Band 31, Heft 6

In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABA A receptor (R) and and N-methyl d -aspartate (NMDA)R agonists and antagonists. In these studies, [ 123 I]iodobenzamide binding to the D 2/3 R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABA A R agonist muscimol (1 mg/kg), the GABA A R antagonist bicuculline (1 mg/kg), the NMDAR agonist d -cycloserine (20 mg/kg) or the NMDAR antagonist amantadine (40 mg/kg). Muscimol reduced D 2/3 R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d -cycloserine elevated D 2/3 R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABA A R agonist and the NMDAR antagonist on the one side and by the GABA A R antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABA A Rs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.

Alzheimer's disease (AD) is a very common cause of dementia in the elderly. It is characterized by progressive amnesia and accretions of neurofibrillary tangles (NFTs) of neurons and senile plaques in the neuropil. After aging, the inheritance of the apolipoprotein E (ApoE) epsilon 4 (ε4) allele is the greatest risk factor for late-onset AD. The ApoE protein is the translated product of the ApoE gene. This protein undergoes proteolysis, and the resulting fragments colocalize with neurofibrillary tangles and amyloid plaques, and for that matter may be involved in AD onset and/or progression. Previous studies have reported the pathogenic potential of various ApoE fragments in AD pathophysiology. However, the pathways activated by the fragments are not fully understood. In this review, ApoE fragments obtained from post-mortem brains and body fluids, cerebrospinal fluid (CSF) and plasma, are discussed. Additionally, current knowledge about the process of fragmentation is summarized. Finally, the mechanisms by which these fragments are involved in AD pathogenesis and pathophysiology are discussed.

In animal models, prolonged exposure (2 h) to high-level noise causes an irreparable damage to the synapses between the inner hair cells and auditory nerve fibers within the cochlea. Nevertheless, this injury does not necessarily alter the hearing threshold. Similar findings have been observed as part of typical aging in animals. This type of cochlear synaptopathy, popularly called “hidden hearing loss,” has been a significant issue in neuroscience research and clinical audiology scientists. The results obtained in different investigations are inconclusive in their diagnosis and suggest new strategies for both prognosis and treatment of cochlear synaptopathy. Here we review the major physiological findings regarding cochlear synaptopathy in animals and humans and discuss mathematical models. We also analyze the potential impact of these results on clinical practice and therapeutic options.

The molecular and chemical properties of neuronal nitric oxide synthase (nNOS) have made it a key mediator in many physiological functions and signaling transduction. The NOS monomer is inactive, but the dimer form is active. There are three forms of NOS, which are neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) nitric oxide synthase. nNOS regulates nitric oxide (NO) synthesis which is the mechanism used mostly by neurons to produce NO. nNOS expression and activation is regulated by some important signaling proteins, such as cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), calmodulin (CaM), heat shock protein 90 (HSP90)/HSP70. nNOS-derived NO has been implicated in modulating many physiological functions, such as synaptic plasticity, learning, memory, neurogenesis, etc. In this review, we have summarized recent studies that have characterized structural features, subcellular localization, and factors that regulate nNOS function. Finally, we have discussed the role of nNOS in the developing brain under a wide range of physiological conditions, especially long-term potentiation and depression.

The ketogenic diet (KD) is characterized by a diet ratio of 4:1 fat to non-fat energy sources. For decades KD has been successfully used to control seizures in epilepsy patients. Investigations into its mechanism of action suggest that it may have an effect on the metabolic, nervous, immune, and digestive systems. In this review, we postulate that KD may also improve depressive symptoms – for that, we highlight the similarities between depression and epilepsy, describe the extent to which body systems involved in both conditions are affected by the KD, and ultimately hypothesize how KD could improve MDD outcomes. Research into animal models and human patients have reported that KD can increase mitochondrial biogenesis and increase cellular resistance to oxidative stress both at the mitochondrial and genetic levels. Its effect on neurotransmitters alters cell-to-cell communication in the brain and may decrease hyperexcitability by increasing Gamma Aminobutyric Acid (GABA) and decreasing excitatory neurotransmitter levels. Its anti-inflammatory effects are mediated by decreasing chemo- and cytokine levels, including TNF-alpha and IL-1 levels. Finally, KD can alter gut microbiota (GM). Certain strains of microbiota predominate in major depressive disorder (MDD) when compared to healthy individuals. Recent evidence points to Bacteroidetes as a potential treatment predictor as it seems to increase in KD treatment responders for epilepsy. Each of these observations contributes to the presumed modulatory effects of KD on mood and supports its potential role as antidepressant.

Major depressive disorder (MDD) is a highly prevalent and disabling condition for which the currently available treatments are not fully effective. Existing unmet needs include rapid onset of action and optimal management of concurrent agitation. Dexmedetomidine (DEX) is a selective and potent α 2-adrenergic receptor ( α 2-AR) agonist, with unique pharmacokinetic and pharmacodynamic properties. In this review, we discuss pre-clinical and clinical studies which focused on DEX in the context of its putative antidepressant effects for the management of MDD. Preliminary data support DEX as an antidepressant with fast onset of action, which would be especially helpful for patients experiencing treatment resistant depression, and agitation. We further explore the mechanistic and clinical implications of considering DEX as a putative antidepressant agent, and the next steps to explore the efficacy of low dose DEX infusion among patients with treatment resistant depression.

Mirror-induced visual illusion obtained through mirror therapy is widely used to facilitate motor recovery after stroke. Activation of primary motor cortex (M1) ipsilateral to the moving limb has been reported during mirror-induced visual illusion. However, the mechanism through which the mirror illusion elicits motor execution processes without movements observed in the mirrored limb remains unclear. This study aims to review evidence based on brain imaging studies for testing the hypothesis that neural processes associated with kinaesthetic motor imagery are attributed to ipsilateral M1 activation. Four electronic databases were searched. Studies on functional brain imaging, investigating the instant effects of mirror-induced visual illusion among stroke survivors and healthy participants were included. Thirty-five studies engaging 78 stroke survivors and 396 healthy participants were reviewed. Results of functional brain scans (n = 20) indicated that half of the studies (n = 10, 50%) reported significant changes in the activation of ipsilateral M1, which mediates motor preparation and execution. Other common neural substrates included primary somatosensory cortex (45%, kinaesthesia), precuneus (40%, image generation and self-processing operations) and cerebellum (20%, motor control). Similar patterns of ipsilateral M1 activations were observed in the two groups. These neural substrates mediated the generation, maintenance, and manipulation of motor-related images, which were the key processes in kinaesthetic motor imagery. Relationships in terms of shared neural substrates and mental processes between mirror-induced visual illusion and kinaesthetic motor imagery generate new evidence on the role of the latter in mirror therapy. Future studies should investigate the imagery processes in illusion training for post-stroke patients.

Persistent postural perceptual dizziness (PPPD) is a relatively newer term, and this term is included in the International Classification of Diseases in its 11th revision. The typical features of PPPD include the presence of persistent dizziness, non-spinning vertigo, and unsteadiness, and these symptoms are exacerbated during upright posture, movement, or visual stimuli. Moreover, the structural changes have also been identified in the brains of PPPD patients, particularly in visual, vestibular, and limbic areas. These include a decrease in the volume and gyration of gray matter, a decrease in the blood flow to the cortex region, and alterations in the structural and functional connectivity, particularly in the visual-vestibular networks. Moreover, the impairment in sensory processing is restricted not only to the vestibular and visual regions; instead, there is a generalized impairment in the sensory processing, and thus, there is a multisensory dimension of sensory impairment. Selective serotonin uptake inhibitors and serotonin-norepinephrine reuptake inhibitors are the mainstay drugs for the management of PPPD patients. However, a significant proportion of PPPD patients do not show improvement in response to standard drug therapy. The employment of alternative and complementary treatment strategies, including vestibular rehabilitation therapy, cognitive behavioral therapy, and non-invasive vagal nerve stimulation, is effective in the management of PPPD patients. The present review discusses the alterations in the brains of PPPD patients along with the possible non-pharmacological treatment options in these types of patients.

Functional magnetic resonance imaging a neuroimaging technique which is used in brain disorders and dysfunction studies, has been improved in recent years by mapping the topology of the brain connections, named connectopic mapping. Based on the fact that healthy and unhealthy brain regions and functions differ slightly, studying the complex topology of the functional and structural networks in the human brain is too complicated considering the growth of evaluation measures. One of the applications of irregular graph deep learning is to analyze the human cognitive functions related to the gene expression and related distributed spatial patterns. Since a variety of brain solutions can be dynamically held in the neuronal networks of the brain with different activity patterns and functional connectivity, both node-centric and graph-centric tasks are involved in this application. In this study, we used an individual generative model and high order graph analysis for the region of interest recognition areas of the brain with abnormal connection during performing certain tasks and resting-state or decompose irregular observations. Accordingly, a high order framework of Variational Graph Autoencoder with a Gaussian distributer was proposed in the paper to analyze the functional data in brain imaging studies in which Generative Adversarial Network is employed for optimizing the latent space in the process of learning strong non-rigid graphs among large scale data. Furthermore, the possible modes of correlations were distinguished in abnormal brain connections. Our goal was to find the degree of correlation between the affected regions and their simultaneous occurrence over time. We can take advantage of this to diagnose brain diseases or show the ability of the nervous system to modify brain topology at all angles and brain plasticity according to input stimuli. In this study, we particularly focused on Alzheimer’s disease.