Advanced Neuro-Psychiartic Research for Scientific Homoeopathic Treatment
Research Continuing…
Independent Researcher : Dr. Jakir Hossain Laskar, PhD
Research Proposal : Underlying Mechanism of Neuro-Psychiatric Disease-associated Memory and Attention Impairment.
Abstract
How are the mechanisms of memory and attention affected due to changes in various sub-strata (neurochemical, cellular, neural, pathophysiological, molecular, neurobiological, etc.) in the human brain for neuro-psychiatric diseases which lead to memory impairments and attention deficit syndromes?
Introduction
The proposed study is designed to address major deficit in knowledge regarding memory impairments and attention deficit syndromes caused by various depressive illnesses including MDD. Several recent studies by researchers have explored a good number of specific phenomena which can help identify underlying mechanisms of depression-associated memory and attention impairment.
Recent overviews of the literature from previous research suggest:
Brain-derived neurotrophic factor (BDNF) plays an important role in repair of neurons in the adult brain. BDNF serum levels have been found to be lower in depressed patients indicating ketamine-induced plasticity in MDD. Also, the alterations in amygdalar glutamatergic neurochemistry and the alteration of monoamine neurotransmission, in particular serotonin (5-HT), have been considered the most significant pathophysiological mechanism of depressive disorders which produce excessive cytokines and interleukins through inflammatory pathways. Has ketamine-induced plasticity in MDD due to decreased BDNF serum levels any role in memory and attention impairment?
Astrocytes, the most numerous and versatile of all types of glial cells, are crucial to the neuronal microenvironment by regulating glucose metabolism, neurotransmitter uptake for glutamate, synaptic development and maturation. Reduced astrocyte cell number occurs in MDD causing altered glutamate neurotransmission and metabolism, with alterations in the expression of protein and mRNA for astrocyte markers, such as, glial fibrilary acidic protein (GFAP), gap junction proteins (connexin 40 and 43), the water channel aquaporin-4 (AQP-4), a calcium-binding protein (S100B) and glutamatergic markers including the excitatory amino acid transporters 1 and 2 (EAAT 1 and EAAT 2) and glutamine synthetase. Also, glial-mediated glutamatergic dysfunction, microglial pathology and impaired oligodendrocytes in the hippocampus which decreases myelination and impairs expression of myelin-related genes, are afflicted in unipolar and bipolar depression. Have astrocyte cell number reduction, glial-mediated glutamatergic dysfunction, microglial pathology and impaired oligodendrocytes in the hippocampus any role in memory and attention impairment?
Cortisol exerts its functions in CNS via binding mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) – both of which are highly expressed in human hippocampus and several studies have suggested that alterations in the levels of MR and GR may contribute to the dysregulation in MDD with elevated cortisol levels and hippocampal atrophy. On the other hand, corticosteroid excess is also associated with declarative (both episodic and semantic) memory impairment and hippocampal atrophy. Have alterations in the levels of MR and GR in MDD with elevated cortisol levels any role in memory and attention impairment?
Reductions in amygdalar and hippocampal volume – caused by decreased granule neurons (GN) in the dentate gyrus (DG) – putatively reflect dendritic atrophy are widely reported in major depressive disorder (MDD) with altered serum concentrations of neuroprotective kynurenic acid (KA), neurotoxic 3-hydroxy kynurenine (3HK) and quinolinic acid (QA) along with kynurenine pathway metabolites. Have reductions in amygdalar and hippocampal volume with dendritic atrophy in MDD any role in memory and attention impairment?
Brain metabolism in depressed unipolar and bipolar patients is hypoactive in the middle frontal gyri, the pregenual and posterior anterior cingulate, the superior temporal gyrus, insula, and the cerebellum, while hyperactivity exists in subcortical (caudate nucleus, thalamus), limbic (amygdala, anterior hippocampus), and medial and inferior frontal regions. Research findings show presynaptic dopaminergic markers are decreased, while postsynaptic markers are increased in MDD. This reduction of serotonin and dopamine in MDD was recently summarized in a revised version of the monoamine hypothesis, which focuses more on a dysfunction at the level of the MAO enzyme. Have hypoactive brain metabolism, decreased presynaptic or increased postsynaptic dopaminergic markers and MAO enzyme dysfunction any role in memory and attention impairment?
Symptoms of depression can be induced through blockade of acetylcholinesterase (AChE) leading to decreased glutamate metabolism which lowers the mitochondrial energy production of glutamatergic neurons. Morphometric changes occur in dentate gyrus and medial prefrontal cortex (mPFC) for MDD. Studies have suggested that low gamma-aminobutyric acid (GABA), impairments in serotonin (5-HT) neurotransmission, progressive decrease of N-acetylaspartate to total creatine ratio in the pregenual anterior cingulate cortex and dysfunction of the lateral habenula are associated with major depression. Have decreased glutamate metabolism, morphometric changes in dentate gyrus and medial prefrontal cortex (mPFC) and dysfunction of the lateral habenula in MDD any role in memory and attention impairment?
Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons which has a possible role in depression-related disorders. Depressive-like beheviours might also be associated to altered amino-acid neurotransmission in cortical and brain stem areas along with increased monoamine oxidase-A (MAO-A) VT in the prefrontal and anterior cingulate cortex. Studies of white matter tracts in patients with depression have shown that frontothalamic loops passing through the anterior limb of the internal capsule (ALIC) are abnormal significantly. Have neuropeptide galanin and frontothalamic loop abnormality any role in memory and attention impairment?
Changes in the circulatory aminopeptidases [decreased plasma Dipeptidyl-peptidase-IV (DPP-IV), Prolyl-oligopeptidase (POP) and increased plasma Leucine aminopeptidase (LAP)] activities have been found in unipolar disorder. Zinc-containing neurons form associational circuitry throughout the cortex, amygdala and hippocampus, which subserve mood regulation and cognitive functions. Neuronal zinc is concentrated within glutamatergic neurons, acting as an allosteric modulator of the N-methyl d-aspartate and other receptors that regulate excitatory neurotransmission and neuroplasticity. Clinically, serum zinc is lower in MDD. Adult neurogenesis, particularly in the subgranular zone, is thought to be linked with learning and memory. Chronic stress inhibits adult hippocampal neurogenesis and also impairs learning and memory. The hippocampus (HC) and prefrontal cortex (PFC) function jointly as a memory system which enables multitask processing (working memory) and consolidation of contextual information. The amygdala, by contrast, is necessary for the consolidation of emotional memories. Cognitive and neurophysiological studies have shown that HC-PFC processing is impaired, and amygdaloid processing is enhanced, by stress and in anxiety and mood disorders, including MDD. Have changes in the circulatory aminopeptidases, impaired HC-PFC processing and enhanced amygdaloid processing any role in memory and attention impairment?
Method
Participants
Required number of people with depressive illnesses (MDD and others), both male and female, both poor and rich, from various nations, of different religious / ethnic background, student population of different age group, depressed women, elderly people and the old will be used as participants.
Procedures
The proposed study will be conducted through a combination of experiments, surveys and interviews, and also data will be analyzed by using special equipment. Deep Brain Stimulation (DBS), Electrophysiological recording procedures, such as, Brain imaging techniques (Computed axial tomography, Diffuse optical imaging, Event-related optical signal, Magnetic resonance imaging (MRI), Functional magnetic resonance imaging, Magneto-encephalography, Positron emission tomography (PET), Single-photon emission computed tomography) will be required. Also, Brain computer interface (BCI), biopotential amplifier, chemical sensing, digital telemetry, electrocorticogram (ECOG), electroencephalogram (EEG), inductive coupling, wireless micropower instrumentation will be required. High-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) detection (using their standard protocols) may be used for the determination of metabolite concentrations.
Commercially available colorimetric sandwich ELISA kits will be used to quantify plasma levels of BDNF. Genomic DNA will be extracted by polymerase chain-reaction and gel electrophoresis. Gene Expression Analysis, Transcriptomics studies for gene expression, Voxel-based morphometry (VBM) for underlying cellular mechanism, 3-D Proton longitudinal 1H-MR spectroscopy study, Cell Culture and Neurogenesis Assay will be conducted. We will develop population-specific expression analysis (PSEA), a computational method of analyzing gene expression in samples of varying composition that can improve analyses of quantitative molecular data in many biological contexts. Analysis of phosphatidylcholine and sphingomyelin molecular species from brain extracts using capillary liquid chromatography electrospray ionization mass spectrometry and Immuno-affinity chromatography will be conducted. Methods of interphase neuromolecular cytogenetics for studying chromosomes and the nuclear organization in brain cells will have to be adopted, whereas, Cerebral microdialysis will be embraced as a research tool to measure the neurochemistry of human brain. Magnetic resonance spectroscopy and Mass spectrometry (MS) provide great opportunities for the sensitive measurement of neurochemicals and neuropeptide analysis.
Predicted Results
Due to depressive neuropathology in human brain, we may find impaired memory encoding (including Acoustic encoding, Visual encoding, Tactile encoding and Semantic encoding), the process of laying down a memory which begins with attention regulated by the thalamus and the frontal lobe. Phonological loop which allows auditory input within our echoic memory to facilitate remembering, and malfunctioning neurons in the primary somatosensory cortex of the brain which react to vibrotactile stimuli may be found impaired. Also, iconic memory where visual sensory information is temporarily stored before being encoded into long-term storage may be found impaired because of reductions in amygdalar volume within the medial temporal lobe. Synaptic memory consolidation (which occurs within the first few hours after learning or encoding) and system consolidation (where hippocampus-dependent memories become independent) along with synaptic plasticity or neural plasticity which is an important neurochemical foundation of memory and learning may be found abnormal. Memory storage and memory retrieval (including Free recall, Cued recall, Serial recall) may also be impaired due to neurochemical changes for MDD and other depressive illnesses.
Due to changes in various sub-strata in the human brain for depressive illnesses, Focused Attention, Sustained Attention (vigilance and concentration), Selective Attention, Alternating Attention, Divided Attention, etc. may be impaired. We may found anterograde amnesia resulting from failure of memory encoding and storage due to malfunctioning of neurons in the mammillary bodies of the damaged hypothalamus that make connections with the thalamus, which in turn makes connections with the cortex of the brain, where long-term memories are stored. In retrograde amnesia, damage to Broca’s area or Wernicke’s areas of the brain can be observed, which are specifically linked to speech production and language information, may probably cause language-related memory loss. Eventually, experiments may show organic amnesia, psychogenic amnesia, conduction aphasia, syntactic aphasia, developmental dyslexia, constructional apraxia, ideokinetic apraxia, optic agnosia, visual shape agnosia, etc.
