IntroductionSymptoms of schizophrenia are closely related to aberrant language comprehension and production. Macroscopic brain changes seen in some patients with schizophrenia are suspected to relate to impaired language production, but this is yet to be reliably characterized. Since heterogeneity in language dysfunctions, as well as brain structure, is suspected in schizophrenia, we aimed to first seek patient subgroups with different neurobiological signatures and then quantify linguistic indices that capture the symptoms of “negative formal thought disorder”.MethodsAtlas-based cortical thickness (...) values of 66 patients with first-episode psychosis and 36 healthy controls were analyzed with hierarchical clustering algorithms to produce neuroanatomical subtypes. We then examined the generated subtypes and investigated the quantitative differences in MRS-based glutamate levels [in the dorsal anterior cingulate cortex ] as well as in three aspects of language production features: fluency, syntactic complexity, and lexical cohesion.ResultsTwo neuroanatomical subtypes among patients were observed, one with near-normal cortical thickness patterns while the other with widespread cortical thinning. Compared to the subgroup of patients with relatively normal cortical thickness patterns, the subgroup with widespread cortical thinning was older, with higher glutamate concentration in dACC and produced speech with reduced mean length of T-units and lower repeats of content words, despite being equally fluent.ConclusionWe characterized a patient subgroup with thinner cortex in first-episode psychosis. This subgroup, identifiable through macroscopic changes, is also distinguishable in terms of neurochemistry and language behavior. This study supports the hypothesis that glutamate-mediated cortical thinning may contribute to a phenotype that is detectable using the tools of computational linguistics in schizophrenia. (shrink)

This hypothesis proposes that increased extracellular glutamate in Amyotrophic Lateral Sclerosis (ALS) and cerebral ischemia, currently viewed as a trigger for excitotoxicity, is actually beneficial as it stimulates the utilization of glutamate as metabolic fuel. Renewed appreciation of glutamate oxidation by ischemic neurons has raised questions regarding the role of extracellular glutamate in ischemia. Is it detrimental, as suggested by excitotoxicity in early in vitro studies, or beneficial, as suggested by its oxidation in later in (...) vivo studies? The answer may depend on the activity of N‐methyl‐D‐aspartate (NMDA) glutamate receptors. Early in vitro procedures co‐activated NMDA receptors (NMDARs) containing 2A (GluN2A) and 2B (GluN2B) subunits, an event now believed to trigger excitotoxicity; however, during in vivo ischemia D‐serine and zinc molecules are released and these ensure only GluN2B receptors are stimulated. This not only prevents excitotoxicity but also initiates signaling cascades that allow ischemic neurons to import and oxidize glutamate. (shrink)

We propose a biochemical mechanism for celiac disease and non‐celiac gluten sensitivity that may rationalize many of the extradigestive disorders not explained by the current immunogenetic model. Our hypothesis is based on the homology between the 33‐mer gliadin peptide and a component of the NMDA glutamate receptor ion channel – the human GRINA protein – using BLASTP software. Based on this homology the 33‐mer may act as a natural antagonist interfering with the normal interactions of GRINA and its (...) partners. The theory is supported by numerous independent data from the literature, and provides a mechanistic link with otherwise unrelated disorders, such as cleft lip and palate, thyroid dysfunction, restless legs syndrome, depression, ataxia, hearing loss, fibromyalgia, dermatitis herpetiformis, schizophrenia, toxoplasmosis, anemia, osteopenia, Fabry disease, Barret's adenocarcinoma, neuroblastoma, urinary incontinence, recurrent miscarriage, cardiac anomalies, reduced risk of breast cancer, stiff person syndrome, etc. The hypothesis also anticipates better animal models, and has the potential to open new avenues of research. (shrink)

Disorders of consciousness and the self are at the forefront of schizophrenia symptomatology. Patients are impaired in feeling themselves as the authors of their thoughts and actions. In addition, their flow of consciousness is disrupted, and thought fragmentation has been suggested to be involved in the patients’ difficulties in feeling as being one unique, unchanging self across time. Both impairments are related to self disorders, and both have been investigated at the experimental level. Here we review evidence that both (...) mechanisms of motor control and the temporal structure of signal processing are impaired in schizophrenia patients. Based on this review, we propose that the sequencing of action and perception plays a key role in the patients’ impairments. Furthermore, the millisecond time scale of the disorders, as well as the impaired sequencing, highlights the cooperation between brain networks including the cerebellum, as proposed by Andreasen (1999). We examine this possibility in the light of recent knowledge on the anatomical and physiological properties of the cerebellum, its role in timing, and its involvement in known physiological impairments in patients with schizophrenia, e.g., resting states and brain dynamics. A disruption in communication between networks involving the cerebellum, related to known impairments in dopamine, glutamate and GABA transmission, may help to better explain why patients experience reduced attunement with the external world and possibly with themselves. (shrink)

Neuroleptic drugs disrupt the learning and performance of operant habits motivated by a variety of positive reinforcers, including food, water, brain stimulation, intravenous opiates, stimulants, and barbiturates. This disruption has been demonstrated in several kinds of experiments with doses that do not significantly limit normal response capacity. With continuous reinforcement neuroleptics gradually cause responding to cease, as in extinction or satiation. This pattern is not due to satiation, however, because it also occurs with nonsatiating reinforcement (such as saccharin or brain (...) stimulation). Repeated tests with neuroleptics result in earlier and earlier response cessation reminiscent of the kind of decreased resistance to extinction caused by repeated tests without the expected reward. Indeed, withholding reward can have the same effect on responding under later neuroleptic treatment as prior experience with neuroleptics themselves; this suggests that there is a transfer of learning (really unlearning) from nonreward to neuroleptic conditions. These tests under continuous reinforcement schedules suggest that neuroleptics blunt the ability of reinforcers to sustain responding at doses which largely spare the ability of the animal to initiate responding. Animals trained under partial reinforcement, however, do not respond as well during neuroleptic testing as animals trained under continuous reinforcement. Thus, neuroleptics can also impair responding (though not responsecapacity) that is normally sustained by environmental stimuli (and associated expectancies) in the absence of the primary reinforcer. Neuroleptics also blunt the euphoric impact of amphetamine in humans. These data suggest that the most subtle and interesting effect of neuroleptics is a selective attenuation of motivational arousal which is (a) critical for goal-directed behavior, (b) normally induced by reinforcers and associated environmental stimuli, and (c) normally accompanied by the subjective experience of pleasure. Because these drugs are used to treat schizophrenia and because they cause parkinsonian-like side effects, this action has implications for a better understanding of human pathology as well as normal motivational processes. (shrink)

Merleau-Ponty finds a philosophical interest in the psychoanalytical clinic, especially in the the clinic of children and hallucinating people, which can support the concepts of flesh and Ineinander. But in the philosophy of Merleau-Ponty there is also a clinical interest, residing in the link he establishes between the flesh, conceived as the origin of existence, and the pathologies that Freud described as “narcissistic” and nowadays called “psychotic” or “borderline” states. To support this hypothesis, we will link Merleau-Ponty’s own “clinic (...) of the origins” and Harold Searles’ theory of narcissistic pathologies based on his clinical experience with schizophrenics. This confrontation will reveal how a philosophy of flesh provides us not only with theoretical points of reference relevant to the clinic of schizophrenia, but also fruitful technical indications regarding the direction towards a cure of such a pathology, indications that join those provided by Searles. (shrink)

This commentary challenges the argument that the diathesis for hallucinations is equivalent to that for schizophrenia. Evidence against this comes from data on the prevalence of hallucinations in schizophrenia, their nonspecificity, and their relationships with moderating variables. We also highlight, however, the manner in which the Behrendt & Young (B&Y) hypothesis extends recent neuroscientific theories of schizophrenia, and its potential treatment applications.

This study compares 20 subjects, in each of three different settings, with serious psychotic disorder who hear voices, and compares their voice-hearing experience. We find that while there is much that is similar, there are notable differences in the kinds of voices that people seem to experience. In a California sample, people were more likely to describe their voices as intrusive unreal thoughts; in the South Indian sample, they were more likely to describe them as providing useful guidance; and in (...) our West African sample, they were more likely to describe them as morally good and causally powerful. What we think we may be observing is that people who fall ill with serious psychotic disorder pay selective attention to a constant stream of many different auditory and quasi-auditory events because of different “cultural invitations”—variations in ways of thinking about minds, persons, spirits and so forth. Such a process is consistent with processes described in the cognitive psychology and psychiatric anthropology literature, but not yet described or understood with respect to cultural variations in auditory hallucinations. We call this process “social kindling.”. (shrink)

Phillips & Silverstein (P&S, 2003) propose that NMDA-receptor dysfunction may be the fundamental neurobiological mechanism underlying and associating impaired holistic perception and cognitive coordination with schizophrenic psychopathology. We discuss how the P&S hypothesis shares different aspects of the weak central coherence account of autism from both theoretical and experimental perspectives. Specifically, we believe that neither those persons with autism nor those with schizophrenia integrate visuo-perceptual information efficiently, resulting in incongruous internal representations of their external world. However, although NMDA-hypofunction (...) may be responsible for perceptual impairments in schizophrenia and possibly autism, we suggest that it is highly unlikely that NMDA-hypofunction is specifically responsible for the autistic behavioral symptomology, as described by P&S in their target article. (shrink)

Phillips & Silverstein's focus on schizophrenia as a failure of “cognitive coordination” is welcome. They note that a simple hypothesis of reduced Gamma synchronisation subserving impaired coordination does not fully account for recent observations. We suggest that schizophrenia reflects a dynamic compensation to a core deficit of coordination, expressed either as hyper- or hyposynchronisation, with neurotransmitter systems and arousal as modulatory mechanisms.

Early-Onset Schizophrenia (EOS) and Attention Deficit-Hyperactivity Disorder (ADHD) are early- onset neurodevelopmental disorders associated with cognitive deficits. The current study represents the first attempt to compare these groups on a comprehensive cognitive test battery in a longitudinal design over 25 years in order to enhance our knowledge of particular patterns resulting from the interaction between normal maturational processes and different illness processes of these disorders. In the baseline study, 19 adolescents with schizophrenia were compared to 20 adolescents with (...) ADHD and 30 healthy controls (HC), all between 12 and 18 years of age. After 13 years (T2) and after 25 years (T3) they were re-evaluated with the cognitive test battery. A cognitive Composite Score was used in a linear mixed model. The EOS group had a significant cognitive stagnation or deterioration from T1 to T2 compared to HC. However, the EOS group had the most positive change from T2 to T3, supporting a stable level of cognitive performance over the 25 year span. The ADHD group improved or had similar development as the HC group from T1 to T2. They continued to improve significantly compared to the HC group from T2 to T3. Individuals in the EOS group performed more impaired on the cognitive composite score compared to the HC group and the ADHD group at all three time points. Results might indicate a neurodevelopmental pathway of EOS with subnormal cognitive development specific in adolescence. In comparison, the ADHD group had a more consistent cognitive maturation supporting a maturational delay hypothesis of ADHD. (shrink)

A number of differences between the dreams of schizophrenia patients and those of healthy participants have been linked to changes in waking life that schizophrenia may cause. This way, the “continuity hypothesis” has become a standard way to relate dreaming and waking experiences in schizophrenia. Nevertheless, some of the findings in dream literature are not compatible with the continuity hypothesis and suggest some other ways how dream content and waking experiences could interact. Conceptually, the continuity (...) hypothesis could be sharpened into the “waking-to-dreaming” and the “dreaming-to-waking” hypotheses, whereas a less explored type of “discontinuity” could embrace the “compensated waking” and the “compensated dreaming” hypotheses. A careful consideration and empirical testing of each of those hypotheses may reveal a multiplicity of the ways how dreaming and waking life interact in schizophrenia. (shrink)

To understand schizophrenia, a linking hypothesis is needed that shows how brain mechanisms lead to behavioral functions in normals, and also how breakdowns in these mechanisms lead to behavioral symptoms of schizophrenia. Such a linking hypothesis is now available that complements the discussion offered by Phillips & Silverstein (P&S).

Given the contemporary ambivalent standpoints toward the future of artificial intelligence, recently denoted as the phenomenon of Singularitarianism, Gregory Bateson’s core theories of ecology of mind, schismogenesis, and double bind, are hereby revisited, taken out of their respective sociological, anthropological, and psychotherapeutic contexts and recontextualized in the field of Roboethics as to a twofold aim: the proposal of a rigid ethical standpoint toward both artificial and non-artificial agents, and an explanatory analysis of the reasons bringing about such a polarized outcome (...) of contradictory views in regard to the future of robots. Firstly, the paper applies the Batesonian ecology of mind for constructing a unified roboethical framework which endorses a flat ontology embracing multiple forms of agency, borrowing elements from Floridi’s information ethics, classic virtue ethics, Felix Guattari’s ecosophy, Braidotti’s posthumanism, and the Japanese animist doctrine of Rinri. The proposed framework wishes to act as a pragmatic solution to the endless dispute regarding the nature of consciousness or the natural/artificial dichotomy and as a further argumentation against the recognition of future artificial agency as a potential existential threat. Secondly, schismogenic analysis is employed to describe the emergence of the hostile human–robot cultural contact, tracing its origins in the early scientific discourse of man–machine symbiosis up to the contemporary countermeasures against superintelligent agents. Thirdly, Bateson’s double bind theory is utilized as an analytic methodological tool of humanity’s collective agency, leading to the hypothesis of collective schizophrenic symptomatology, due to the constancy and intensity of confronting messages emitted by either proponents or opponents of artificial intelligence. The double bind’s treatment is the mirroring “therapeutic double bind,” and the article concludes in proposing the conceptual pragmatic imperative necessary for such a condition to follow: humanity’s conscience of habitualizing danger and familiarization with its possible future extinction, as the result of a progressive blurrification between natural and artificial agency, succeeded by a totally non-organic intelligent form of agency. (shrink)

A host of metabolic enzymes reversibly self‐assemble to form membrane‐less, intracellular filaments under normal physiological conditions and in response to stress. Often, these enzymes reside at metabolic control points, suggesting that filament formation affords an additional regulatory mechanism. Examples include cytidine‐5′‐triphosphate (CTP) synthase (CTPS), which catalyzes the rate‐limiting step for the de novo biosynthesis of CTP; inosine‐5′‐monophosphate dehydrogenase (IMPDH), which controls biosynthetic access to guanosine‐5′‐triphosphate (GTP); and ∆1‐pyrroline‐5‐carboxylate (P5C) synthase (P5CS) that catalyzes the formation of P5C, which links the Krebs (...) cycle, urea cycle, and proline metabolism. Intriguingly, CTPS can exist in co‐assemblies with IMPDH or P5CS. Since GTP is an allosteric activator of CTPS, the association of CTPS and IMPDH filaments accords with the need to coordinate pyrimidine and purine biosynthesis. Herein, a hypothesis is presented furnishing a biochemical connection underlying co‐assembly of CTPS and P5CS filaments – potent inhibition of CTPS by glutamate γ‐semialdehyde, the open‐chain form of P5C. (shrink)

Vincent proposes that the extracellular cGMP found in cerebellum after glutamate receptor activation is released mainly from Purkinje cells because in these neurons the presence of guanylate cyclase has been shown using monoclonal antibodies. It is uncertain, however, whether Purkinje cells are the only source of extracellular cGMP in the cerebellum. This commentary examines the possibility that glial and cerebellar granule cells may also participate in cGMP synthesis and release, Moreover, the hypothesis of transcellular metabolism of citrulline and (...) arginine is discussed. [VINCENT]. (shrink)

Recent studies have demonstrated neural overlap between resting state activity and self-referential processing. This “rest-self” overlap occurs especially in anterior cortical midline structures like the perigenual anterior cingulate cortex (PACC). However, the exact neurotemporal and biochemical mechanisms remain to be identified. Therefore, we conducted a combined electroencephalography (EEG)-magnetic resonance spectroscopy (MRS) study. EEG focused on pre-stimulus (e.g., prior to stimulus presentation or perception) power changes to assess the degree to which those changes can predict subjects’ perception (and judgment) of subsequent (...) stimuli as high or low self-related. MRS measured resting state concentration of glutamate, focusing on PACC. High pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power significantly correlated with both perception of stimuli judged to be highly self-related and with resting state glutamate concentrations in the PACC. In sum, our results show (i) pre-stimulus (e.g., prior to stimulus presentation or perception) alpha power and resting state glutamate concentration to mediate rest-self overlap that (ii) dispose or incline subjects to assign high degrees of self-relatedness to perceptual stimuli. (shrink)

IntroductionCognitive impairment is a highly prevalent non-motor feature of Parkinson’s disease. A better understanding of the underlying pathophysiology may help in identifying therapeutic targets to prevent or treat dementia. This study sought to identify metabolic alterations in the prefrontal cortex, a key region for cognitive functioning that has been implicated in cognitive dysfunction in PD.MethodsProton Magnetic Resonance Spectroscopy was used to investigate metabolic changes in the PFC of a cohort of cognitively normal individuals without PD, as well as PD participants (...) with either normal cognition, mild cognitive impairment, or dementia. Ratios to Creatine resonance were obtained for glutamate, glutamine and glutamate combined, N-acetylaspartate, myoinositol, and total choline, and correlated with cognitive scores across multiple domains administered to the PD participants only.ResultsWhen individuals retain cognitive capabilities, the presence of Parkinson’s disease does not create metabolic disturbances in the PFC. However, when cognitive symptoms are present, PFC Glu/Cre ratios decrease with significant differences between the PD-NC and PPD groups. In addition, Glu/Cre ratios and memory scores were marginally associated, but not after Bonferroni correction.ConclusionThese preliminary findings indicate that fluctuations in prefrontal glutamate may constitute a biomarker for the progression of cognitive impairments in PD. We caution for larger MRS investigations of carefully defined PD groups. (shrink)

“Dutch Book” arguments and references to gambling theorems are typical in the debate between Bayesians and scientists committed to “classical” statistical methods. These arguments have rarely convinced non-Bayesian scientists to abandon certain conventional practices, partially because many scientists feel that gambling theorems have little relevance to their research activities. In other words, scientists “don’t bet.” This article examines one attempt, by Schervish, Seidenfeld, and Kadane, to progress beyond such apparent stalemates by connecting “Dutch Book”–type mathematical results with principles actually endorsed (...) by practicing experimentalists. (shrink)

Preregistration has been proposed as a useful method for making a publicly verifiable distinction between confirmatory hypothesis tests, which involve planned tests of ante hoc hypotheses, and exploratory hypothesis tests, which involve unplanned tests of post hoc hypotheses. This distinction is thought to be important because it has been proposed that confirmatory hypothesis tests provide more compelling results (less uncertain, less tentative, less open to bias) than exploratory hypothesis tests. In this article, we challenge this proposition (...) and argue that there are several advantages of exploratory hypothesis tests that can make their results more compelling than those of confirmatory hypothesis tests. We also consider some potential disadvantages of exploratory hypothesis tests and conclude that their advantages can outweigh the disadvantages. We conclude that exploratory hypothesis tests avoid researcher commitment and researcher prophecy biases, reduce the probability of data fraud, are more appropriate in the context of unplanned deviations, facilitate inference to the best explanation, and allow peer reviewers to make additional contributions at the data analysis stage. In contrast, confirmatory hypothesis tests may lead to an inappropriate level of confidence in research conclusions, less appropriate analyses in the context of unplanned deviations, and greater bias and errors in theoretical inferences. (shrink)

Realism about the external, natural world is an overarching empirical hypothesis. The method of hypothetical realism rejects as an excessive concession to the skeptic these two assumptions of constructivist intuitionism: first, that everything real must be exhaustively inspectable; and second, that our beliefs are to be justified to the point of certainty. We prefer to say that nothing is ever known directly; that all of our contact with the world is mediated by thoughts, words, and percepts construed as signs (...) having referents distinct from themselves. We organize these signs into meaningful and possibly true hypotheses as we speculate--in practice, science and metaphysics--about a world we have not made. (shrink)

It is generally accepted among philosophers of science that hypothesis testing is a key methodological feature of science. As far as philosophical theories of confirmation are con...

A traditional problem with the performative hypothesis is that it cannot assign proper truth-conditions to a declarative sentence. This paper shows that the problem is solved by adopting a multidimensional semantics on which sentences have more than just truth-conditions. This is good news for those who want to at least partially revive the hypothesis. The solution also brings into focus a lesson about what issues to consider when drawing the semantics/pragmatics boundary.

The eukaryotic genome is organized into different domains by cis‐acting elements, such as boundaries/insulators and matrix attachment regions, and is packaged with different degrees of condensation. In the M phase, the chromatin becomes further highly condensed into chromosomes. The first step for transcriptional activation of a given gene, at a particular time during development, in any locus, is the opening of its chromatin domain. This locus needs to be kept in this state in each early G1 phase during every cell (...) cycle. Certain distal enhance elements, including locus control regions (LCRs) and enhancers, are believed to perform this target chromatin domain opening process and several models have been proposed to explain distal enhance action. But they did not explain precisely how a given chromatin domain is opened. Based on various studies, we propose a hypothesis for the mechanism of opening chromatin on a large scale. One important mechanism may involved breaking one or two DNA strands and reducing the linking numbers within chromatin domain. The topological changes can overpass some complexes formed on DNA strands and can be transmitted from specific localized points over a broad region, until boundary elements or insulators are reached. These may initiate downstream events such as propagation of histone acetylation and the binding of transcription factors to proximal promoters and may further augment the action mediated by distal enhancer elements. BioEssays 25:507–514, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The singularity hypothesis is a radical hypothesis about the future of artificial intelligence on which self-improving artificial agents will quickly become orders of magnitude more intelligent than the average human. Despite the ambitiousness of its claims, the singularity hypothesis has been defended at length by leading philosophers and artificial intelligence researchers. In this paper, I argue that the singularity hypothesis rests on scientifically implausible growth assumptions. I show how leading philosophical defenses of the singularity hypothesis (...) (Chalmers 2010, Bostrom 2014) fail to overcome the case for skepticism. I conclude by drawing out philosophical implications of this discussion for our understanding of consciousness, personal identity, digital minds, existential risk, and ethical longtermism. GPI Working Paper No . 19-2022. (shrink)

According to one theory, the brain is a sophisticated hypothesis tester: perception is Bayesian unconscious inference where the brain actively uses predictions to test, and then refine, models about what the causes of its sensory input might be. The brain’s task is simply continually to minimise prediction error. This theory, which is getting increasingly popular, holds great explanatory promise for a number of central areas of research at the intersection of philosophy and cognitive neuroscience. I show how the theory (...) can help us understand striking phenomena at three cognitive levels: vision, sensory integration, and belief. First, I illustrate central aspects of the theory by showing how it provides a nice explanation of why binocular rivalry occurs. Then I suggest how the theory may explain the role of the unified sense of self in rubber hand and full body illusions driven by visuotactile conflict. Finally, I show how it provides an approach to delusion formation that is consistent with one-deficit accounts of monothematic delusions. (shrink)