Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.

/pdf/the-endophenotype-concept-in-psychiatry-etymology-and-2w2rrj3jlx.pdf

The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions

There is disagreement in the literature about the exact nature of the phenomenon of empathy. There are emotional, cogni- tive, and conditioning views, applying in varying degrees across species. An adequate description of the ultimate and proximate mecha- nism can integrate these views. Proximately, the perception of an object's state activates the subject's corresponding representations, which in turn activate somatic and autonomic responses. This mechanism supports basic behaviors (e.g., alarm, social facilitation, vicar- iousness of emotions, mother-infant responsiveness, and the modeling of competitors and predators) that are crucial for the reproduc- tive success of animals living in groups. The Perception-Action Model (PAM), together with an understanding of how representations change with experience, can explain the major empirical effects in the literature (similarity, familiarity, past experience, explicit teach- ing, and salience). It can also predict a variety of empathy disorders. The interaction between the PAM and prefrontal functioning can also explain different levels of empathy across species and age groups. This view can advance our evolutionary understanding of empa- thy beyond inclusive fitness and reciprocal altruism and can explain different levels of empathy across individuals, species, stages of de- velopment, and situations.

/pdf/empathy-its-ultimate-and-proximate-bases-3gnr9okjki.pdf

Empathy: Its ultimate and proximate bases.

The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

/pdf/the-dopamine-hypothesis-of-schizophrenia-version-iii-the-3pqlczm8om.pdf

The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway

It has been argued that emotion, pain and cognitive control are functionally segregated in distinct subdivisions of the cingulate cortex. However, recent observations encourage a fundamentally different view. Imaging studies demonstrate that negative affect, pain and cognitive control activate an overlapping region of the dorsal cingulate — the anterior midcingulate cortex (aMCC). Anatomical studies reveal that the aMCC constitutes a hub where information about reinforcers can be linked to motor centres responsible for expressing affect and executing goal-directed behaviour. Computational modelling and other kinds of evidence suggest that this intimacy reflects control processes that are common to all three domains. These observations compel a reconsideration of the dorsal cingulate's contribution to negative affect and pain.

The integration of negative affect, pain and cognitive control in the cingulate cortex

Increasing interest in the role of the frontal lobe in relation to psychiatric and neurologic disorders has popularized tests of frontal function. One of these is the antisaccade task, in which both frontal lobe patients and schizophrenics are impaired despite normal performance on (pro)saccadic tasks. We used position emission tomography to examine the cerebral blood flow changes associated with the performance of antisaccades in normal individuals. We found that the areas of the brain that were more active during antisaccades than saccades were highly consistent with the oculomotor circuit, including frontal eye fields (FEFs), supplementary motor area, thalamus, and putamen. Superior parietal lobe and primary visual cortex were also significantly more active. In contrast, prefrontal areas 46 and 9 were not more active during antisaccades than during saccades. Performance of some frontal patients on the antisaccade task has been likened to a bradykinesia, or the inability to initiate a willed movement. It is the necessity to will the movement and inhibit competing responses that intuitively linked this task to the dorsolateral prefrontal cortex in frontal patients. Our data suggest that it is the FEFs in prefrontal cortex that differentiate between conditions in which the required oculomotor response changes while the stimulus remains the same, rather than areas 46 and 9, which, in human studies, have been linked to the performance of complex cognitive tasks. Such a conclusion is consistent with single-unit studies of nonhuman primates that have found that the FEFs, the executive portion of the oculomotor circuit, can trigger, inhibit, and set the target of saccades.

https://www.pnas.org/content/pnas/92/3/925.full.pdf

Functional neuroanatomy of antisaccade eye movements investigated with positron emission tomography

Nicotine and Behavioral Markers of Risk for Schizophrenia: A Double-Blind, Placebo-Controlled, Cross-Over Study

Background Eye tracking deficits are one of a few widely validated behavioral markers of risk for schizophrenia. Recently, it has been proposed that antisaccade performance may also constitute a marker of schizophrenia risk. This study investigated whether eye tracking and antisaccade deficits could be found in another population with putative liability to schizophrenia—nonclinical subjects with elevated scores on a psychometric index of perceptual aberrations. Methods Subjects were 55 university students who received either high or normal scores on the Perceptual Aberration Scale, a measure of schizotypy indexing body image and perceptual distortions. Subjects completed a smooth pursuit eye tracking task and an antisaccade task. Eye movements were monitored using an infrared limbus tracker. Results Subjects with high Perceptual Aberration Scale scores (putative "schizotypes") had lower pursuit quality and a lower percentage correct on the antisaccade task than the controls. The 2 groups did not differ in antisaccade or error latencies. The increase in antisaccade errors in the schizotypes was accounted for almost entirely by an increase in perseverative errors, but virtually no difference between groups on random errors. Antisaccade performance was significantly related to pursuit quality. Conclusions Subjects with elevated Perceptual Aberration Scale scores have performance deficits on oculomotor tasks that have been linked to latent liability to schizophrenia, namely, smooth pursuit and antisaccade performance. The antisaccade errors in the schizotype group were primarily perseverations, a behavioral pattern often associated with frontal lobe dysfunction and observed in the performance of schizophrenic patients.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/204216/yoa7127.pdf

Gillian A. O'Driscoll

Papers

Functional neuroanatomy of antisaccade eye movements investigated with positron emission tomography

Nicotine and Behavioral Markers of Risk for Schizophrenia: A Double-Blind, Placebo-Controlled, Cross-Over Study

Antisaccades and Smooth Pursuit Eye Tracking and Schizotypy

Executive functions and methylphenidate response in subtypes of attention-deficit/hyperactivity disorder.

Smooth pursuit in schizophrenia: a meta-analytic review of research since 1993.