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This review article explores the intricate relationship between nutrition, metabolism, brain function and mental health. It highlights two key complementary models: the energy balance model and the more comprehensive carbohydrate-insulin model, to understand the development of obesity and metabolic dysfunctions. It particularly focuses on the role of dopamine in dietary regulation and insulin in the brain, both of which are crucial in the pathogenesis of neurodegenerative and stress-associated mental disorders. Additionally, the significance of sleep and dietary habits, such as medically assisted calorie restriction for mental health and the concept of "brain food" are described. These findings emphasize the importance of nutritional medicine in psychiatry and psychotherapy and the consideration of metabolic states for the prevention and treatment of mental and neurodegenerative diseases., (© 2024. The Author(s).)

Caffeine is the worldwide most frequently consumed psychostimulant. Its availability is nearly unlimited and in Europe it is not subject to state regulation. Apart from its primary role as an ingredient or additive in numerous beverages it also has medical use in apnea of prematurity, as an adjuvant in pain therapy and has regulatory approval for the short-term treatment of symptoms of fatigue. In doses typically administered caffeine's mechanism of action as a psychostimulant is presumably primarily based on central antagonism at adenosine receptors (A 1 - und A 2A -receptors), which facilitates central inhibition of adenosine-mediated reduction of the activity of the dopaminergic and ascending arousal system. Metabolisation of caffeine mainly depends on cytochrome P450 1A2. Thus, factors that influence the activity of CYP 1A2 (e. g. medication, pregnancy), may induce remarkable changes of pharmacokinetic parameters. Caffeine improves vigilance, attention and reaction time, particularly in sleep-deprived individuals. Moreover, it may improve endurance performances in sports and muscle strength. Intoxications with caffeine are rare, however can be fatal. In general, caffeine use seems not harmful within typical doses of intake. Caffeine features several, however not all characteristics of potentially addictive drugs; withdrawal after termination of a longer period of use and tolerance are known. In the DSM-5 "caffeine use disorder" is categorized as a possible future disorder that currently needs further study. The pattern of caffeine use of patients should be considered in the medical practice., Competing Interests: Der Autor erklärt, dass keine Interessenkonflikte vorliegen,, (© Georg Thieme Verlag KG Stuttgart · New York.)

Myeloperoxidase (MPO) is a hemoprotein which is involved in the unspecific immune response. In this process hypochloric acid is released. Hypochloric acid can react with lipids and proteins and thus lead to cell damage. We were able to show that MPO, as well as a biomarker for MPO - 3-Chlorotyrosine - are upregulated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model of Parkinson's disease as well as in the disease itself. Ablation of MPO resulted in a neuroprotective effect in the MPTP-model. Herein we describe the different function of MPO, and how these can lead to the cellular demise as seen in Parkinson's disease., (© Georg Thieme Verlag KG Stuttgart · New York.)

There is a high comorbidity between cannabis use and schizophrenia. Several factors contribute to this comorbidity: secondary development of addiction, cannabis-related induction of psychosis and shared neurobiological alterations. Meanwhile, there is evidence that cannabis use is associated with an increased risk of schizophrenia. Prospective epidemiological studies have shown that a frequent cannabis use doubles the risk for schizophrenia. Interestingly, schizophrenic patients with comorbid cannabis use often show significantly better performances in neuropsychological tests than patients without cannabis use. This is nevertheless not due to a positive effect of cannabis, but a sign of cannabis-related psychosis induction in subjects with a higher level of function and less cognitive impairment. Whether cannabis use leads to schizophrenia is determined by the individual vulnerability.

Objectives: Reduced concentrations of dopamine in prefrontal brain structures may play a role in alexithymia. Dopamine degradation in the orbitofrontal cortex is regulated by catechol-O-methyltransferase (COMT), and a functional single nucleotide polymorphism of the COMT gene, Val158Met, has been related to psychiatric illness. This study examines the association between the COMT Val158Met gene polymorphism, and alexithymia., Methods: 120 healthy students and 120 patients with mental disorders were genotyped for the COMT Val158Met polymorphism. Additionally, the Toronto Alexithymia Scale (TAS-20) was administered., Results: COMT genotype did not show a significant correlation with the TAS-20 in either group., Conclusions: COMT Val158Met polymorphism alone does not seem to be a major factor in alexithymia in healthy students. This is true even if patients with mental disorders covering a broader range of alexithymia are included. Thus, other genes, possibly interacting with cultural, environmental, and developmental factors, may be implicated.

Nuclear medicine imaging using positron emission tomography (PET) or single photon emission computed tomography (SPECT) has enabled to study not only the metabolism and blood flow in specific brain areas but also the quantification of the function of distinct molecules. With respect to Parkinson's disease PET and later SPECT allowed the number of dopaminergic neurons to be assessed in vivo. These quantifications are relevant to establishing a clinical diagnosis, assessing the progression of the disease or the survival of transplanted dopaminergic neurons. In addition both techniques have markedly contributed to our understanding of the pathophysiology of this disorder. More recently, molecular imaging has been directed towards understanding the pathophysiology of non-motor symptoms in this disorder.

Although the mechanisms which cause Parkinson's disease (PD) are still poorly understood, research on monogenic forms of PD have demonstrated a significant genetic contribution to its etiology. Monogenic forms of PD only account for a minority of cases but offer a unique avenue of research into the pathogenesis of PD. In this article the potential of structural and functional neuroimaging in monogenic forms to provide general insights into the pathophysiology of PD, including the more common idiopathic disease is reviewed. The review has a particular focus on neuroimaging of non-manifesting mutation carriers to study functional and structural changes in the brain at the asymptomatic stage of PD. This line of research has started to provide valuable insights into how the brain can cope with a latent nigrostriatal dopaminergic deficit and thereby delay the clinical onset of PD.

Functional brain imaging allows the effects of deep brain stimulation (DBS) on the living human brain to be investigated. In patients with advanced Parkinson's disease (PD), positron emission tomography (PET) studies were undertaken at rest as well as under motor, cognitive or behavioral activation. DBS leads to a reduction of abnormal PD-related network activity in the motor system, which partly correlates with the improvement of motor symptoms. The local increase of energy consumption within the direct target area suggests a predominant excitatory influence of the stimulation current on neuronal tissue. Remote effects of DBS of the subthalamic nucleus (STN) on frontal association cortices indicate an interference of stimulation energy with associative and limbic basal ganglia loops. Taken together, functional brain imaging provides very valuable data for advancement of the DBS technique in PD therapy.

Objective: The case of a schizoaffective patient suffering from a malignant catatonic syndrome following combined lithium-risperidone therapy is explored., Method: A case report and relevant deliberations regarding pathophysiology of the catatonic dilemma are discussed., Conclusions: There are two critical transitions in the development of a malignant catatonic syndrome. Dopaminergic system and psychopharmacological factors are supposed to play a key role. However, other neurotransmitter systems and the individual predisposition must be considered.

Deep brain stimulation at high frequencies has emerged as a powerful therapeutic strategy in the treatment of basal ganglia-related movement disorders. Attempts have also been made to establish this for the treatment of therapy-resistant psychiatric disorders. To date the mechanisms underlying the clinical efficacy of high frequency stimulation remain largely unknown. Their detailed description, however, is essential for promoting the extended application of high frequency stimulation as a therapeutic alternative and may simultaneously allow conclusions to be drawn on the pathophysiological mechanisms underlying the diseases benefiting from deep brain stimulation. This review demonstrates how animal models contribute to i) further understand the mechanisms underlying deep brain stimulation at high frequencies and ii) promote the establishment of high frequency stimulation for the treatment of therapy-resistant psychiatric disorders.

The traditional model of corticostriatal-thalamocortical projections, with indirect and direct pathways, provides a simplified and useful explanation for the motor deficits (hypokinesia, bradykinesia) that develop in the course of sporadic Parkinson's disease. In the classic model, major emphasis is placed on the dopamine deficiency in the dorsal striatum that occurs as a result of neuronal loss in the substantia nigra of the midbrain. Nevertheless, because the pathological process that underlies Parkinson's disease also involves many key nondopaminergic connectivities, a revised model is needed that incorporates these projections. The focus on damage to nondopaminergic and extranigral sites is becoming increasingly important for clinical practice.

Objectives: Both omega-3 and omega-6 long-chain polyunsaturated fatty acids (PUFA) have a substantial impact on human brain development and function. However, in western industrial countries omega-3 LC-PUFA in particular are often lacking in diets. Increasing evidence indicates that LC-PUFA imbalance or deficiencies may be associated with Attention Deficit/Hyperactivity Disorder (ADHD) through involvement in the dopaminergic corico-striatal metabolism. Preliminary study result suggest that dietary supplementation with LC-PUFA might be effective in the treatment of ADHD., Methods: This review summarizes the knowledge in terms of a hypothesized pathogenetic relationship between fatty acid metabolism and ADHD and discusses the possible clinical benefit of a primary or combined treatment with LC-PUFA., Results: Actually it is unclear whether a deficit in intake or metabolism of LC-PUFA may play a major role in the pathogenesis of ADHD. Moreover treatment studies yielded conflicting results. A combination of Omega-3 and Omega-6 - fatty acids might attenuate the symptoms of ADHD significantly, thus making this dietary intake useful., Conclusions: Considerable research has to be done in the future to identify ideal therapeutic combinations and dosages of various fatty acids, and to develop reliable ways of defining those individuals to benefit from this treatment access.

Brain imaging studies with PET, SPECT, functional magnetic resonance imaging, and spectroscopy provide evidence of prefrontal dysfunction in schizophrenia. Dysfunction of the prefrontal cortex is associated with cognitive impairment and negative symptoms. Combined multimodal imaging shows that a developmentally early disturbance of frontotemporal-limbic neuronal networks is associated with a disinhibition of subcortical dopaminergic neurotransmission. Current studies imply genetic factors in the regulation of dopaminergic neurotransmission and their effects on prefrontal cortex function. Some studies also indicate that atypical neuroleptics may at least partially improve frontal cortex function. We review the literature and discuss genotype and medication effects on frontal dysfunction in schizophrenia. Molecular brain imaging combines imaging techniques with the assessment of genotype effects and represents a powerful tool for the understanding of neuropsychiatric disorders.

The differential diagnosis of most parkinsonian syndromes can be adequately established on the basis of clinical criteria alone. The characterization of the dopaminergic system using nuclear imaging techniques such as PET and SPECT, is gaining in importance, in particular for the diagnosis of clinically unclear cases. For the first time, these techniques permit the investigation of the presynaptic and postsynaptic dopaminergic system in vivo, and thus the establishment of the differential diagnosis of parkinsonian syndromes at an early stage. Furthermore, the severity and progression of the disease can be assessed and the effect of putative neuroprotective drugs can be documented.

Patients with idiopathic Parkinson's disease display a 60% degeneration of the nigrostriatal neurons before motor symptoms have progressed enough to allow clinical diagnosis. It is clear that any neuroprotective therapy starting at such a late stage can have no substantial effect on the disease progression. Therefore, earlier diagnosis must be the goal of future research,when at most mild motor or non-motor symptoms are present or when only risk factors can be identified. Evidence of various gene mutations associated with idiopathic Parkinsonism raise the hope that these or other biological markers will allow earlier identification of patients at risk. A possibly significant vulnerability factor for developing Parkinson's disease can also be demonstrated by means of transcranial sonography. Since the individual tests are not sufficiently specific or sensitive, a gradual, precise, and inexpensive battery of tests needs to be developed for the successful identification of a risk group for this disease. The extent of damage to the dopaminergic system in these patients can be quantified using nuclear techniques.

Idiopathic Parkinson's disease (IPD) results from a largely selective degeneration of nigrostriatal dopaminergic neurons. Therefore, compounds which strengthen dopaminergic transmission in the striatum are the most important therapeutic approach. These include L-dopa, dopamine receptor agonists, selegeline, and entacapon. Since nigrostriatal degeneration leads to secondary alterations of cholinergic and glutamatergic transmission to the basal ganglia,nondopaminergic compounds such as anticholinergics and N-methyl-D-aspartate (NMDA) receptor antagonists are also used in the management of IPD. L-dopa is the most effective substance but after 3-5 years of L-dopa treatment, approximately half of all IPD patients develop fluctuations. Therefore, initial treatment with a dopamine receptor agonist is recommended.

The primary pathomechanism of restless legs syndrome is unclear. Neurophysiological, pharmacological, and imaging studies have demonstrated a complex interaction between central and peripheral structures. The degree of integration of central and peripheral mechanisms is not known. Altered excitability at a spinal level modulated by supraspinal rhythms of the brainstem possibly plays an important role. There is no anatomical structural lesion and it is more likely that circadian disturbances of dopaminergic and/or opioidergic neurotransmission are involved.

Objective: Alterations of motor phenomena are observable clinical phenomena of depressed patients. In addition to cognitive and emotional disturbances, motor dysfunctions are frequent psychopathological features which relate to neurobiological mechanisms of depression. Specific functions of various motor domains, pathophysiological concepts, and relevance of motor functions for diagnosis and prognosis of depression are summarized., Methods: The contemporary literature regarding clinical and research aspects of differential diagnosis, treatment response and pathophysiology as well as the current knowledge regarding objective measures of motor signs in depression are reviewed., Results: Alterations in motility (gross motor activity), locomotion, gestures, mimic, speech characteristics, and tremor are relevant for diagnosis, therapy and prognosis of depression. A large body of literature exists regarding qualitative, indirect measures of motor phenomena and quantitative analysis of motility. Only few unidimensional studies exist in respect to locomotion, gait and tremor in depression. The low correlation between physiological and clinical features may be due to methodological issues. Whereas most publications investigate motor functions indirectly using different functional coding and classification systems, only few studies report direct, physical, characteristics (kinematics) of motor phenomena in depression., Conclusions: Existing concepts do not clarify the relation of psychological and somatic components of motor signs. Agitation and retardation should be analyzed as multidimensional and independent variables. New psychometric instruments for documentation of motor phenomena in depression need further evaluation. Application of current technology and quantitative movement analysis may yield further insights in pathophysiological mechanisms and therapeutic strategies and represent important aspects of neurobiological research of depression.

These studies were performed in an attempt to clarify some of the pathophysiologic mechanisms which occur during and after global ischemia. Both nitric oxide and endothelin were demonstrated in gerbils to participate in responses to ischemia. It was shown that endogenous nitric oxide influences early postischemic reperfusion, systemic blood pressure and postischemic dopamine metabolism. Furthermore, the results indicated that nitric oxide played a role in dopamine release and that preischemic intracerebral nitric oxide formation significantly decreased ischemic dopamine release. In addition, ischemic release of endothelin-1 was detected; participation of nitric oxide in this release was observed. Further indication of functional interactions between nitric oxide and endothelin-1 in postischemic reperfusion were indicated by observations that endothelin-1 antagonists inhibited early hypoperfusion caused by Nitro-L-arginin and late hypoperfusion caused by endogenous endothelin-1. Nitric oxide was shown to decrease edema formation during the early postischemic period but contribute to edema formation during the late postischemic period. The findings indicate the importance of nitric oxide in stroke and ischemia.

Neuronal transplantation of dopaminergic embryonic ventral mesencephalic cells aims at replacing the lost striatal dopamine in Parkinson's disease. Functional effects of intrastriatal ventral mesencephalic transplants are reflected in improvements of bradykinesia and rigidity. However, a more widespread clinical application critically depends on further technical refinements, specifically in the area of improved survival of the grafted ventral mesencephalic dopamine neurones. This review highlights some of the progress made in the field of ventral mesencephalic transplantation in animal models of Parkinson's disease and also discusses issues and results obtained by our own research group in Munich. Thus we studied whether cryo- or neuroprotective additives during cryopreservation of ventral mesencephalic tissue can improve survival of such tissue/cells following transplantation. Concerning immunological aspects we studied the effects of pooled or co-transplanted embryonic tissue on survival and function of grafts and whether immunosuppression with cyclosporine A has beneficial effects. Possible neurotoxic effects of cyclosporine A were considered in a separate study. Finally, we established in vivo voltammetry to measure dopamine release from the graft and effects of the grafts on related parts of the dopaminergic system in the living animal. In the clinic we employed guidelines for preoperative patient evaluation and respective tests are described.

Valproic acid has a wider antiepileptic spectrum than any other antiepileptic drug (AED) in clinical use. Valproate administration causes many neurochemical and neurophysiological alterations, including increased GABA levels, modified GABA turnover and release, decreased gamma-hydroxybutyrate synthesis and release, increased serotonin and dopamine release, decreased aspartate levels, reduction of repetitive firing of neurons, and possibly a reduction in calcium (T) currents; however, none of these effects have consistently and unequivocally been linked to the antiepileptic action of valproate.

Dopamine is an important mediator of the neuronal adaptation mechanism of the retina. Tetrahydrobiopterin (BH4) is cofactor of the rate-limiting enzymatic tyrosine-hydroxylase step in the biosynthetic pathway of dopamine. This enzymatic step causes an oxidation of BH4 to dihydrobiopterin (BH2), which is reduced again to BH4 by action of dihydropterin-reductase (DHPR) and dihydrofolate-reductase (DHFR). Triamterene, a pterin derivate, is known to induce DHFR after initial inhibition. Concomitant elevation of retinal BH4 will result in a higher dopamine concentration. ERG changes of Long-Evans rats mediated by this triamterene effect on dopamine concentration were examined after the rats received triamterene with tap water in two experimental series for 5 and 11 days. After 5 days of triamterene administration a significant decrease of scotopic a- and b-wave ERG amplitudes were registered. After 11 days of triamterene application the decrease could be shown to be even more substantial. This effect was completely reversible: 10 weeks after cessation of triamterene supply ERG amplitudes increased to previous levels. The observed transient ERG changes support the concept of biopterin as an mediator of neuronal adaptation mechanisms of the retina.

In this work 23 month old rats were fed for 200 days with different protein diets (NT-diet: 19% protein, 72% of animal origin and LP-diet: 8.8% protein exclusively of vegetable origin). Some metabolic parameters and lifespan (on the base of a 50% death-rate) were determined. The relations of the liver free amino acids glycine + alanine and tyrosine + phenylalanine + branched chain amino acids and the ratio of phenylalanine/tyrosine were determined to be higher in the LP-group. Phenylalanine in liver and urea concentrations in liver and serum were lower in the LP-group. Furthermore the dopamine or serotonin levels were significantly lower in lateral and medial or lateral regions of the hypothalamus respectively in LP-diet fed rats. The norepinephrine content was not modified by the diets. The median lifespan of 23 month old rats was higher by 24% following LP-treatment. These results suggest that the protein component (amino acids) of different diets may modify metabolic parameters and lifespan of animals by mechanisms in which the central regulation may be involved.

The racemic and optically active 2-chloroethylcarbamoyl derivatives of 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines 6 and 8 were synthesized. The enantiomers of the benzazepine 5 were obtained by consecutive treatment of (+/-)-5 with (-) and (+)-dibenzoyl-tartaric acids. Compounds 6 are strong DA and NE uptake inhibitors while 8 exhibits inhibition towards 5-HT. The inhibitory effect of 6 is characterized by clearly expressed enantioselectivity. So 1-S-6 is a 26, resp. a 40 times stronger inhibitor of DA and NE uptake than 1-S-6. (+/-)-6 shows moderate antiulcer activity on water-immersion stress ulcer.

Increased hypothalamic dopamine turnover may prevent the ovulatory LH peak by different mechanisms and may in this way result in anovulation. Ten patients with anovulatory menstrual cycles who had been treated with clomiphene citrate without success were given the dopaminolytic drug pimozide (Antalon) at a dose of 5 mg/day orally either from day 7 to day 11 (7 women; group 1) or from day 11 to day 15 of the menstrual cycle (4 women; group 2). One patient from group 2 ovulated during the treatment cycle. A further woman from this group exhibited an LH peak, but did not ovulate, whereas a slow increase of the circulating LH level was recorded in the remaining two patients. Systematic investigations should clarify whether introduction of dopaminolytic therapy in the treatment of hypothalamic anovulation may be justified.

The effects of the oxygen radical generating system hypoxanthine (HX)/xanthine oxidase (XO) on the [3 H]--dopamine uptake, the TBARS- and thiol content in striatal synaptosomes of adult rats were examined. Preincubation of synaptosomes with 20 mU XO/0.25 mM HX diminished the dopamine uptake and oxidized thiol groups of synaptosomes. Under these conditions no increase of TBARS, an indicator of lipid peroxidation, was observed. We concluded that in the used hypoxia model free radical mediated damage does not occur.

Recovery of the dopamine storage pool after depletion by reserpine was slightly enhanced by treatment with nandrolone but remained unaffected by nootropic drugs.

The authors describe the synthesis of a shorter-chained somatostatin analogue in which the ring size of the native molecule is largely preserved by incorporation of S-carboxymethyl-L-homocysteinamid and ring closure via its side-chain function. This synthesis involves the linkage of Boc-Phe-D-Trp-Lys[Z(pCl)]-Thr-Phe-Thr-Ser-OH to H-Hcy(CH2-CO-Lys[Z(oCl)]-Asn-Phe-OMe)-NH2 and subsequent azide cyclization. In contrast to somatostatin, the somatostatin analogue thus obtained produces, when applied intracerebroventricularly to rats, a decrease in the dopamine content of the striatum.

The tuberculum olfactorium of the adult rat was investigated by means of neurohistological, fluorescence histochemical and enzyme histochemical methods. Using the rapid Golgi impregnation technique, seven neuron types could be demonstrated which can clearly be differentiated according to morphological criteria. Using the glyoxylic acid techniques, strongly fluorescent dopamine fibers are, in different densities, visible within the various laminae. Kainic acid application into the ventral tegmental area is followed by a strikingly reduced, no more structurally associated dopamine fiber fluorescence. After DFP intoxication, only a small proportion of the neuron population of the tuberculum olfactorium does exhibit an AChE activity; the AChE containing neurons are different as to their size and shape. The findings presented here are discussed with respect to the attributability of histochemical findings to cytoarchitectural features of this brain area.