I explicate how various relational interactions between (M,R)-systems may have realizations in pathophysiology, and how the possible reversals of the effects of these interactions then become therapeutic models. Functional entailment receives a rigorous category-theoretic treatment, and plays a crucial role in this continuing saga of relational biology.
Evidence for a dysfunction in cognitive coordination in schizophrenia is emerging, but it is not specific enough to prove (or disprove) this long-standing hypothesis. Many aspects of the external world are spatially mapped in the brain. A comprehensive internal representation relies on integration of information across space. Focus on spatial integration in the perceptual and cognitive processes will generate empirical data that shed light on the pathophysiology of schizophrenia.
A number of cognitive and behavioral variables influence the performance in tasks of theory of mind (ToM). Since two of the most important variables, memory and explicit expression, are impaired in schizophrenic patients, the ToM appears inconsistent in these patients. An ideal instrument of ToM should therefore account for deficient memory and impaired ability of these patients to explicitly express intentions. If such an instrument is developed, it should provide information that can be used not only to understand the (...) class='Hi'>pathophysiology but also to monitor patients. (shrink)
Using three paradigm cases of persons living with Parkinson's Disease (PD) the authors make a case for augmenting and enriching a Cartesian medical account of the pathophysiology of PD with an enriched understanding of the lived body experience of PD, the lived implications of PD for a particular person's concerns and coping with the illness. Linking and adding a thick description of the lived experience of PD can enrich caregiving imagination and attunement to the patient's possibilities, concerns and constraints. (...) The work of Merleau-Ponty is used to articulate the middle terms of the lived experience of dwelling in a lifeworld. Examining lived experience of embodied intentionality, skilled bodily capacities as highlighted in Merleau-Ponty's non-mechanistic physiology opens new therapeutic, coping and caregiving possibilities. Matching temporal rhythms can decrease the stress of being assisted with activities of daily living. For example, caregivers and patients alike can be taught strategies for extending their lived bodily capacities by altering rhythms, by shifting hyperactivity to different parts of the body and other strategies that change the perceptual experience associated with walking in different environment. A medical account of the pathophysiology of PD is nessessary and useful, but not sufficient for designing caregiving in ways that enrich and extend the existential skills of dwelling of persons with PD. The dominance of mechanistic physiology makes caregivers assume that it is the 'real discourse' about the disease, causing researchers and caregivers alike to overlook the equally real lived experience of the patient which requires different descriptive discourses and different sources of understanding. Lack of dialogue between the two discourses is tragic for patients because caregivers need both in order to provide attuned, effective caregiving. (shrink)
The human self model comprises essential features such as the experiences of ownership, of body-centered spatial perspectivity, and of a long-term unity of beliefs and attitudes. In the pathophysiology of schizophrenia, it is suggested that clinical subsyndromes like cognitive disorganization and derealization syndromes reflect disorders of this self model. These features are neurobiologically instantiated as an episodically active complex neural activation pattern and can be mapped to the brain, given adequate operationalizations of self model features. In its unique capability (...) of integrating external and internal data, the prefrontal cortex (PFC) appears to be an essential component of the neuronal implementation of the self model. With close connections to other unimodal association cortices and to the limbic system, the PFC provides an internally represented world model and internal milieu data of the organism, both serving world orientation. In the pathophysiology of schizophrenia, it is the dysfunction of the PFC that is suggested to be the neural correlate for the different clinical schizophrenic subsyndromes. The pathophysiological study of psychiatric disorders may contribute to the theoretical debate on the neuronal basis of the self model. (shrink)
The Unified Medical Language System and the Gene Ontology are among the most widely used terminology resources in the biomedical domain. However, when we evaluate them in the light of simple principles for wellconstructed ontologies we find a number of characteristic inadequacies. Employing the theory of granular partitions, a new approach to the understanding of ontologies and of the relationships ontologies bear to instances in reality, we provide an application of this theory in relation to an example drawn from the (...) context of the pathophysiology of hypertension. This exercise is designed to demonstrate how, by taking ontological principles into account we can create more realistic biomedical ontologies which will also bring advantages in terms of efficiency and robustness of associated software applications. (shrink)
We outline some ways in which motor neglect (the underutilization of a limb despite adequate strength) and hysterical paralysis (failure to move a limb despite no relevant structural damage or disease) may throw light on the pathophysiology of catatonia. We also comment on the manifold inadequacies of distinguishing too firmly between symptoms of “neurologic origin” and of “psychiatric origin.”.
BackgroundBioethics and law distinguish between the practices of "physician-assisted death" and "allowing the patient to die."DiscussionAdvances in biotechnology have allowed medical devices to be used as destination therapy that are designed for the permanent support of cardiac function and/or respiration after irreversible loss of these spontaneous vital functions. For permanent support of cardiac function, single ventricle or biventricular mechanical assist devices and total artificial hearts are implanted in the body. Mechanical ventilators extrinsic to the body are used for permanent support (...) of respiration. Clinical studies have shown that destination therapy with ventricular assist devices improves patient survival compared to medical management, but at the cost of a substantial alteration in end-of-life trajectories. The moral and legal assessment of the appropriateness and permissibility of complying with a patient's request to electively discontinue destination therapy in a life-terminating act in non-futile situations has generated controversy. Some argue that complying with this request is ethically justified because patients have the right to request withdrawal of unwanted treatment and be allowed to die of preexisting disease. Other commentators reject the argument that acceding to an elective request for death by discontinuing destination therapy is 'allowing a patient to die' because of serious flaws in interpreting the intention, causation, and moral responsibility of the ensuing death.SummaryDestination therapy with cardiac and/or ventilatory medical devices replaces native physiological functions and successfully treats a preexisting disease. We posit that discontinuing cardiac and/or ventilatory support at the request of a patient or surrogate can be viewed as allowing the patient to die if--and only if--concurrent lethal pathophysiological conditions are present that are unrelated to those functions already supported by medical devices in destination therapy. In all other cases, compliance with a patient's request constitutes physician-assisted death because of the pathophysiology induced by the turning off of these medical devices, as well as the intention, causation, and moral responsibility of the ensuing death. The distinction between allowing the patient to die and physician-assisted death is pivotal to the moral and legal status of elective requests for death by discontinuing destination cardiac and/or ventilatory medical devices in patients who are not imminently dying. This distinction also represents essential information that must be disclosed to patients and surrogates in advance of consent to this type of therapy. (shrink)
Georg Northoff employs a comparison with Parkinson's disease in an effort to tease apart the underlying pathophysiology of psychogenic catatonia. Northoff's extensive treatment of the subject is abetted by his own research as well as the research of others. Nevertheless, a number of points concerning basal ganglia/thalamocortical processing need to be raised, some adding support to his hypothesis and others detracting from it.
Dr. Northoff's comprehensive comparison of clinical symptoms and neurobiological findings in catatonia with that of Parkinson's disease through integration of various levels of investigation, from neurochemistry up to the subjective experience, is a good example of the new strategies we need to improve our understanding of psychiatric disorders. His multimodal approach, leading to the hypothesis that different pathophysiologies of transcortical “horizontal modulation” and “bottom-up/top-down” – orbitofrontal/basal ganglia – “vertical modulations,” may explain many clinical aspects of catatonia and Parkinson's disease, and (...) thereby fills an important gap in current theories of psychomotor syndromes. However, to analyze more specifically the pathophysiology of catatonia, comparison not only with Parkinson's disease, but also with schizophrenia and anxiety disorders would be helpful. As long as the pathohistological and molecular basis of catatonic syndromes is unknown, theories based mainly on functional considerations remain preliminary. (shrink)
The neurosciences are generating new findings regarding genetic and neurobiological aspects of the pathophysiology of mental disorders. Especially, certain genetic risk factors like neuregulin-1 seem to predispose individuals to a psychotic phenotype beyond the limits of traditional classificatory boundaries between organic psychoses in Alzheimerâs disease, bipolar affective disorder and schizophrenia. Little, however, is known about how such genetic risk factors actually confer an increased risk for psychosis in an individual patient. A gap between neuroscientific findings and psychopathological phenomena exists. (...) The main hypothesis how this gap may be bridged is that mental disorders arise as a consequence of dysfunctions of normal mental functions. Modularity may provide a useful conceptual framework in that temporally and/or spatially stable neural circuits subserve certain physiological functions of the human brain, which become the target of pathophysiological effectors. The idea of a modular construction of the human brain is based on neurobiological evidence regarding the columnar architecture of the cerebral cortex, which provides certain elementary analytical functions. Modular dysfunctions may be assessed with methods of experimental psychopathology, in which subsystems of brain functions are tested with standardized experimental psychological techniques (functional psychopathology). The main questions here are how to define a module, and whether the classical neuroscientific definitions can be used to characterize higher integrative functions of the human brain. (shrink)
An examination of the early history of Nobel Committee deliberations, coupled with a survey of discoveries for which prizes have been awarded to date – and, equally revealing, discoveries for which prizes have not been awarded – reveals a pattern. This pattern suggests that Committee members may have internalized the received, biomedical model and conferred awards in accord with the physicalistic premises that ground this model. I consider the prospect of a paradigm change in medical science and the possible repercussions (...) of such a change on the distribution of Nobel prizes within the domain of physiology or medicine. For expository purposes, I contrast a model based on a science of pathophysiology with one based on a science of pathopsychophysiology. I propose a means whereby members might minimize the potentially blinding effects of model-dependence and come to evaluate medical discoveries from an inter-model rather than an exclusively intra-model perspective. By bringing to light questions rarely asked and proposing answers, I seek to open a dialogue and furnish a vehicle by which the putative delimiting effects of model-dependence might be overcome. (shrink)
Gliomas can display marked changes in the concentrations of energy metabolism molecules such as creatine (Cr), phosphocreatine (PCr) and lactate, as measured using magnetic resonance spectroscopy (MRS). Moreover, the BOLD (blood oxygen level dependent) contrast enhancement in functional magnetic resonance imaging (fMRI) can be reduced or missing within or near gliomas, while neural activity is not significantly reduced (so-called neurovascular decoupling), so that the location of functionally eloquent areas using fMRI can be erroneous. In this paper, we adapt a previously (...) developed model of the coupling between neural activation, energy metabolism and hemodynamics, by including the venous dilatation Balloon model of Buxton and Frank. We show that decreasing the cerebral blood flow (CBF) baseline value, or the CBF increase fraction, results in a decrease of the BOLD signal and an increase of the lactate peak during a sustained activation. Baseline lactate and PCr levels are not significantly affected by CBF baseline reduction, but are altered even by a moderate decrease of mitochondrial respiration. Decreasing the total Cr and PCr concentration reduces the BOLD signal after the initial overshoot. In conclusion, we suggest that the coupled use of BOLD fMRI and MRS could contribute to a better understanding of the neurovascular and metabolic decoupling in gliomas. (shrink)
Depue & Morrone-Strupinsky's (D&M-S's) model of affiliation meets the criteria advanced for the definition of behavior systems and endophenotypes. We argue that its application in psychiatry could be useful for identifying a biological pathophysiology common to a variety of conditions that are currently classified in very different categories of psychiatric nosography, including autism, schizoid personality, primary psychopathy, and dismissing attachment.
Carbon monoxide (CO) intoxication leads to acute and chronic neurological deficits, but little is known about the specific noxious mechanisms. 1 H magnetic resonance spectroscopy (MRS) may allow insight into the pathophysiology of CO poisoning by monitoring neurochemical disturbances, yet only limited information is available to date on the use of this protocol in determining the neurological effects of CO poisoning. To further examine the short-term and long-term effects of CO on (...) the central nervous system, we have studied seven patients with CO poisoning assessed by gray and white matter MRS, magnetic resonance imaging (MRI) and neuropsychological testing. Five patients suffered from acute high-dose CO intoxication and were in coma for 1–6 days. In these patients, MRI revealed hyperintensities of the white matter and globus pallidus and also showed increased choline (Cho) and decreased N -acetyl aspartate (NAA) ratios to creatine (Cr), predominantly in the white matter. Lactate peaks were detected in two patients during the early phase of high-dose CO poisoning. Two patients with chronic low-dose CO exposure and without loss of consciousness had normal MRI and MRS scans. On follow-up. five of our seven patients had long-lasting intellectual impairment, including one individual with low-dose CO exposure. The MRS results showed persisting biochemical alterations despite the MRI scan showing normalization of morphological changes. In conclusion, the MRS was normal in patients suffering from chronic low-dose CO exposure; in contrast, patients with high-dose exposure showed abnormal gray and white matter levels of NAA/Cr, Cho/Cr and lactate, as detected by 1 H MRS, suggesting disturbances of neuronal function, membrane metabolism and anaerobic energy metabolism, respectively. Early increases in Cho/Cr and decreases of NAA/Cr may be related to a poor long-term outcome, but confirmation by future studies is needed. (shrink)
Developmental stuttering is a speech disorder in fluency characterized by repetitions, prolongations and silent blocks, especially in the initial parts of utterances. Although their symptoms are motor related, people who stutter show abnormal patterns of cerebral hemispheric dominance in both anterior and posterior language areas. It is unknown whether the abnormal functional lateralization in the posterior language area starts during childhood or emerges as a consequence of many years of stuttering. In order to address this issue, we measured the lateralization (...) of hemodynamic responses in the auditory cortex during auditory speech processing in adults and children who stutter, including preschoolers, with near-infrared spectroscopy (NIRS). We used the analysis-resynthesis technique to prepare two types of stimuli: (i) a phonemic contrast embedded in Japanese spoken words (/itta/ vs. /itte/) and (ii) a prosodic contrast (/itta/ vs. /itta?/). In the baseline blocks, only /itta/ tokens were presented. In phonemic contrast blocks, /itta/ and /itte/ tokens were presented pseudo-randomly, and /itta/ and /itta?/ tokens in prosodic contrast blocks. In adults and children who do not stutter, there was a clear left-hemispheric advantage for the phonemic contrast compared to the prosodic contrast. Adults and children who stutter, however, showed no significant difference between the two stimulus conditions. A subject-by-subject analysis revealed that not a single subject who stutters showed a left advantage in the phonemic contrast over the prosodic contrast condition. These results indicate that the functional lateralization for auditory speech processing is in disarray among those who stutter, even at preschool age. These results shed light on the neural pathophysiology of developmental stuttering. (shrink)
Although several studies have suggested that cortical alterations underlie such age-related visual deficits as decreased acuity, little is known about what changes actually occur in visual cortex during healthy aging. Two recent studies showed changes in primary visual cortex (V1) during normal aging; however, no studies have characterized the effects of aging on visual cortex beyond V1, important measurements both for understanding the aging process and for comparison to changes in age-related diseases. Similarly, there is almost no information about changes (...) in visual cortex in Alzheimer’s disease (AD), the most common form of dementia. Because visual deficits are often reported as one of the first symptoms of AD, measurements of such changes in the visual cortex of AD patients might improve our understanding of how the visual system is affected by neurodegeneration as well as aid early detection, accurate diagnosis and timely treatment of AD. Here we use fMRI to first compare the visual field map (VFM) organization and population receptive fields (pRFs) between young adults and healthy aging subjects for occipital VFMs V1, V2, V3, and hV4. Healthy aging subjects do not show major VFM organizational deficits, but do have reduced surface area and increased pRF sizes in the foveal representations of occipital VFMs relative to healthy young control subjects. These measurements are consistent with behavioral deficits seen in healthy aging. We then demonstrate the feasibility and first characterization of these measurements in two patients with mild AD, which reveal potential changes in visual cortex as part of the pathophysiology of AD. Our data aid in our understanding of the changes in the visual processing pathways in normal aging and provide the foundation for future research into earlier and more definitive detection of AD. (shrink)
It is one of the central aims of the philosophy of science to elucidate the meanings of scientific terms and also to think critically about their application. The focus of this essay is the scientific term predict and whether there is credible evidence that animal models, especially in toxicology and pathophysiology, can be used to predict human outcomes. Whether animals can be used to predict human response to drugs and other chemicals is apparently a contentious issue. However, when one (...) empirically analyzes animal models using scientific tools they fall far short of being able to predict human responses. This is not surprising considering what we have learned from fields such evolutionary and developmental biology, gene regulation and expression, epigenetics, complexity theory, and comparative genomics. (shrink)
Studies of aging and autism as outlined by Bertone, Mottron, & Faubert (Bertone et al.) and by Faubert & Bertone suggest that disorders of cognitive coordination involving impairments of dynamic gestalt grouping and context-sensitivity may be common to several different disorders. We agree that such studies may shed light on these processes and their neuronal bases. However, we also emphasize that dynamic grouping and context-sensitivity can fail in various ways, and that, although the underlying pathophysiology may often involve NMDA-receptor (...) malfunction, many different malfunctions are possible, and each of these may result from any one of a number of different etiologies. (shrink)
Centuries of scientific progress have been devoted to reducing uncertainty. Newtonian physics, introduced over 300 years ago, allowed for precise prediction of planetary and tidal motion, falling bodies and infinitely more, in addition to allowing the construction of the material world. The 20th century witnessed a revolution in our understanding of organ and cellular function and dysfunction, elucidation of pathways, mediators, receptors, and molecular interactions, and breakthroughs in the characterization of replication, transcription, and translation, all of which has been integral (...) to our understanding of human physiology and pathophysiology. Clinical epidemiology has had a revolutionary impact on our .. (shrink)
Depression occurs frequently with sleep disturbance such as insomnia. Sleep in depression is associated with disinhibition of the rapid eye movement (REM) sleep. Despite the coincidence of the depression and sleep disturbance, neural substrate for depressive behaviors and sleep regulation remains unknown. Habenula is an epithalamic structure regulating the activities of monoaminergic neurons in the brain stem. Since the imaging studies showed blood flow increase in the habenula of depressive patients, hyperactivation of the habenula has been implicated in the (...) class='Hi'>pathophysiology of the depression. Recent electrophysiological studies reported a novel role of the habenular structure in regulation of REM sleep. In this article, we propose possible cellular mechanisms which could elicit the hyperactivation of the habenular neurons and a hypothesis that dysfunction in the habenular circuit causes the behavioral and sleep disturbance in depression. Analysis of the animals with hyperactivated habenula would open the door to understand roles of the habenula in the heterogeneous symptoms such as reduced motor behavior and altered REM sleep in depression. (shrink)
Northoff's target article presents a unifying theory of the pathophysiology of catatonia, as compared to Parkinson's disease. We address two arguments in particular that do not appear justified by available evidence: (1) The physiological basis of catatonia is the breakdown of right hemisphere prefrontal-parietal cortical connectivity, and (2) Dysfunction in this system results in specific deficits in termination of action.
Adenosine 5′-triphosphate (ATP) was identified in 1970 as the transmitter responsible for non-adrenergic, non-cholinergic neurotransmission in the gut and bladder and the term ‘purinergic’ was coined. Purinergic cotransmission was proposed in 1976 and ATP is now recognized as a cotransmitter in all nerves in the peripheral and central nervous systems. P1 (adenosine) and P2 (ATP) receptors were distinguished in 1978. Cloning of these receptors in the early 1990s was a turning point in the acceptance of the purinergic signalling hypothesis. There (...) are both short-term purinergic signalling in neurotransmission, neuromodulation and secretion and long-term (trophic) purinergic signalling of cell proliferation, differentiation and death in development and regeneration. Much is known about the mechanisms of ATP release and its breakdown by ectonucleotidases. Recently, there has been emphasis on purinergic pathophysiology, including neurodegenerative and neuropsychiatric disorders. Purinergic therapeutic strategies are being developed for treatment of gut, kidney, bladder, lung, skeletal and reproductive system disorders, pain and cancer. (shrink)
Chlorpromazine efficacy in schizophrenia was observed 60 years ago. Advances in pharmacotherapy of this disorder have been modest with effectiveness still limited to the psychosis psychopathology and mechanism still dependent on dopamine antagonism. While a look backward may generate pessimism, future discovery may be far more robust. The near future will see significant changes in paradigms applied in discovery. Rather than viewing schizophrenia as a disease entity represented by psychosis, the construct will be deconstructed into component psychopathology domains. Each domain (...) will represent a clinical target for aetiologic and therapeutic discovery. Research on pathophysiology will shift to the neural circuit level in relation to specific behavioural constructs. Progress at the molecular, genetic, cellular and network levels will be more robust. The behavioural paradigm will map on to the deconstructed clinical paradigm and in the process discovery will cut across current classification boundaries. (shrink)
K L Kahlbaum published in 1874 the ﬁrst recorded description of catatonia. Akinetic catatonia is now deﬁned as a neuropsychiatric syndrome principally characterised by akinesia, mutism, stupor, and catalepsy. 1 Even if some advances have been made in the recognition of catatonia, in particular by the development of different rating scales, 1 the pathophysiology of this syndrome is not clearly established. A right handed 14 year old girl presented with akinetic catatonia during an episode of depression in the context (...) of a bipolar type I disorder. Her catatonic status was characterised by akinesia with brief episodic spontaneous stereotyped movements, mutism, no spontaneous oral intake, catalepsy, waxy ﬂexibility, and stupor with brief occasional eye contacts. This corresponded to a total score of 19 on the Northoff Catatonia Scale.1 Electroencephalogram performed one day after onset of symptoms showed diffuse theta activity with sporadic diffuse delta activity. Cerebral magnetic resonance imaging was normal. Brain positron emission tomographies (PET) were obtained on a CTI-Siemens HR+ tomograph. A ﬁrst PET (PET1) using (18F(- ﬂuorodeoxyglucose (FDG) was performed on day 2 in a drug free state. Thereafter, intramuscular injection of 2 mg of lorazepam induced rapid clinical remission of the akinetic phase. Oral lorazepam was then given (3.75 mg/day) during ﬁve days. On day 8, a second PET with FDG was performed while the patient was treated by olanzapine (15 mg/day) and presented hyperactivity, logorrhoea, and disinhibition characterised by uncontrolled social interactions and physical contacts. Neuropsychological testing performed some days after remission revealed no apraxia or language disturbances but dysfunction of executive tasks manifested in the revised Wisconsin card sorting, the Tower of London, Stroop, and Trailmaking tests. Voxel based analyses comparing patient’s cerebral glucose metabolism with that of 29 right handed healthy controls (16 women and 13 men, mean age 32) were performed using Statistical Parametric Mapping (SPM99) (Wellcome Department of Cognitive Neurology, London, UK).. (shrink)
Sensory dysfunction has been shown to be a part of the pathophysiology of schizophrenia. Nowadays we have an objective, non-invasive tool with which to measure neural manifestations of sensory dysfunction. Defined as time-locked changes to external stimuli in the EEG, event-related potentials (ERPs) provide an objective index of information processing in the human brain. Importantly, ERPs may be analyzed through a variety of approaches such as conventional ERP analysis, analysis in the time-frequency domain, microstate segmentation and topographical analysis, as (...) well as source localisation analysis. Each of the methods gives distinct information; they also supplement each other. Here, an attempt is made to verify the validity of combining different approaches to study sensory dysfunction in neuropsychiatric disorders. For example, the data from a schizophrenic patient and an age- and sex-matched healthy subject generate a picture of the events which emerges after visual, proprioceptive and simultaneous presentation of stimuli in both modalities. This approach, though time-consuming, allows the visualisation of changes appearing in the malfunctioning brain as compared to the healthy brain. These methods could ultimately lead to a better establishment of one or more endophenotypes for the schizophrenic disorders. They might also serve as a way to track changes in response to various medications and therapies. (shrink)
This perspective considers the present and the future role of different neuroimaging techniques in the field of psychiatry. After identifying shortcomings of the mainly symptom-focussed diagnostic processes and treatment decisions in modern psychiatry, we suggest topics where neuroimaging methods have the potential to help. These include better understanding of the pathophysiology, improved diagnoses, assistance in therapeutic decisions and the supervision of treatment success by direct assessment of improvement in disease-related brain functions. These different questions are illustrated by examples from (...) neuroimaging studies, with a focus on severe mental and neuropsychiatric illnesses such as schizophrenia, depression and dementia. Despite all reservations addressed in the article, we are optimistic, that neuroimaging has a huge potential with regard to the above-mentioned questions. We expect that neuroimaging will play an increasing role in the future refinement of the diagnostic process and aid in the development of new therapies in the field of psychiatry. (shrink)
Although disturbed sleep is a prominent feature of schizophrenia, its relation to the pathophysiology, signs, and symptoms of schizophrenia remains poorly understood. Sleep disturbances are well known to impair cognition in healthy individuals. Yet, in spite of its ubiquity in schizophrenia, abnormal sleep has generally been overlooked as a potential contributor to cognitive deficits. Amelioration of cognitive deficits is a current priority of the schizophrenia research community, but most efforts to define, characterize, and quantify cognitive deficits focus on cross-sectional (...) measures. While this approach provides a valid snapshot of function, there is now overwhelming evidence that critical aspects of learning and memory consolidation happen offline, both over time and with sleep. Initial memory encoding is followed by a prolonged period of consolidation, integration, and reorganization, that continues over days or even years. Much of this evolution of memories is mediated by sleep. This article briefly reviews (i) abnormal sleep in schizophrenia, (ii) sleep-dependent memory consolidation in healthy individuals, (iii) recent findings of impaired sleep-dependent memory consolidation in schizophrenia, and (iv) implications of impaired sleep-dependent memory consolidation in schizophrenia. This literature suggests that abnormal sleep in schizophrenia disrupts attention and impairs sleep-dependent memory consolidation and task automation. We conclude that these sleep-dependent impairments may contribute substantially to generalized cognitive deficits in schizophrenia. Understanding this contribution may open new avenues to ameliorating cognitive dysfunction and thereby improve outcome in schizophrenia. (shrink)
In complex genetic disorders such as schizophrenia, endophenotypes have potential utility both in identifying risk genes and in illuminating pathophysiology. This is due to their presumed status as closer in the etiopathological pathway to the causative genes than is the currently defining clinical phenomenology of the illness and thus their simpler genetic architecture than that of the full syndrome. There, many genes conferring slight individual risk are additive or epistatic (interactive) with regard to cumulative schizophrenia risk. In addition the (...) use of endophenotypes has encouraged a conceptual shift away from the exclusive study of categorical diagnoses in manifestly ill patients, towards the study of quantitative traits in patients, unaffected relatives and healthy controls. A more recently employed strategy is thus to study unaffected first degree relatives of schizophrenia patients, who share some of the genetic diathesis without illness-related confounds that may themselves impact fMRI task performance. Consistent with the multiple biological abnormalities associated with the disorder, many candidate endophenotypes have been advanced for schizophrenia, including measures derived from structural brain imaging, EEG, sensorimotor integration, eye movements and cognitive performance (Allen 2009), but recent data derived from quantitative functional brain imaging measures present additional attractive putative endophenotypes. We will review two major, conceptually different approaches that use fMRI in this context. One, the dominant paradigm, employs defined cognitive tasks on which schizophrenia patients perform poorly as “cognitive stress tests”. The second uses very simple probes or “task-free” approaches where performance in patients and controls is equal. We explore the potential advantages and disadvantages of each method, the associated data analytic approaches and recent studies exploring their interface with the genetic risk architecture of schizophrenia. (shrink)
_The first part called the Preamble tackles: (a) the issues of silence and speech, and life and disease; (b) whether we need to know some or all of the truth, and how are exact science and philosophical reason related; (c) the phenomenon of Why, How, and What; (d) how are mind and brain related; (e) what is robust eclecticism, empirical/scientific enquiry, replicability/refutability, and the role of diagnosis and medical model in psychiatry; (f) bioethics and the four principles of beneficence, non-malfeasance, (...) autonomy, and justice; (g) the four concepts of disease, illness, sickness, and disorder; how confusion is confounded by these concepts but clarity is imperative if we want to make sense out of them; and how psychiatry is an interim medical discipline. The second part called The Issues deals with: (a) the concepts of nature and nurture; the biological and the psychosocial; and psychiatric disease and brain pathophysiology; (b) biology, Freud and the reinvention of psychiatry; (c) critics of psychiatry, mind-body problem and paradigm shifts in psychiatry; (d) the biological, the psychoanalytic, the psychosocial and the cognitive; (e) the issues of clarity, reductionism, and integration; (f) what are the fool-proof criteria, which are false leads, and what is the need for questioning assumptions in psychiatry. The third part is called Psychiatric Disorder, Psychiatric Ethics, and Psychiatry Connected Disciplines. It includes topics like (a) psychiatric disorder, mental health, and mental phenomena; (b) issues in psychiatric ethics; (c) social psychiatry, liaison psychiatry, psychosomatic medicine, forensic psychiatry, and neuropsychiatry. The fourth part is called Antipsychiatry, Blunting Creativity, etc. It includes topics like (a) antipsychiatry revisited; (b) basic arguments of antipsychiatry, Szasz, etc.; (c) psychiatric classification and value judgment; (d) conformity, labeling, and blunting creativity. The fifth part is called The Role of Philosophy, Religion, and Spirituality in Psychiatry. It includes topics like (a) relevance of philosophy to psychiatry; (b) psychiatry, religion, spirituality, and culture; (c) ancient Indian concepts and contemporary psychiatry; (d) Indian holism and Western reductionism; (e) science, humanism, and the nomothetic-idiographic orientation. The last part, called Final Goal, talks of the need for a grand unified theory. The whole discussion is put in the form of refutable points._. (shrink)
At the end of the 19th century, medical research in the United States was descriptive and rudimentary. American physician-investigators were primarily defining and categorizing disease entities. However, seeds of more mechanistic research had been laid in Europe, particularly in Germany, including the germ theory of disease etiology resulting from Pasteur and Koch's discoveries and the detailed descriptive pathology of the human body by Virchow and others. Prior to World War I, a graduate of an American medical school with an interest (...) in research commonly spent time in a laboratory of a productive European investigator. This European influence on American medicine and medical research was greatly respected, and a .. (shrink)
Phillips & Silverstein offer an exciting synthesis of ongoing efforts to link the clinical and cognitive manifestations of schizophrenia with cellular accounts of its pathophysiology. We applaud their efforts but wonder whether the highly inclusive notion of “context” adequately captures some important details regarding schizophrenia and NMDA/glutamate function that are suggested by work on language processing and cognitive electrophysiology.
Based on recent insight into the thalamocortical system and its role in perception and conscious experience, a unified pathophysiological framework for hallucinations in neurological and psychiatric conditions is proposed, which integrates previously unrelated neurobiological and psychological findings. Gamma-frequency rhythms of discharge activity from thalamic and cortical neurons are facilitated by cholinergic arousal and resonate in networks of thalamocortical circuits, thereby transiently forming assemblies of coherent gamma oscillations under constraints of afferent sensory input and prefrontal attentional mechanisms. If perception is based (...) on synchronisation of intrinsic gamma activity in the thalamocortical system, then sensory input to specific thalamic nuclei may merely play a constraining role. Hallucinations can be regarded as underconstrained perceptions that arise when the impact of sensory input on activation of thalamocortical circuits and synchronisation of thalamocortical gamma activity is reduced. In conditions that are accompanied by hallucinations, factors such as cortical hyperexcitability, cortical attentional mechanisms, hyperarousal, increased noise in specific thalamic nuclei, and random sensory input to specific thalamic nuclei may, to a varying degree, contribute to underconstrained activation of thalamocortical circuits. The reticular thalamic nucleus plays an important role in suppressing random activity of relay cells in specific thalamic nuclei, and its dysfunction may be implicated in the biological vulnerability to hallucinations in schizophrenia. Combined with general activation during cholinergic arousal, this leads to excessive disinhibition in specific thalamic nuclei, which may allow cortical attentional mechanisms to recruit thalamic relay cells into resonant assemblies of gamma oscillations, regardless of their actual sensory input, thereby producing an underconstrained perceptual experience. Key Words: Charles Bonnet syndrome; gamma oscillations; hallucinations; late paraphrenia; Lewy body dementia; perception; schizophrenia; thalamocortical system. (shrink)
The DSM-III, DSM-IV, DSM-IV-TR and ICD-10 have judiciously minimized discussion of etiologies to distance clinical psychiatry from Freudian psychoanalysis. With this goal mostly achieved, discussion of etiological factors should be reintroduced into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). A research agenda for the DSM-V advocated the "development of a pathophysiologically based classification system". The author critically reviews the neuroevolutionary literature on stress-induced and fear circuitry disorders and related amygdala-driven, species-atypical fear behaviors of clinical severity in (...) adult humans. Over 30 empirically testable/falsifiable predictions are presented. It is noted that in DSM-IV-TR and ICD-10, the classification of stress and fear circuitry disorders is neither mode-of-acquisition-based nor brain-evolution-based. For example, snake phobia (innate) and dog phobia (overconsolidational) are clustered together. Similarly, research on blood-injection-injury-type-specific phobia clusters two fears different in their innateness: 1) an arguably ontogenetic memory-trace-overconsolidation-based fear (hospital phobia) and 2) a hardwired (innate) fear of the sight of one's blood or a sharp object penetrating one's skin. Genetic architecture-charting of fear-circuitry-related traits has been challenging. Various, non-phenotype-based architectures can serve as targets for research. In this article, the author will propose one such alternative genetic architecture. This article was inspired by the following: A) Nesse's "Smoke-Detector Principle", B) the increasing suspicion that the "smooth" rather than "lumpy" distribution of complex psychiatric phenotypes (including fear-circuitry disorders) may in some cases be accounted for by oligogenic (and not necessarily polygenic) transmission, and C) insights from the initial sequence of the chimpanzee genome and comparison with the human genome by the Chimpanzee Sequencing and Analysis Consortium published in late 2005. Neuroevolutionary insights relevant to fear circuitry symptoms that primarily emerge overconsolidationally (especially Combat related Posttraumatic Stress Disorder) are presented. Also introduced is a human-evolution-based principle for clustering innate fear traits. The "Neuroevolutionary Time-depth Principle" of innate fears proposed in this article may be useful in the development of a neuroevolution-based taxonomic re-clustering of stress-triggered and fear-circuitry disorders in DSM-V. Four broad clusters of evolved fear circuits are proposed based on their time-depths: 1) Mesozoic (mammalian-wide) circuits hardwired by wild-type alleles driven to fixation by Mesozoic selective sweeps; 2) Cenozoic (simian-wide) circuits relevant to many specific phobias; 3) mid Paleolithic and upper Paleolithic (Homo sapiens-specific) circuits (arguably resulting mostly from mate-choice-driven stabilizing selection); 4) Neolithic circuits (arguably mostly related to stabilizing selection driven by gene-culture co-evolution). More importantly, the author presents evolutionary perspectives on warzone-related PTSD, Combat-Stress Reaction, Combat-related Stress, Operational-Stress, and other deployment-stress-induced symptoms. The Neuroevolutionary Time-depth Principle presented in this article may help explain the dissimilar stress-resilience levels following different types of acute threat to survival of oneself or one's progency (aka DSM-III and DSM-V PTSD Criterion-A events). PTSD rates following exposure to lethal inter-group violence (combat, warzone exposure or intentionally caused disasters such as terrorism) are usually 5-10 times higher than rates following large-scale natural disasters such as forest fires, floods, hurricanes, volcanic eruptions, and earthquakes. The author predicts that both intentionally-caused large-scale bioevent-disasters, as well as natural bioevents such as SARS and avian flu pandemics will be an exception and are likely to be followed by PTSD rates approaching those that follow warzone exposure. During bioevents, Amygdala-driven and locus-coeruleus-driven epidemic pseudosomatic symptoms may be an order of magnitude more common than infection-caused cytokine-driven symptoms. Implications for the red cross and FEMA are discussed. It is also argued that hospital phobia as well as dog phobia, bird phobia and bat phobia require re-taxonomization in DSM-V in a new "overconsolidational disorders" category anchored around PTSD. The overconsolidational spectrum category may be conceptualized as straddling the fear circuitry spectrum disorders and the affective spectrum disorders categories, and may be a category for which Pitman's secondary prevention propranolol regimen may be specifically indicated as a "morning after pill" intervention. Predictions are presented regarding obsessive-compulsive disorder (OCD) (e.g., female-pattern hoarding vs. male-pattern hoarding) and "culture-bound" acute anxiety symptoms (taijin-kyofusho, koro, shuk yang, shook yong, suo yang, rok-joo, jinjinia-bemar, karoshi, gwarosa, Voodoo death). Also discussed are insights relevant to pseudoneurological symptoms and to the forthcoming Dissociative-Conversive disorders category in DSM-V, including what the author terms fright-triggered acute pseudo-localized symptoms (i.e., pseudoparalysis, pseudocerebellar imbalance, psychogenic blindness, pseudoseizures, and epidemic sociogenic illness). Speculations based on studies of the human abnormal-spindle-like, microcephaly-associated (ASPM) gene, the microcephaly primary autosomal recessive (MCPH) gene, and the forkhead box p2 (FOXP2) gene are made and incorporated into what is termed "The pre-FOXP2 Hypothesis of Blood-Injection-Injury Phobia." Finally, the author argues for a non-reductionistic fusion of "distal (evolutionary) neurobiology" with clinical "proximal neurobiology," utilizing neurological heuristics. It is noted that the value of re-clustering fear traits based on behavioral ethology, human-phylogenomics-derived endophenotypes and on ontogenomics (gene-environment interactions) can be confirmed or disconfirmed using epidemiological or twin studies and psychiatric genomics. (shrink)
Psychiatry is a discipline on the border between the biomedical sciences on the one hand and the humanities and social sciences (most notably psychology and anthropology) on the other. This unique position undoubtedly contributes to the attractiveness of psychiatry as a medical specialism for many young doctors, but it also causes significant problems. Unlike other medical disciplines, in which the definitions of diseases are based on objective, measurable pathophysiological underpinnings, psychiatric diagnosis and classification has been based on descriptions of inherently (...) subjective mental and behavioral symptoms that are supposed to be deviant from "normal" psychology or behavior, as reflected in the current .. (shrink)
The reinforcement/extinction disorder hypothesis (Sagvolden et al.) is an important counterweight to the executive dysfunction model of attention-deficit/hyperactivity disorder (ADHD). However, like that model, it conceptualises ADHD as pathophysiologically homogeneous, resulting from a common core dysfunction. Recent studies reporting neuropsychological heterogeneity suggest that this common core dysfunction may be the scientific equivalent of a red herring.
This article considers the foundation of nursing as a moral practice. Its basic claim is that all nursing knowledge and action reside on a moral foundation. The clinical gaze meets vulnerability in the patient’s human condition. To see a patient’s wound is to see his or her hurt and discomfort; it is a concerned observation. To see the factual and pathophysiological is at the same time to see the ethical: the moral realities of suffering, pain and discomfort. A nurse’s emotional (...) sensitivities are central to understanding a patient’s experiences of illness. Emotions reveal value and ascribe moral importance to certain situations; they are addressed centrally by vulnerability and the moral realities of illness. Hence, the essence of nursing knowledge and nursing performance cannot be understood merely as ontology (i.e. as being-with-the-other). Nursing is basically being-for-the-other; it is responsibility; it is ethics. (shrink)
Since the time of Hippocrates, medical science sought to develop a practice based on "knowledge rather than opinion". However, in the light of recent alternative approaches to healing and a philosophy of science that, through thinkers like Kuhn, Rorty, and Foucault, is critical of claims to objective truth, we must reappraise the way in which medical interventions can be based on proven pathophysiological knowledge rather than opinion. Developing insights in Foucault, Lacan, and Wittgenstein, this essay argues for a recovery of (...) the Aristotelian idea of a techne, where there is a dynamic interplay between praxis and conceptualization. The result is a post-Kuhnian epistemology for medical science that recognizes the evaluative dimension of knowledge, but that also looks to a Platonic conception of the good as the ultimate constraint on human thought, thus avoiding the radically self-contained accounts of truth found in some post-modern thinkers. Keywords: normal science, power, truth, virtue CiteULike Connotea Del.icio.us What's this? (shrink)
Abundant pathophysiological and clinical evidence suggests that the algogenic code responsible for cardiac pain is not based on mechanisms (mcmahon). Recent evidence, however, has led various authors to postulate that some degree of specificity might be involved in visceral pain arising from other sources, but a intensity pattern is still the most plausible hypothesis for the genesis of visceral pain.
A common theme in the contemporary medical model of psychiatry is that pathophysiological processes are centrally involved in the explanation, evaluation, and treatment of mental illnesses. Implied in this perspective is that clinical descriptors of these pathophysiological processes are sufficient to distinguish underlying etiologies. Psychiatric classification requires differentiation between what counts as normality (i.e.- order), and what counts as abnormality (i.e.- disorder). The distinction(s) between normality and pathology entail assumptions that are often deeply presupposed, manifesting themselves in statements about what (...) mental disorders are. (shrink)
Evolutionary medicine (EM) is an emerging field of medical studies that uses evolutionary theory to explain the ultimate causes of health and disease. The field’s main objective is to reconceptualize bodily vulnerabilities and pathophysiologies as evolutionary tradeoffs—many the result of an evolutionary mismatch between our ancient genome and modern lifestyle. This conceptual shift allows EM to describe health and disease in terms of adaptive functions and to prescribe treatments that best complement our evolved bodies. The goal is to “transform the (...) way patients and doctors see disease” (Nesse and Williams 1994, p. 245) in order to harness a renewed “feeling for the organism as a product of natural selection” .. (shrink)
This commentary on blumberg et al. addresses complications associated with diagnostic testing for sympathetic dependence of pain that can lead to inappropriate positive and negative conclusions. In addition, it is suggested that their test be conceived as a test of the effect of local vascular pressure and that the two types of sensory disorders presented may differ primarily in the degree of sensitization of central pain pathways. Detailed reports with functionally-oriented testing like that done by BLUMBERG are essential for an (...) understanding the pathophysiological mechanisms. (shrink)
The central hyperexcitability observed in animal models supports a pathophysiological explanation for chronic human pain. Novel information on cholecystokinin (CCK) upregulation offers a rationale for reduced opioid response in neuropathic pain. However, the basic information provided by scientists should not lead clinicians to equate experimental models to chronic human conditions. Clinicians should provide careful reports and attempt to classify pathophysiologically clinical conditions that have so far been grouped generically. [blumberg et al.; coderre & katz; dickenson; wiesenfeld-hallin et al.].
Using dimensional analysis, we demonstrate that it is possible to quantify changes in the topological structure of cardiac dynamics over long periods of time. A method was developed to calculate a dimension-like measure (referred to here as apparent dimension) from a correlation algorithm within a data window of 500 heart beats which is moved in equidistant steps over the time series of the RR intervals over 24 hours. The correspondence between the apparent dimension and the correlation dimension was tested using (...) artificial data sequences. Furthermore 24 hour electrocardiographic recordings of two healthy subjects and of a patient with acute myocardial infarction were examined. The reliability of the analysis could be demonstrated and changes in dimension reflecting physiological as well as pathophysiological changes were observed. (shrink)
Visual information is fundamental to how we understand our environment, make predictions and interact with others. Recent research has underscored the importance of visuo-perceptual dysfunctions for cognitive deficits and pathophysiological processes in schizophrenia. In the current paper, we review evidence for the relevance of high frequency (beta/gamma) oscillations associated with the visuo-perceptual dysfunctions in schizophrenia. In the first part of the paper, we examine the relationship between beta/gamma band oscillations and visual processing during normal brain functioning. We then summarize studies (...) employing EEG/MEG which demonstrate reduced amplitude and synchrony of high-frequency activity during visual stimulation in schizophrenia. In the final part of the paper, we identify neurobiological correlates as well as offer perspectives for future research to stimulate further inquiry into the role of high-frequency oscillations in visual processing impairments in the disorder. (shrink)