RATIONALE, AIMS AND OBJECTIVE: We questioned: what kind of relationships between mental and neurobiological levels of complexity is or could become useful in the psychiatric practice? The concept of mind and associated mood states defended here is that they are physically emergent, subjective, qualitative, unified features of the brain. We compared our neurobiological assessment also to psychoanalytical practice (first person's perspective). ARGUMENT: Applied to recent work on major depressive disorder (MDD), our ideas are among other supported by clinical and experimental studies on sleep deprivation, deep brain stimulation and epidemiological assessments of time-to-recovery. CLINICAL IMPLICATIONS: We suggest that depression is a transient state of the brain, that is mutually exclusive to the state of pleasure (in the Freudian context), rather than a disorder or disease with a characteristic time course (like many reversible somatic diseases). MDD can best be described with stochastic transition models, which is discussed in the context of a presumed brain serotonin dysfunction in depression. Our ideas invite a reconsideration of some concepts underlying current diagnostic and therapeutic approaches in the clinical practice.

Comparison of brain and blood gene expression in an animal model of negative symptoms in schizophrenia.

OBJECTIVES: To investigate the potential of white blood cells as probes for central processes we have measured gene expression in both the anterior cingulate cortex and white blood cells using a putative animal model of negative symptoms in schizophrenia. METHODS: The model is based on the capability of ketamine to induce psychotic symptoms in healthy volunteers and to worsen such symptoms in schizophrenic patients. Classical fear conditioning is used to assess emotional processing and cognitive function in animals exposed to sub-chronic ketamine vs. controls. Gene expression was measured using a commercially sourced whole genome rat gene array. Data analyses were performed using ANOVA (Systat 11). RESULTS: In both anterior cingulate cortex and white blood cells a significant interaction between ketamine and fear conditioning could be observed. The outcome is largely supported by our subsequent metagene analysis. Moreover, the correlation between gene expression in brain and blood is about constant when no ketamine is present (r~0.4). With ketamine, however, the correlation becomes very low (r~0.2) when there is no fear, but it increases to ~0.6 when fear and ketamine are both present. Our results show that under normal conditions ketamine lowers gene expression in the brain, but this effect is completely reversed in combination with fear conditioning, indicating a stimulatory action. CONCLUSION: This paradoxical outcome indicates that extreme care must be taken when using gene expression data from white blood cells as marker for psychiatric disorders, especially when pharmacological and environmental interactions are at play.

The age-dependency of genetic and environmental influences on serum cytokine levels: a twin study.

UNLABELLED: Previous epidemiologic studies have evaluated the use of immunological markers as possible tools for measuring ageing and predicting age-related pathology. The importance of both genetic and environmental influences in regulation of these markers has been emphasized. In order to further evaluate this relationship, the present study aims to investigate the relative influence of genetic and environmental factors on four key cytokines involved in the human immune response (Interleukin (IL)-1ß, IL-6, IL-10 and Tumor Necrosis Factor (TNF)-α). In addition, the role of age as a possible moderator on these influences was evaluated. METHODS: The study was conducted in 1603 females from the Twins UK registry, with mean age ± SD of 60.4 ± 12.2 years, including 863 monozygotic twins (385 pairs and 93 singletons) and 740 dizygotic twins (321 pairs and 98 singletons). Heritability was estimated using structural equation modeling. The role of age as a moderator was evaluated using gene-age interaction models. RESULTS: Heritabilities were moderate for IL-1ß (range: 0.27-0.32) and IL-10 (0.30) and low for IL-6 (range: 0.15-0.16) and TNF-α (range: 0.17-0.23). For IL-1ß, heritability declines with age due to an increase in unique environmental factors. For TNF-α, heritability increases with age due to a decrease in unique environmental factors. CONCLUSION: The current findings illustrate the importance of genetic and environmental influences on four cytokines involved in the human immune response. For two of these there is evidence that heritability changes with age owing to changes in environmental factors unique to the individual.

Cortisol-induced increases of plasma oxytocin levels predict decreased immediate free recall of unpleasant words.

Cortisol and oxytocin have been shown to interact in both the regulation of stress responses and in memory function. In the present study we administered cortisol to 35 healthy female subjects in a within-subject double-blind placebo-controlled design, while measuring oxytocin levels, adrenocorticotropic hormone (ACTH) levels, and free recall of pleasant and of unpleasant words. We found that cortisol administration suppressed ACTH levels and (1) induced a decrease in oxytocin associated with ACTH suppression and (2) an increase in oxytocin that was independent from ACTH suppression. This cortisol-induced increase in plasma oxytocin was associated with a selective decrease in immediate free recall of unpleasant words from primacy positions. The present results add to evidence that cortisol-induced increases in oxytocin could mediate some of the effects of stress and cortisol on memory, and possibly play a role in the regulation of the hypothalamo-pituitary-adrenal stress response. This mechanism could significantly impact affective and social behaviors, in particular during times of stress.

Gompertz' survivorship law as an intrinsic principle of aging.

We defend the hypothesis that life-spanning population survivorship curves, as described by Gompertz' law and composed from cross-sectional data (here mortality), reflect an intrinsic aging principle active in each subject of that population. In other words Gompertz' law reflects aging of a prototypical subject, provided minimal (or no) external causes of death (i.e. fatal infections, starvation, accidents). Our approach deviates from the traditional (exponential) Gompertz' hazard function. For instance, the here formulated Gompertz' law accurately describes old-age deceleration of both all-cause mortality and the incidence of some ageing-associated cancers, as illustrated for the Dutch population. We consider the possibility that the old-age expression and progression of cancer and other pathologies becomes suppressed, because of random (and exponential) accumulation of damage during life. Gompertz' law may trigger new concepts and models describing life-spanning physiological and pathological processes of aging. We discuss (and reject) various aging models (e.g. a predominant role of individual variations at birth; reliability theory) and point to the explanatory potential of network models and systemic regulatory models.

The role of indoleamine 2,3-dioxygenase in a mouse model of neuroinflammation-induced depression.

Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases (like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS). Cerebral inflammation was monitored 1, 2, 3 and 4 days after the injection with small-animal positron emission tomography (PET) using the inflammatory marker [(11)C]-PK11195. In the presence or absence of systemically applied 1-methyl-tryptophan (1-MT), a competitive IDO-inhibitor, we assessed the development of depressive-like behavioral symptoms in parallel with IDO expression and activity. The PK11195 PET signal reached a highly significant peak 3 days after LPS injection, while these animals displayed a significant increase of depressive-like behavior in the forced swim test compared to vehicle-injected animals. These findings were paralleled by a significant increase of IDO in the brainstem, and an increased kynurenine/tryptophan ratio in the serum. Moreover, we report here for the first time, that inhibition of IDO by 1-MT in centrally induced neuroinflammation under experimental conditions can prevent the development of depressive-like behavior.

The possibility of evidence-based psychiatry: depression as a case.

Considering psychiatry as a medical discipline, a diagnosis identifying a disorder should lead to an effective therapy. Such presumed causality is the basis of evidence-based psychiatry. We examined the strengths and weaknesses of research onto the causality of relationship between diagnosis and therapy of major depressive disorder and suggest what could be done to strengthen eventual claims on causality. Four obstacles for a rational evidence-based psychiatry were recognised. First, current classification systems are scientifically nonfalsifiable. Second, cerebral processes are-at least to some extent-nondeterministic, i.e. they are random, stochastic and/or chaotic. Third, the vague or lack of relationship between therapeutic regimens and suspected pathogenesis. Fourth, the inadequacy of tools to diagnose and delineate a functional disorder. We suggest a strategy to identify diagnostic prototypes that are characterised by a limited number of parameters (symptoms, markers and other characteristics). A prototypical diagnosis that may either support or reject particular elements of current diagnostic systems. Nevertheless, one faces the possibility that psychiatry will remain a relatively weak evidence-based medical discipline.

Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: role of serotonin synthesis.

We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function, and attempted to identify underlying mechanisms. Biochemistry of serotonin was assessed with brain tissue assays and microdialysis; behavior was assessed as the acoustic startle reflex. Long-term SSRI administration to rats reduced the content of 5-HT and its main metabolite shortly after inhibition of 5-HT synthesis in many brain areas with more than 50%. Turnover was not appreciably decreased, but significantly increased within 48h of drug discontinuation. The microdialysis experiments indicate that neuronal release of 5-HT depends strongly on new synthesis and emphasize the role of 5-HT(1B) receptors in the regulation of these processes. Discontinuation of the SSRI rapidly increased behavioral reactivity to the external stimulus. Additional startle experiments suggest that the increased reactivity is more likely related to the reduced extracellular 5-HT levels than to impaired synthesis. The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment. These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes following non-compliance.

The isoenergetic brain: the idea and some implications.

The brain is often considered an ensemble of clusters of independently interacting neurons. Here the brain is proposed as an isoenergetic structure having little energy barriers that limit the distribution of neuronal information, thereby facilitating unitary brain functioning. Isoenergicity is achieved and maintained by energy metabolism and must be seen as an evolutionary conserved property. Isoenergicity enables efficient coordination of neural activities, thus facilitating, among others, fast access to memory. One implication is the virtual complete dissociation of energy metabolism from higher brain functioning. Another implication is a supervening private space-time configuration that is continuously (re)constructed during life.

Ultraslow microdialysis and microfiltration for in-line, on-line and off-line monitoring.

In medicine and biotechnology, close monitoring of molecular processes might assist to optimise therapeutic interventions and production of biochemicals, respectively. Here, we summarize the current status of two automatic and continuous sampling technologies, microdialysis and microfiltration, which facilitate both in vivo and in vitro monitoring of nearly any analyte, because they can be combined easily with many analytical techniques. Conventional microdialysis and microfiltration, which require collecting relatively large samples, are however often impractical and semi-quantitative; hence, we focus on ultraslow sampling to circumvent such limitations. Ultraslow microdialysis and microfiltration already have been used successfully for quantitative pharmacokinetics, glucose metabolism (e.g. of the brain), cytokines and proteomics (e.g. tumour secretomes), both in vivo and in vitro.

Microfiltration sampling in rats and in cows: toward a portable device for continuous glucocorticoid hormone sampling.

To monitor temporal patterns of glucocorticoids hormones in living animals, most often blood samples are collected. Blood sampling is invasive and subjects may find it--in particular--unpleasant when multiple samples are collected. We have developed a microfiltration collection device (MCD) sampling continuously, pulse-free, over a selected period of time, with minimum invasiveness as the device is inserted with only one venipuncture. The MCD consists of a hollow fiber membrane (probe), capillary collection coil and flow creator. Three biocompatible hollow fiber membranes were assessed on flow rate in rats, by placing the probe intraperitoneally, subcutaneously, or intravascularly and with or without heparin coating. The probe made from polyethylene coated with ethylene vinyl alcohol-heparin conveyed the best results and had the most benefit of the heparin coating. Consequently this probe was built into a collection device and tested in cows, sampling blood microfiltrate. Cortisol (protein-bound and -free) could be monitored in cows over a period of 7 hours. This device has several major advantages compared to manual blood collection: minor stress is induced by the application of the device; it has a low weight and can therefore be used in freely active subjects being in their own surroundings. The device can be sterilized and manufactured as a disposable tool, and the filled MCD can be shipped by regular mail to a specialized laboratory facility for analysis.

Duration of subsequent episodes and periods of recovery in recurrent major depression.

BACKGROUND: Little is known about the duration of subsequent depressive episodes and periods of recovery, and much is based on potentially biased retrospective data. We therefore prospectively assessed whether duration of depressive episodes and recoveries is correlated within subjects and across episodes, and whether duration of subsequent depressive episodes and recoveries increases or decreases over time. METHODS: From a sample of 267 depressed primary care patients enrolled in a RCT, we identified 279 depressive episodes and 455 recovery periods during a 3-year follow-up. We correlated durations of depressive episodes and of recovery within subjects, and compared within subjects the duration of first depressive episodes after index depression with second and third episodes, and similarly with recovery periods. RESULTS: No significant correlations were found between duration of depressive episodes or between recovery periods within subjects (Rs ranging from -0.17 to 0.08; all Ps >0.05). Median duration of first and second depressive episodes was 11 (IQR 6-19) and 9 weeks (IQR 5-14). Median duration of first and second recovery periods was 16.5 (IQR 7-31) and 17.5 weeks (IQR 9-32). No significant increase or decrease was observed in duration of consecutive depressive episodes, nor in recovery periods across episodes (all Ps >0.05). CONCLUSIONS: In this prospective study, we found no correlation between duration of depressive episodes or between recovery periods within subjects. Moreover, we found no support for an increase or decrease in subsequent duration of depressive episodes or a decrease in recovery periods across episodes. These findings do not support the notion that experiencing multiple depressive episodes results in a growing vulnerability.

Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications.

The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signalling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan.

Perspectives for on-site monitoring of progesterone.

The steroid hormone progesterone is the primary biomarker of the reproductive status of female mammals. Current techniques of monitoring progesterone are based predominantly on (enzyme) immunoassays, but these are too expensive to be affordable in daily screening programmes because of their associated labour costs and the need for laboratory facilities and/or equipment. Here, we discuss existing methods as well as new perspectives for (automated) application at point of care/need, e.g. the milking parlour. These make it apparent that a low-cost, fully automated progesterone assay system to monitor the reproductive status is far from being realised at present. Timely ovulation prediction techniques for artificial insemination and reproductive cycling are thus urgently needed, and promising perspectives will be highlighted.

The development of peripartum depressive symptoms is associated with gene polymorphisms of MAOA, 5-HTT and COMT.

BACKGROUND: Polymorphisms of monoamine-related genes have been associated with depression following life events. The peripartum is a physiologically and psychologically challenging period, characterized by fluctuations in depressive symptoms, therefore facilitating prospective investigations in this gene x environment (G x E) interaction. METHODS: Eighty nine pregnant women filled in two Edinburgh Postpartum Depression Scale (EPDS) questionnaires during pregnancy and two in the postpartum period. MAOA, COMT and 5-HTT polymorphisms were analyzed. RESULTS: We found a significant interaction between the development of depressive symptoms in the course of pregnancy and polymorphisms in 5-HTT (p=0.019); MAOA (p=0.044) and COMT (p=0.026), and MAOA x COMT (p<0.001). Particularly, women carrying the combination of low activity variants of MAOA and COMT showed increased EPDS scores at week 36 of pregnancy and 6 weeks postpartum, but not during early pregnancy or 12 weeks postpartum. CONCLUSION: We found that MAOA in combination with COMT appears to regulate not only the stress response in laboratory experiments, but also seems to influence the stress-evoked onset of mood during normal, mild, stressful events, such as experienced in the peripartum period. These findings support the GxE concept for depression, but they underline the complexity of this concept, as the cumulating effects of these polymorphic genes (i.e. MAOA+COMT) might be needed and the effects of these polymorphic genes becomes apparent in special environmental or physiological conditions (i.e. the peripartum period). We therefore suggest that G x E interactions become especially noticeable from longitudinal study designs in specific physiological or social challenging periods.

Circulating cerebral S100B protein is associated with depressive symptoms following myocardial infarction.

BACKGROUND: Prevalence of depressive symptoms in the post-myocardial infarction (MI) period varies from 8 to 30%. Cerebral damage after MI, caused by transient ischemia, an inflammatory response or both, may contribute to development of post-MI depression. S100B is an established protein marker of cerebral damage. In a pilot study, the authors assessed whether S100B serum levels are: (1) increased during the week after MI, and (2) related to depressive symptoms during index hospital admission and the year following MI. METHODS: This pilot study is a substudy of the Myocardial Infarction and Depression Intervention Trial (MIND-IT). In 48 patients, serum levels of S100B were available at 1, 2, 3, 4 and 8 days following MI. Subsequently, in 27 patients, depressive symptoms were measured at 0, 3, 6, 9 and 12 months following MI with the Beck Depression Inventory (BDI). In 21 of the initial 48 patients, BDI data were lacking due to refusals to fill out BDI forms or missing data. RESULTS: Significant and transient increases in serum S100B were observed in 81.3% of the 48 patients: 37.5% reached S100B serum levels comparable to serum levels found in acute brain injury (>0.20 microg/l) and 43.8% reached mildly elevated S100B serum levels comparable to serum levels found in depressive disorder (0.10-0.20 microg/l). In 18.7%, no S100B was detected in serum. Using non-parametric Spearman rank correlation tests, a trend towards an association was found between serum S100B and depressive symptoms during the post-MI year (rho values between 0.16 and 0.53) in 27 patients who completed both the S100B serum study and the BDI study. CONCLUSION: Transiently elevated levels of S100B are suggestive of minor acute cerebral damage in the first days following MI and associated with depressive symptoms in the year following MI. Cerebral damage could be an important mechanism in the pathogenesis in a subtype of post-MI depression.