Final Common Path Research Articles

Mechanisms underlying firing in healthy and sick human motoneurons.

In an address to the British Association for the Advancement of Science in Cambridge, Professor Sherrington introduced the terms “motor neurone” and “the final common path,” the latter term implying that all motor commands converge onto the motoneuron which integrates the incoming information and passes the net information to the muscle for contraction (Sherrington, 1904). The relative ease of access of the spinal motoneuron made it feasible to set up techniques for investigating the physiological, biophysical and molecular properties of these neurons. It became the most investigated neuron of the CNS in the twentieth century and the information gained from studies on motoneurons formed the basis for examining the other neurons of the CNS. Since the compound action potential of a muscle unit is strictly related one-to-one to the action potential arriving from the innervating motoneuron, the statistical analysis of muscle unit action potentials provides an investigator with an elegant way to probe the properties of motoneurons in behaving humans. In the following review the terms motoneuron and motor unit might be used interchangeably. Different aspects of human motoneuron investigations in health and disease are presented in 16 articles of this topic which are summarized below.

Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1.

Axonal degeneration is the final common path in many neurological disorders. Subsets of neuropathies involving the sensory neuron are known as hereditary sensory neuropathies (HSNs). Hereditary sensory neuropathy type I (HSN-I) is the most common subtype of HSN with autosomal dominant inheritance. It is characterized by the progressive degeneration of the dorsal root ganglion (DRG) with clinical symptom onset between the second or third decade of life. Heterozygous mutations in the serine palmitoyltransferase (SPT) long chain subunit 1 (SPTLC1) gene were identified as the pathogenic cause of HSN-I. Ultrastructural analysis of mitochondria from HSN-I patient cells has displayed unique morphological abnormalities that are clustered to the perinucleus where they are wrapped by the endoplasmic reticulum (ER). This investigation defines a small subset of proteins with major alterations in abundance in mitochondria harvested from HSN-I mutant SPTLC1 cells. Using mitochondrial protein isolates from control and patient lymphoblasts, and a combination of 2D gel electrophoresis, immunoblotting and mass spectrometry, we have shown the increased abundance of ubiquinol-cytochrome c reductase core protein 1, an electron transport chain protein, as well as the immunoglobulin, Ig kappa chain C. The regulation of these proteins may provide a new route to understanding the cellular and molecular mechanisms underlying HSN-I.

How to read neuron-dropping curves?

Methods for decoding information from neuronal signals (Kim et al., 2006; Quiroga and Panzeri, 2009) have attracted much interest in recent years, in a large part due to the rapid development of brain-machine interfaces (BMIs) (Lebedev and Nicolelis, 2006; Lebedev, 2014). BMIs strive to restore brain function to disabled patients or even augment function to healthy individuals by establishing direct communications between the brain and external devices, such as computers and robotic limbs. Accordingly, BMI decoders convert neuronal activity into font characters (Birbaumer et al., 1999), position and velocity of a robot (Carmena et al., 2003; Velliste et al., 2008), sound (Guenther et al., 2009), etc. Large-scale recordings, i.e., simultaneous recordings from as many neurons and as many brain areas as possible, have been suggested as a fundamental approach to improve BMI decoding (Chapin, 2004; Nicolelis and Lebedev, 2009; Schwarz et al., 2014). To this end, the dependency of decoding accuracy on the number of recorded neurons is often quantified as a neuronal dropping curve (NDC) (Wessberg et al., 2000). The term “neuron dropping” refers to the procedure, where neurons are randomly removed from the sample until there is only one neuron left. In this analysis, large neuronal populations usually outperform small ones, the result that accords with the theories of distributed neural processing (Rumelhart et al., 1986). In addition to BMIs based on large-scale recordings, several studies have adapted an alternative approach, where a BMI is driven by a small neuronal population or even a single neuron that plastically adapts to improve BMI performance (Ganguly and Carmena, 2009; Moritz and Fetz, 2011). In such BMIs, a small number of neurons serve as a final common path (Sherrington, 1906) to which inputs from a vast brain network converge. While the utility of large-scale BMIs vs. small-scale BMIs has not been thoroughly investigated, several studies reported that information transfer by BMIs starts to saturate after the population size reaches approximately 50 neurons (Sanchez et al., 2004; Batista et al., 2008; Cunningham et al., 2008; Tehovnik et al., 2013). In one paper, this result was interpreted as mass effect principle, i.e., stabilization of BMI performance after neuronal sample reaches a critical mass (Nicolelis and Lebedev, 2009). However, another recent paper claimed that large-scale recordings cannot improve BMI performance because of the saturation (Tehovnik et al., 2013). This controversy prompted me to clarify here what NDCs show, whether or not they saturate, and how they can be applied to analyze BMI performance.

What's Special about the Ethical Challenges of Studying Disorders with Altered Brain Activity?

Where there is no viable alternative, studies of neuronal activity are conducted on animals. The use of animals, particularly for invasive studies of the brain, raises a number of ethical issues. Practical or normative ethics are enforced by legislation, in relation to the dominant welfare guidelines developed in the United Kingdom and elsewhere. Guidelines have typically been devised to cover all areas of biomedical research using animals in general, and thus lack any specific focus on neuroscience studies at the level of the ethics, although details of the specific welfare recommendations are different for invasive studies of the brain. Ethically, there is no necessary distinction between neuroscience and other biomedical research in that the brain is a final common path for suffering, irrespective of whether this involves any direct experience of pain. One exception arises in the case of in vitro studies, which are normally considered as an acceptable replacement for in vivo studies. However, to the extent sentience is possible, maintaining central nervous system tissue outside the body naturally raises ethical questions. Perhaps the most intractable challenge to the ethical use of animals in order to model neuronal disorder is presented by the logical impasse in the argument that the animal is similar enough to justify the validity of the experimental model, but sufficiently different in sentience and capacity for suffering, for the necessary experimental procedures to be permissible.

Book Review: Chronic Medical Disease & Cognitive Aging: Toward a Healthy Body and Brain, edited by Kristine Yaffe (New York Oxford University Press, 2013)

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Control and Role of Plateau Potential Properties in the Spinal Cord

In this review we will first give a historical account of how the discovery of persistent inward currents (PICs) and plateau potentials changed the understanding of the operation and function of the "final common path", i.e. the motoneurons themselves. A major function of voltage-dependent PICs is to serve as an adjustable amplifier of classical synaptic inputs. The complex control of this, and other intrinsic properties, certainly adjusts the performance of the motoneurons to the needs of the behavioral settings. It has emerged that supraspinal facilitation, mainly by monoaminergic projections, is a prerequisite for the normal function of the PIC channels. When these pathways are interrupted following a spinal lesion the "gain" of the transmission across the motoneurons is reduced and this is likely to be an important explanation for the spinal shock. However, after a few weeks the "plateau properties" of the motoneurons return - now without descending monoaminergic control. This plasticity after spinal lesion is likely to contribute to the hyperreflexia (spasticity) seen after spinal lesions. We then review the current knowledge on PICs in other spinal (inter-)neurons. The monoaminergic systems seem to play a pivotal role in activating the spinal network generating the rhythm and basic motor pattern of locomotion and scratch - the spinal "central pattern generators" (CPGs). We give a short historical background of this research with a special emphasis on the importance of the descending monoaminergic systems.

Short cervix syndrome: current knowledge from etiology to the control

Preterm delivery is one of the most serious public health problems and is the most important factor relating to neonatal morbidity and mortality. The strategies for preventing it include understanding the risk factors, with specific interventions. Recently, uterine cervix measurements using ultrasonography and vaginal administration of progesterone have gained importance in predicting and secondarily preventing spontaneous preterm delivery. To describe the short cervix syndrome, including its etiology, diagnosis, and possible therapies. Research in ISI, Pubmed, and Scielo database using the words short cervix, preterm delivery, sludge, cervical funneling, cervical gland area, progesterone, cerclage, and pessary. We found a lot of articles about this topic, including randomized controlled trials. The etiology is multifactorial, being the diagnosis based in a cervix shortening at 20-24 weeks. The history and measurement of cervix length by transvaginal ultrasound have been shown to be effective to select the high risk pregnancies. The progesterone, cervical cerclage, and cervical pessary showed to be effective to reduce the preterm delivery in pregnant women with short cervix. The successful management of pregnant women presenting a short cervix depends on the understanding that cervical shortening is the final common path for several causes of preterm delivery. The best approach should be individualized to each patient.

Commentary: netazepide for gastric acid suppression – another kid on the block?

Just when it seemed all over, the manuscript by Boyce et al.1 examining the pharmacokinetics and pharmacodynamics of single dose administration of netazepide, a peripheral CCK-B (gastrin) receptor antagonist, in normal volunteers will most certainly reinvigorate interest in gastric acid secretion and its pharmacological inhibition. Netazepide appears to be a potent inhibitor of gastric acid secretion with rapid onset and a prolonged duration of action.1 If it can be shown to be both safe and effective as maintenance therapy, it may well give proton pump inhibitors (PPIs) a real run for their money. The PPIs, which irreversibly block the final common path of gastric acid production,2 have been the dominant class of antisecretory drugs for over two decades and their continuing supremacy was all but assured with the demise of the potassium competitive acid blockers (PCABs) (although there may be a comeback for this class of agents too3). In addition, concerns have surfaced recently about potential adverse effects from prolonged PPI use4 which has opened the door to other novel compounds such as netazepide. Of course, much work remains to be done with this agent and there are, as yet, many unanswered questions (some of which the authors may well address in two upcoming manuscripts concerning repetitive dosing of netazepide). For example, will tachyphylaxis develop after repeated administration of this competitive receptor antagonist, a phenomenon that has been well described with histamine H2 receptor antagonists, which act one step further along the gastric acid secretory pathway?5 In addition, the endocrine, neurocrine and paracrine networks that control gastric acid secretion and its feedback are redundant.6 It remains to be seen whether upregulation of other pathways could occur leading to additional loss of efficacy (tolerance) with time. Alternatively, will the drug, which appears to have a long secondary half-life, accumulate after repeated dosing leading to unexpected side effects? Moreover, little is known about the metabolism of this agent which has only been administered to a small cadre of normal volunteers. Will the effect of this agent be predictable in patients or will alterations in metabolism lead to ‘slow’ and ‘fast’ metabolisers and unpredictable antisecretory effects? Finally, will potent ECL-cell inhibition by netazepide lead to G-cell hyperplasia and hypergastrinaemia, with the potential for rebound ECL-cell histamine release and excessive gastric acid production4 on withdrawal of the drug? This possibility is of some interest given current concerns regarding rebound gastric acid hypersecretion in double-blind randomised trials of PPI use vs. placebo in normal volunteers.7, 8 On the other hand, judicious use of netazepide in concert with PPIs may lead to more precise titration of individual antisecretory effects, thereby mitigating ECL-cell hyperplasia and parietal cell hypertrophy. This is an exciting and provocative first-in-human study of a novel compound with significant potential. I fully agree with the authors' conclusions that ‘studies of repeated doses of netazepide are justified’.1 Declaration of personal interests: David Metz has served as a consultant and advisory board member for Novartis, as a consultant for AstraZeneca and Takeda, and has received research funding from Fercica. Declaration of funding interests: None

Towards a vaccine for chronic obstructive pulmonary disease

This review discusses chronic obstructive pulmonary disease as an outcome of two pathogenic pathways: the first resulting from inhalation of toxins and the second a consequence of bacterial colonisation of damaged airways. Earlier assessment of the role played by bacteria in acute exacerbations was compromised by a deficiency of quality data and the use of parameters more relevant to invasive infection. Data are reviewed to support a hypothesis that states intrabronchial inflammation reflects an excessive and inappropriate host response (largely mediated by Th17 cells derived from gut-associated lymphoid tissues) to colonising bacteria acting as an 'antigen sump' (in essence, a hypersensitivity reaction). It is proposed that both viral and bacterial infections exacerbate inflammation through a common pathway that involves colonising bacteria. An oral vaccine containing inactivated non-typeable Haemophilus influenzae augments a protective loop that involves the aspiration of bronchus content into the gut and reduces the severity of acute exacerbations including the need for hospital admission by reducing the 'load' of bacteria comprising this final common path. The positive clinical results from trials using oral NTHi support both the concept that bacterial colonisation of damaged airways is a potent second pathogenic pathway and that oral immunotherapy provides a significant therapeutic advance in limiting damage in chronic obstructive pulmonary disease.

Role for ventral pallidal GABAergic mechanisms in the regulation of ethanol self-administration

The striatopallidal medium spiny neurons have been viewed as a final common path for drug reward, and the ventral pallidum (VP) as a convergent point for hedonic and motivational signaling. The medium spiny neurons are GABAergic, but they colocalize enkephalin. The present study investigated the role of the GABAergic mechanisms of the VP in ethanol consumption. The effects of bilateral microinjections of GABA(A) and GABA(B) receptor agonists and antagonists into the VP on voluntary ethanol consumption were monitored in alcohol-preferring Alko alcohol rats given 90 min limited access to ethanol in their home cages every other day. The influences of coadministration of GABA and opioid receptor modulators were also studied. The GABA(A) receptor agonist muscimol (1-10 ng/site) decreased ethanol intake dose-dependently, while administration of the GABA(A) receptor antagonist bicuculline (10-100 ng) had an opposite effect. The GABA(B) receptor agonist baclofen (3-30 ng) also suppressed ethanol intake, but the GABA(B) receptor antagonist saclofen (0.3-3 μg) failed to modify it. Animals coadministered with bicuculline (30 ng) and baclofen (30 ng) consumed ethanol significantly less than those treated with bicuculline alone. Coadministration of the μ-receptor agonist D-Ala2,N-Me-Phe4,Glyol5-enkephalin (DAMGO, 0.1 μg) with bicuculline counteracted, whereas the μ-receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 1 μg) enhanced the bicuculline-induced increase of ethanol intake. When given alone, DAMGO decreased while CTOP increased ethanol intake. The study provides evidence for the ventral pallidal GABAergic mechanisms participating in the regulation of ethanol consumption and supports earlier work suggesting a role for pallidal opioidergic transmission in ethanol reward.

The Physiology of Human Defecation

Human defecation involves integrated and coordinated sensorimotor functions, orchestrated by central, spinal, peripheral (somatic and visceral), and enteric neural activities, acting on a morphologically intact gastrointestinal tract (including the final common path, the pelvic floor, and anal sphincters). The multiple factors that ultimately result in defecation are best appreciated by describing four temporally and physiologically fairly distinct phases. This article details our current understanding of normal defecation, including recent advances, but importantly identifies those areas where knowledge or consensus is still lacking. Appreciation of normal physiology is central to directed treatment of constipation and also of fecal incontinence, which are prevalent in the general population and cause significant morbidity.

Insulin Protects Pancreatic Acinar Cells from Cytosolic Calcium Overload and Inhibition of Plasma Membrane Calcium Pump

Acute pancreatitis is a serious and sometimes fatal inflammatory disease of the pancreas without any reliable treatment or imminent cure. In recent years, impaired metabolism and cytosolic Ca(2+) ([Ca(2+)](i)) overload in pancreatic acinar cells have been implicated as the cardinal pathological events common to most forms of pancreatitis, regardless of the precise causative factor. Therefore, restoration of metabolism and protection against cytosolic Ca(2+) overload likely represent key therapeutic untapped strategies for the treatment of this disease. The plasma membrane Ca(2+)-ATPase (PMCA) provides a final common path for cells to "defend" [Ca(2+)](i) during cellular injury. In this paper, we use fluorescence imaging to show for the first time that insulin treatment, which is protective in animal models and clinical studies of human pancreatitis, directly protects pancreatic acinar cells from oxidant-induced cytosolic Ca(2+) overload and inhibition of the PMCA. This protection was independent of oxidative stress or mitochondrial membrane potential but appeared to involve the activation of Akt and an acute metabolic switch from mitochondrial to predominantly glycolytic metabolism. This switch to glycolysis appeared to be sufficient to maintain cellular ATP and thus PMCA activity, thereby preventing Ca(2+) overload, even in the face of impaired mitochondrial function.

Retinoid receptors trigger neuritogenesis in retinal degenerations.

Anomalous neuritogenesis is a hallmark of neurodegenerative disorders, including retinal degenerations, epilepsy, and Alzheimer's disease. The neuritogenesis processes result in a partial reinnervation, new circuitry, and functional changes within the deafferented retina and brain regions. Using the light-induced retinal degeneration (LIRD) mouse model, which provides a unique platform for exploring the mechanisms underlying neuritogenesis, we found that retinoid X receptors (RXRs) control neuritogenesis. LIRD rapidly triggered retinal neuron neuritogenesis and up-regulated several key elements of retinoic acid (RA) signaling, including retinoid X receptors (RXRs). Exogenous RA initiated neuritogenesis in normal adult retinas and primary retinal cultures and exacerbated it in LIRD retinas. However, LIRD-induced neuritogenesis was partly attenuated in retinol dehydrogenase knockout (Rdh12(-/-)) mice and by aldehyde dehydrogenase inhibitors. We further found that LIRD rapidly increased the expression of glutamate receptor 2 and β Ca(2+)/calmodulin-dependent protein kinase II (βCaMKII). Pulldown assays demonstrated interaction between βCaMKII and RXRs, suggesting that CaMKII pathway regulates the activities of RXRs. RXR antagonists completely prevented and RXR agonists were more effective than RA in inducing neuritogenesis. Thus, RXRs are in the final common path and may be therapeutic targets to attenuate retinal remodeling and facilitate global intervention methods in blinding diseases and other neurodegenerative disorders.

Excitatory effect of histamine on rat spinal motoneurons by activation of both H1 and H2 receptors in vitro

The central histaminergic nervous system, originating from the tuberomammillary nucleus of the hypothalamus, widely innervates almost the whole brain as well as the spinal cord. However, the effect of histamine on spinal motoneurons, the final common path for motor control, is still unknown. By using 8-14-day-old rat spinal slice preparations and intracellular recordings, the effect of histamine on motoneurons in lumbar spinal cord and the underlying mechanisms were studied. Bath application of histamine (30-300 μM) induced a membrane depolarization in the majority of recorded spinal motoneurons (78/90, 86%). Perfusing slices with tetrodotoxin or low-Ca(2+) /high-Mg(2+) medium did not block the histamine-induced excitation, indicating a direct postsynaptic action of histamine on motoneurons. Separate application of the selective histamine H(1) receptor antagonist mepyramine or the selective histamine H(2) receptor antagonist ranitidine partially suppressed the histamine-induced excitation, whereas a combination of ranitidine and mepyramine totally blocked the excitatory effect of histamine on motoneurons. On the other hand, both the selective histamine H(1) receptor agonist 2-pyridylethylamine and the selective histamine H(2) receptor agonist dimaprit mimicked the excitation of histamine on spinal motoneurons. These agonist-induced excitations were also blocked by mepyramine or ranitidine. Furthermore, histamine affected membrane input resistance and potentiated repetitive firing behavior of spinal motoneurons. These results demonstrate that histamine excites rat spinal motoneurons via the histamine H(1) and H(2) receptors and increases their excitability, suggesting that the hypothalamospinal histaminergic fibers may directly modulate final motor outputs and actively regulate ongoing motor execution andspinal motor reflexes.

Opioidergic Modulation of Ethanol Self‐Administration in the Ventral Pallidum

Striatopallidal medium spiny neurons have been viewed as a final common path for drug reward and the ventral pallidum as an essential convergent point for hedonic and motivational signaling in the brain. The medium spiny neurons are GABAergic, but they colocalize enkephalin. Purpose of this study was to investigate the role of the opioidergic mechanisms of the ventral pallidum in ethanol self-administration behavior. Effects of bilateral microinjections of μ-, δ-, and κ-opioid receptor agonists and antagonists into the ventral pallidum on voluntary ethanol consumption were monitored in alcohol-preferring Alko Alcohol (AA) rats using the 90-minute limited access paradigm. Stimulation of μ-opioid receptors with DAMGO (0.01 to 0.1 μg) or morphine (1 to 10 μg) in the ventral pallidum decreased ethanol intake dose-dependently. Conversely, blocking μ-receptors with CTOP (0.3 to 3 μg) increased ethanol intake significantly. Unlike CTOP, DAMGO also increased locomotor activity. Consumption of ethanol was not modified significantly by a broad-spectrum opioid receptor antagonist naltrexone, by δ-opioid receptor agonist DPDPE or antagonist naltrindole, or by a κ-opioid receptor agonist U50,488H or antagonist nor-BNI. The study provides evidence for μ- but not δ- or κ-opioid receptors in the ventral pallidum playing a role in the regulation of voluntary ethanol consumption. Furthermore, present findings give support to earlier work, suggesting an essential role of pallidal opioidergic transmission in drug reward.

What Sherrington missed: the ubiquity of the neural integrator

Despite its numerous illustrations unequivocally demonstrating the phenomenon, in Sherrington's Integrative Action of the Nervous System, he considered "integration" only in its spatial and coordinative aspects, and failed to notice time integration as an equally pervasive feature of all motor systems. First demonstrated in the oculomotor system by Robinson and others, in the vestibulo-ocular reflex, and then as a necessary component of the oculomotor "final common path" (another Sherringtonian concept), integration is manifested at two further levels: in generating optokinetic responses and in the mechanism of saccadic decision. But integration is not a purely oculomotor phenomenon: behind it lie two fundamental motor principles. First, that the brain operates in terms of change, implying differentiation in sensory systems and integration in motor ones. Second, that the molecular physiology of muscle contraction means that remaining still requires not only continual expenditure of energy but also continual computational effort--a firm and precise integrator.

Is BDNF Sufficient for Information Transfer between Microglia and Dorsal Horn Neurons during the Onset of Central Sensitization?

Peripheral nerve injury activates spinal microglia. This leads to enduring changes in the properties of dorsal horn neurons that initiate central sensitization and the onset of neuropathic pain. Although a variety of neuropeptides, cytokines, chemokines and neurotransmitters have been implicated at various points in this process, it is possible that much of the information transfer between activated microglia and neurons, at least in this context, may be explicable in terms of the actions of brain derived neurotrophic factor (BDNF). Microglial-derived BDNF mediates central sensitization in lamina I by attenuating inhibitory synaptic transmission. This involves an alteration in the chloride equilibrium potential as a result of down regulation of the potassium-chloride exporter, KCC2. In lamina II, BDNF duplicates many aspects of the effects of chronic constriction injury (CCI) of the sciatic nerve on excitatory transmission. It mediates an increase in synaptic drive to putative excitatory neurons whilst reducing that to inhibitory neurons. CCI produces a specific pattern of changes in excitatory synaptic transmission to tonic, delay, phasic, transient and irregular neurons. A very similar 'injury footprint' is seen following long-term exposure to BDNF. This review presents new information on the action of BDNF and CCI on lamina II neurons, including the similarity of their actions on the kinetics and distributions of subpopulations of miniature excitatory postsynaptic currents (mEPSC). These findings raise the possibility that BDNF functions as a final common path for a convergence of perturbations that culminate in the generation of neuropathic pain.

Effect of activation of viral receptors on the gelatinases MMP-2 and MMP-9 in human mesothelial cells

Background Extracellular matrix (ECM) not only provides molecular and spatial information that influence cell proliferation, differentiation and apoptosis but also has the potential to bind and present or release cytokines and cytotactic factors. Synthesis and degradation of extracellular matrix components are balanced by matrix metalloproteinases (MMP) and their inhibitors. In the pericardium as well as in the pleural and peritoneal cavities a multitude of clinically relevant disease states ranging from inflammation to fibrosis and tumor invasion result from altered regulation of MMP activity and are known to be associated with viral disease. Methods Therefore, the functional linkage between viral receptors of the innate immune system, the toll-like receptors (TLR), and control of MMP activity was exemplarily analyzed by stimulating human mesothelial cells with poly (I:C) RNA. Results We hereby show that human mesothelial cells (MC) express TLR3. After stimulation of MC with the cytokines TNF-α, IL-1β and IFN-γ alone or in combination to simulate a proinflammatory milieu as would occur during immune-mediated inflammatory disease, an upregulation of TLR3 is seen. Furthermore, a selectively TLR3 mediated, time- and dose-dependent upregulation of MMP-9 and TIMP-1 is found, whereas MMP-2 expression is not significantly affected by TLR3 stimulation. Conclusions With these results we provide evidence for a mechanism by which infectious agents can mediate processes of the final common path of inflammation as fibrosis via regulation of MMP and TIMP.

Why IQ is not a covariate in cognitive studies of neurodevelopmental disorders

IQ scores are volatile indices of global functional outcome, the final common path of an individual's genes, biology, cognition, education, and experiences. In studying neurocognitive outcomes in children with neurodevelopmental disorders, it is commonly assumed that IQ can and should be partialed out of statistical relations or used as a covariate for specific measures of cognitive outcome. We propose that it is misguided and generally unjustified to attempt to control for IQ differences by matching procedures or, more commonly, by using IQ scores as covariates. We offer logical, statistical, and methodological arguments, with examples from three neurodevelopmental disorders (spina bifida meningomyelocele, learning disabilities, and attention deficit hyperactivity disorder) that: (1) a historical reification of general intelligence, g, as a causal construct that measures aptitude and potential rather than achievement and performance has fostered the idea that IQ has special status and that in studying neurocognitive function in neurodevelopmental disorders; (2) IQ does not meet the requirements for a covariate; and (3) using IQ as a matching variable or covariate has produced overcorrected, anomalous, and counterintuitive findings about neurocognitive function.

Multiple sclerosis: relation to scrapie and slow infection; ageing and measles.

Multiple Sclerosis (MS) is shown to have no relation to scrapie and the evidence for a "slow infective" aetiology is very meagre. It is not related to an ageing process during which scrapie-like antigens make their appearance as they do in young animal with the disease. The emergence of scrapie-like antigens in ageing tissues is discussed. The increased sensitization of MS lymphocytes to scrapie, as opposed to normal brain (or spleen), is not characteristic of the disease, but occurs in other conditions with astroglial overgrowth. On the other hand, special lymphocyte sensitivity to inhibition by linoleic acid is limited to MS (and not shared by scrapie). The familial background of MS is briefly discussed, and an important line of study which might bring together classical genetic markers, HLA studies, and linoleic acid lymphocyte study is indicated. The role commonly ascribed to measles is critically reviewed. Measles may be of special importance in one (childhood-acquired) group of MS subjects, but there is no evidence of a special role in most cases. Raised antibodies to viruses other than measles have, however, been described. It is concluded that an immunological mechanism is still the most likely "final common path" by which MS lesions develop.