Neurocognitive deficits in major depression and a new theory of ADHD: a model of impaired antagonism of cholinergic-mediated prepotent behaviours in monoamine depleted individuals.

The study builds on the propositions introduced in a companion paper on the neuropharmacology of cognition and its relation to key findings in psychiatry. Cognitive inhibition is often invoked to explain performance in psychiatric illness. Yet it remains only a general conceptual model of executive dysfunction. Premotor theory proposes both neuroanatomical and neuropharmacological equivalents of conscious and unconscious processes. The interaction between monoaminergic and cholinergic neurotransmission is stated to have an inverse effect on these two fundamental psychological processes. If one conceives of cognitive inhibition as a failure to voluntarily suppress unconscious prepotent responses, then a deficit in monoaminergic antagonism of cholinergic facilitated prepotent responses accounts for the observed behavioural phenotypes. The plasticity of behaviour is further hypothesized to have an equivalent in intracellular signalling leading to plastic changes in neural networks. Apart from inhibition of prepotent responses it permits the formulation of new behavioural phenotypes. At the receptor level Gi-Gq/11 transduction coupling is proposed to mediate this effect. A hypofunctioning monoaminergic system is thought to underlie the clinical pictures of major depression and ADHD. The neurocognitive deficits of depression include memory loss, poor concentration and rumination. ADHD is characterized by inattention, impulsivity and hyperactivity. Both these syndromes effectively respond to raising serotonin and dopamine levels, respectively. The core symptoms can usefully be attributed to an imbalance between the neuromodulatory effects of monoamines and ACh. Taking the model of monoaminergic-muscarinic receptor interactions presented previously and extended here, a new hypothesis is proposed for the core symptoms of ADHD. Accordingly, impulsivity and hyperactivity result from impaired dopaminergic inhibition and remodelling of muscarinic mediated prepotent responses. The model also predicts memory impairment in major depression by proposing that low serotonin levels in the neocortex is linked to focal hippocampal dysfunction. Hippocampal theta is proposed to trigger phasic monoaminergic activation involved in encoding of cortical traces and plasticity of propotent networks. It proposes a hypothesis for the enhancement of mood and behaviour induced by antidepressants is partly a response to plasticity of neural networks, that is, remodelling of cholinergic-mediated negative habitual behaviours.

Unilateral neglect: a theory of proprioceptive space of a stimulus as determined by the cerebellar component of motor efference copy (and is autism a special case of neglect).

Unilateral neglect is a devastating condition, which manifests as a loss of a person's spatial awareness opposite the damaged side of the brain. It challenges our conception of the seat of the soul and its explanation is at the heart of the mind-body problem. A heuristic definition of the dorsal stream of a modality is here based on the categorization of parietal networks by the cerebellar component of motor efference copy. Taking this premise, the proprioceptive space of a stimulus is established as a concept in this paper. It is proposed that unilateral neglect is typically a dysfunction of proprioceptive space of a stimulus associated with lesions of the dorsal stream. Furthermore, most experimental findings of unilateral visual neglect (and by extrapolation, other sensory modalities), can be explained by two developmental mechanisms by which the proprioceptive space of a stimulus is encoded in the parietal cortex. Its right and left hemisphere representation can be dissociated from the hemifield of presentation of perceptual information, such that the left hemifield can have a left hemisphere representation through callosal connections and likewise, the right hemifield can have a right hemifield representation. The processing of a sensory stimulus in either parietal hemisphere is dynamically determined as shown by experimental modulation of performance. A theory of historical precedence will provide a developmental background to the organization of proprioceptive space and will invoke separate models according to specified terms of engagement. A model based on the expansion and contraction of the proprioceptive space of a stimulus as a gradient across both hemispheres and modulated by concurrent proprioceptive state will be differentiated from a model that is non-graduating but competitive and lacks such modulation. In other words, the dorsal representation of a sensory stimulus in the former case is shared to a varying degree by the two parietal hemispheres, whereas in the latter case the representation of left and right aspects of the same object stimulus is strictly divided between the two hemispheres. A further hypothesis of a dorsoventral gradient of the peripheral and foveal components of proprioceptive space characterizing dorsal stream networks will predict the double dissociation revealed by experimental paradigms. It will explain why some patients show neglect only in foveal while others only in peripheral vision. The paper proposes to unify neglect, extinction and optic ataxia on the one hand, and spatial and object-based neglect on the other hand, under a singularly proficient paradigmatic structure. A binding model as described is a component theory that acknowledges how the involved pathways or transitional zones in a pathway may contribute to a differential clinical picture as one progresses from posterior to anterior parietal cortex. Finally, a brief discussion is given on how autistic subjects neglect spatial cues and the inability of a spatial cognitive transformation underlies the impairments postulated for 'a theory of mind'.

A scientific paradigm for consciousness: a theory of premotor relations.

Consciousness has become a holy grail for scientific research only in the last few decades. In spite of the extensive recent research in the field agreement on a correct approach to a theory has been elusive. We all have an intuitive idea of what we mean by the term and at the very least relate awareness to a descriptive phenomenology. I present a theory of consciousness based on motor capacity. An organism may exert control through movement and any action it performs on its surroundings results in a reaction. This type of reafference generated by movement provides the organism with a unique opportunity to compare perceptual information, for example, a retinal image of a ball with what the body is telling the agent about the object. In other words, limb movements will describe a certain physical distance to the object and the shape will be conveyed by the arc described around it by any part of the body that comes into contact with it. The reafference, also called motor efference copy, can modulate neocortical networks strictly associated with concurrent perceptual information via input to thalamocortical projections. Concurrent perceptual and motor reafferent input provide the critical organizing principles bestowing on a neural assembly the capacity of conscious awareness. The cortical neural coding represents an interactive history and is what I call a premotor relation. It avoids the trap of behaviorism by emphasizing a developmental causality such that, once the networks are established no further motoric component is required. Supportive evidence for this position comes from the classic psychological studies of perceptual adaptation to distorting lenses facilitated by movement and elegant animal experiments dissociating sensorimotor development from visual exposure. One of the most innovative and useful conceptions advanced in the paper is a component theory of motor efference copy analyzing the two key parameters of any action namely force and proprioceptive change. There is massive neocortical input to the basal ganglia and cerebellum and recent research has implicated cognitive roles for these structures. I propose they serve the respective component parameters of motor efference copy. Finally, a theory of premotor relations provides a model for understanding how dysfunction in the basal ganglia and cerebellum relates to cognitive features of schizophrenia and autism, respectively. Motor dysfunction figures prominently in the early literature on these syndromes and I make the case for a fundamental causal connection between motor and cognitive symptoms.

Plasma atrial natriuretic peptide in essential hypertension after treatment with terazocin.

The aim of this study was to evaluate the medium term effects of the selective alpha1-adrenenergic- blocker terazocin on atrial natriuretic peptide (ANP) levels in patients with moderate essential hypertension. The drug was given orally for 30 days. The daily dose was 1 mg for the first 7 days, 2 mg for the next 7 days and 5 mg for the remaining period of this clinical trial. At the end of this clinical trial, plasma ANP levels increased by 16.40% despite the drop in blood pressure while left atrial and ventricular diameters remained unchanged. These findings indicate that the increase of ANP plasma levels is not the result of a mechanical load on the left cardiac chambers but the result of a pharmacological action. These observations also indicate that terazocin exerts part of its antihypertensive action by increasing ANP plasma levels.