Somatostatin and the pathophysiology of Alzheimer's disease.

Among the central features of Alzheimer's disease (AD) progression are altered levels of the neuropeptide somatostatin (SST), and the colocalisation of SST-positive interneurons (SST-INs) with amyloid-ß plaques, leading to cell death. In this theoretical review, I propose a molecular model for the pathogenesis of AD based on SST-IN hypofunction and hyperactivity. Namely, hypofunctional and hyperactive SST-INs struggle to control hyperactivity in medial regions in early stages, leading to axonal Aß production through excessive presynaptic GABAB inhibition, GABAB1a/APP complex downregulation and internalisation. Concomitantly, excessive SST-14 release accumulates near SST-INs in the form of amyloids, which bind to Aß to form toxic mixed oligomers. This leads to differential SST-IN death through excitotoxicity, further disinhibition, SST deficits, and increased Aß release, fibrillation and plaque formation. Aß plaques, hyperactive networks and SST-IN distributions thereby tightly overlap in the brain. Conversely, chronic stimulation of postsynaptic SST2/4 on gulutamatergic neurons by hyperactive SST-INs promotes intense Mitogen-Activated Protein Kinase (MAPK) p38 activity, leading to somatodendritic p-tau staining and apoptosis/neurodegeneration - in agreement with a near complete overlap between p38 and neurofibrillary tangles. This model is suitable to explain some of the principal risk factors and markers of AD progression, including mitochondrial dysfunction, APOE4 genotype, sex-dependent vulnerability, overactive glial cells, dystrophic neurites, synaptic/spine losses, inter alia. Finally, the model can also shed light on qualitative aspects of AD neuropsychology, especially within the domains of spatial and declarative (episodic, semantic) memory, under an overlying pattern of contextual indiscrimination, ensemble instability, interference and generalisation.

Semantic processing and neurobiology in Alzheimer's disease and Mild Cognitive Impairment.

In the present theoretical review we will perform a critical surveillance of linguistic and semantic processing in Mild Cognitive Impairment and Alzheimer's disease, explicitly favouring a neurobiological prism. We conjecture that most linguistic alterations arise from semantic indiscrimination through inhibitory hypofunction. Specifically, a conjoint cluster of cholinergic dysfunction, Aß load and somatostatin-positive cell loss renders the semantic network disinhibited and overly noisy: fine discriminatory processes in temporal and medial-frontal regions cannot differentiate semantic representations from baseline unconscious activity, which leads to failures in faithful retrieval (preferentially idiosyncratic lexical-semantic links, e.g., proper names), verbal fluency anomalies, semantic interference, dampened N400 effects, and various semiological deviances.

The neural hierarchy of consciousness: A theoretical model and review on neurophysiology and NCCs.

The chief undertaking in the studies of consciousness is that of unravelling the neural correlates of consciousness. To this day, this crusade remains at an impasse, with a clash of two main theoretical stances: the Global Neuronal Workspace and the Recurrent Processing. Yet, cellular and neurophysiological studies of consciousness have been mostly dissociated from the two. Herein, a theoretical review will be put forth with the aim to change that. In its first half, I will cover the hard available evidence on the neurophysiology of consciousness, and in its second half, I will weave a theoretical model that reconciles the all-or-none cortical ignition (P3b) and graded recurrent processing (VAN) theories on the basis of neurophysiological evidence. As should be made clear, this Neural Hierarchy model substantiates and expands on a novel take on conscious awareness: the levels of processing approach, partitioning the conscious architecture into lower- and higher-order, graded and nonlinear.

Subcortical Aphasia.

PURPOSE OF REVIEW: Subcortical structures have long been thought to play a role in language processing. Increasingly spirited debates on language studies, arising from as early as the nineteenth century, grew remarkably sophisticated as the years pass. In the context of non-thalamic aphasia, a few theoretical frameworks have been laid out. The disconnection hypothesis postulates that basal ganglia insults result in aphasia due to a rupture of connectivity between Broca and Wernicke's areas. A second viewpoint conjectures that the basal ganglia would more directly partake in language processing, and a third stream proclaims that aphasia would stem from cortical deafferentation. On the other hand, thalamic aphasia is more predominantly deemed as a resultant of diaschisis. This article reviews the above topics with recent findings on deep brain stimulation, neurophysiology, and aphasiology. RECENT FINDINGS: The more recent approach conceptualizes non-thalamic aphasias as the offspring of unpredictable cortical hypoperfusion. Regarding the thalamus, there is mounting evidence now pointing to leading contributions of the pulvinar/lateral posterior nucleus and the anterior/ventral anterior thalamus to language disturbances. While the former appears to relate to lexical-semantic indiscrimination, the latter seems to bring about a severe breakdown in word selection and/or spontaneous top-down lexical-semantic operations. The characterization of subcortical aphasias and the role of the basal ganglia and thalamus in language processing continues to pose a challenge. Neuroimaging studies have pointed a path forward, and we believe that more recent methods such as tractography and connectivity studies will significantly expand our knowledge in this particular area of aphasiology.

Semantic priming and neurobiology in schizophrenia: A theoretical review.

In this theoretical review we bridge the cognitive and neurobiological sciences to shed light on the neurocognitive foundations of the semantic priming effect in schizophrenia. We review and theoretically evaluate the neurotransmitter systems (dopaminergic, GABAergic and glutamatergic) and neurobiological underpinnings of behavioural and electrophysiological (N400) semantic priming in the pathology, and the main hypotheses on their geneses: a disinhibition of the semantic spread of activation, a disorganised semantic storage or noisy lexical-semantic associations, a psychomotor artefact, an artefact of relatedness proportions, or an inability to mobilise contextual information. We further assess the literature on the endophenotype of Formal Thought Disorder from multiple standpoints, ranging from neurophysiology to cognition: considerations are weaved on neuronal (PV basket cell, SST, VIP) and receptor deficits (DRD1, NMDA), neurotransmitter imbalances (dopamine), cortical and dopaminergic lateralisation, inter alia. In conclusion, we put forth novel postulates on the underlying causes of controlled hypopriming, automatic hyperpriming, N400 reversals (larger amplitudes for close associations), indirect versus direct hyperpriming, and the endophenotype of lexical-semantic disturbances in schizophrenia.

Neurophysiological basis of the N400 deflection, from Mismatch Negativity to Semantic Prediction Potentials and late positive components.

The first theoretical model on the neurophysiological basis of the N400: the deflection reflects layer I dendritic plateaus on a preparatory state of synaptic integration that precedes layer V somatic burst firing for conscious identification of the higher-order features of the stimulus (a late positive shift). Plateaus ensue from apical disinhibition by vasoactive intestinal polypeptide-positive interneurons (VIPs) through suppression of Martinotti cells, opening the gates for glutamatergic feedback to trigger dendritic regenerative potentials. Cholinergic transients contribute to these dynamics directly, holding a central role in the N400 deflection. The stereotypical timing of the (frontal) glutamatergic feedback and the accompanying cholinergic transients account for the enigmatic "invariability" of the peak latency in the face of a gamut of different stimuli and paradigms. The theoretical postulations presented here may bring about unprecedented level of detail for the N400 deflection to be used in the study of schizophrenia, Alzheimer's disease and other higher-order pathologies. The substrates of a late positive component, the Mismatch Negativity and the Semantic Prediction Potentials are also surveyed.