A pathology of the animal spirits – the clinical neurology of Thomas Willis (1621–1675) Part II – Disorders of intrinsically abnormal animal spirits

Thomas Willis (1621-1675), author of the classical work Cerebri Anatome (1664), was arguably the father of the modern era of neurology. His clinical neurology, as described in his Pathologiae Cerebri (1667) and De Anima Brutorum (1672), was largely derived from personal observations and not from traditional authorities and was based around his concept of the animal spirits, a fictitious entity in many ways analogous to the present day idea of the nerve impulse. This concept allowed him to develop a pathology of the animal spirits which embraced the whole content of the clinical neurology and psychiatry of his times. The anatomical and physiological background to Willis' concepts of animal spirit dysfunction, and those disorders he regarded as due to disturbed function of intrinsically normal animal spirits, have been dealt with in the previous part of this paper. The disorders he attributed to intrinsically abnormal animal spirits, dealt with in this part of the paper, comprised two categories. In one, the animal spirits possessed explosive properties, whilst in the other the abnormalities were non-explosive in their nature. The former category included epilepsy, hysteria and hypochondriasis, whilst the latter included mainly disorders now considered psychiatric e.g. delirium, melancholy, madness and stupidity. Willis' ideas about the pathogenesis of nervous system disorder seem never to have been generally accepted, partly because they appeared at a time when others were increasingly calling into question the existence of the animal spirits. Nevertheless, Willis' attempt to record and interpret all nervous system disease on the basis of disorder of function of a single underlying mechanism represents a formidable synthetic intellectual endeavour on the part of a very busy physician. (C) 2002 Elsevier Science Ltd. All rights reserved.

An 18th century understanding of migraine - Samuel Tissot (1728-1797)

During the period 1778-1780 the Swiss physician Samuel A A D Tissot (1728-1797) published his Traite des nerfs et de leur maladies, a work which continued to be available and widely influential until at least the middle of the following century. It contained a long chapter dealing with migraine, based on the earlier literature on the topic and on Tissot's own clinical experience. The work appeared at the beginning of the modern era of interest in migraine, and provided the first reasonably adequate and systematic account of the disorder to become widely available. Its descriptions of migraine phenomena have an enduring validity, though Tissot's ideas on the pathogenesis of the disorder, viz. that it usually arose from stomach disturbance, were not founded on satisfactory evidence and are long since superseded. (C) 2003 Elsevier Science Ltd. All rights reserved.

Polymorphisms in the 5 '-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression

We present evidence of complex balancing regulation of HTR1B transcription by common polymorphisms in its promoter. Computational analysis of the HTR1B gene predicted that a 50 segment, spanning common DNA sequence variations, T-261G, A-161T, and -182INS/DEL-181, contained a putative functional promoter. Using a secreted alkaline phosphatase (SEAP) reporter gene system, we found that the haplotype -261G_-182INS-181_A-161 enhanced transcriptional activity 2.3-fold compared with the haplotype T-261_-182INS-181_A-161. Conversely, -161T reversed this, and the net effect when -261G and -161T were in the same haplotype (-261G_-182INS-181_-161T) was equivalent to the major haplotype (T-261_-182INS-181_A-161). Electrophoretic mobility shift experiments showed that -261G and -161T modify the binding of transcription factors (TFs): -261G generates a new AP2 binding site, while alleles A-161 and -161T exhibit different binding characteristics to AP1. T-261G and A-161T were found to be in linkage disequilibrium (LD) with G861C in a European ancestry population. Interestingly, G861C has been reported to be associated with several psychiatric disorders. Our results indicate that HTR1B is the target of substantial transcriptional genetic regulation by common haplotypes, which are in LD with the HTR1B single-nucleotide polymorphism (SNP) most commonly used in association studies.

Temporal precision of interceptive action: differential effects of target size and speed

The duration of movements made to intercept moving targets decreases and movement speed increases when interception requires greater temporal precision. Changes in target size and target speed can have the same effect on required temporal precision, but the response to these changes differs: changes in target speed elicit larger changes in response speed. A possible explanation is that people attempt to strike the target in a central zone that does not vary much with variation in physical target size: the effective size of the target is relatively constant over changes in physical size. Three experiments are reported that test this idea. Participants performed two tasks: (1) strike a moving target with a bat moved perpendicular to the path of the target; (2) press on a force transducer when the target was in a location where it could be struck by the bat. Target speed was varied and target size held constant in experiment 1. Target speed and size were co-varied in experiment 2, keeping the required temporal precision constant. Target size was varied and target speed held constant in experiment 3 to give the same temporal precision as experiment 1. Duration of hitting movements decreased and maximum movement speed increased with increases in target speed and/or temporal precision requirements in all experiments. The effects were largest in experiment 1 and smallest in experiment 3. Analysis of a measure of effective target size (standard deviation of strike locations on the target) failed to support the hypothesis that performance differences could be explained in terms of effective size rather than actual physical size. In the pressing task, participants produced greater peak forces and shorter force pulses when the temporal precision required was greater, showing that the response to increasing temporal precision generalizes to different responses. It is concluded that target size and target speed have independent effects on performance.

Mapping of autosomal recessive chronic distal spinal muscular atrophy to chromosome 11q13

Distal spinal muscular atrophy is a heterogeneous group of neuromuscular disorders caused by progressive anterior born cell degeneration and characterized by progressive motor weakness and muscular atrophy, predominantly in the distal parts of the limbs. Here we report on chronic autosomal recessive distal spinal muscular atrophy in a large, inbred family with onset at various ages. Because this condition had some of the same clinical features as spinal muscular atrophy with respiratory distress, we tested the disease gene for linkage to chromosome 11q and mapped the disease locus to chromosome 11q13 in the genetic interval that included the spinal muscular atrophy with respiratory distress gene (D11S1889-D11S1321, Z(max) = 4.59 at theta = 0 at locus D11S4136). The sequencing of IGHMBP2, the human homologue of the mouse neuromuscular degeneration gene (nmd) that accounts for spinal muscular atrophy with respiratory distress, failed to detect any mutation in our chronic distal spinal muscular atrophy patients, suggesting that spinal muscular atrophy with respiratory distress and chronic distal spinal muscular atrophy are caused by distinct genes located in the so-me chromosomal region. In addition, the high intrafamilial variability in age at onset raises the question of whether nonallelic modifying genes could be involved in chronic distal spinal muscular atrophy.

Human brain regions required for the dividing and switching of attention between two features of a single object

This combined PET and ERP study was designed to identify the brain regions activated in switching and divided attention between different features of a single object using matched sensory stimuli and motor response. The ERP data have previously been reported in this journal [64]. We now present the corresponding PET data. We identified partially overlapping neural networks with paradigms requiring the switching or dividing of attention between the elements of complex visual stimuli. Regions of activation were found in the prefrontal and temporal cortices and cerebellum. Each task resulted in different prefrontal cortical regions of activation lending support to the functional subspecialisation of the prefrontal and temporal cortices being based on the cognitive operations required rather than the stimuli themselves. (C) 2003 Elsevier Science B.V. All rights reserved.

Spreading and synchronization of intrinsic signals in visual cortex of macaque monkey evoked by a localized visual stimulus

Spatio-temporal maps of the occipital cortex of macaque monkeys were analyzed using optical imaging of intrinsic signals. The images obtained during localized visual stimulation (IS) were compared with the images obtained on presentation of a blank screen (IB). We first investigated spontaneous variations of the intrinsic signals by analyzing the 100 IBs for each of the three cortical areas. Slow periodical activation was observed in alternation over the cortical areas. Cross-correlation analysis indicated that synchronization of spontaneous activation only took place within each cortical area, but not between them. When a small, drifting grating (2degreesX2degrees) was presented on the fovea. a dark spot appeared in the optical image at the cortical representation of this retinal location. It spread bilaterally along the border between V1 and V2, continuing as a number of parallel dark bands covering a large area of the lateral surface of V1. Cross-correlation analysis showed that during visual stimulation the intrinsic signals over all of the three cortical areas were synchronized, with in-phase activation of V1 and V2 and anti-phase activation of V4 and V1/V2. The significance of these extensive synergistic and antagonistic interactions between different cortical areas is discussed. (C) 2003 Elsevier B.V. All rights reserved.

Topographic plasticity in primary visual cortex is mediated by local corticocortical connections

The placement of monocular laser lesions in the adult cat retina produces a lesion projection zone (LPZ) in primary visual cortex (V1) in which the majority of neurons have a normally located receptive field (RF) for stimulation of the intact eye and an ectopically located RF ( displaced to intact retina at the edge of the lesion) for stimulation of the lesioned eye. Animals that had such lesions for 14 - 85 d were studied under halothane and nitrous oxide anesthesia with conventional neurophysiological recording techniques and stimulation of moving light bars. Previous work suggested that a candidate source of input, which could account for the development of the ectopic RFs, was long-range horizontal connections within V1. The critical contribution of such input was examined by placing a pipette containing the neurotoxin kainic acid at a site in the normal V1 visual representation that overlapped with the ectopic RF recorded at a site within the LPZ. Continuation of well defined responses to stimulation of the intact eye served as a control against direct effects of the kainic acid at the LPZ recording site. In six of seven cases examined, kainic acid deactivation of neurons at the injection site blocked responsiveness to lesioned-eye stimulation at the ectopic RF for the LPZ recording site. We therefore conclude that long-range horizontal projections contribute to the dominant input underlying the capacity for retinal lesion-induced plasticity in V1.

The interactive effects of alcohol and temazepam on P300 and reaction time

The present research investigated the separate and interactive effects of the minor tranquilliser, temazepam, and a low dose of alcohol on the amplitude and latency of P300 and on reaction time. Twenty-four participants completed four drug treatments in a repeated measures design. The four drug treatments, organised as a fully repeated 2 x 2 design, included a placebo condition, an alcohol only condition, a temazepam only condition, and an alcohol and temazepam combined condition. Event-related potentials were recorded from midline sites Fz, Cz, and Pz within an oddball paradigm. The results indicated that temazepam, with or without the presence of alcohol, reduced P300 amplitude. Alcohol, on the other hand, with or without the presence of temazepam, affected processing speed and stimulus evaluation as indexed by reaction time and P300 latency. At the low dose levels used in this experiment alcohol and temazepam appear not to interact, which suggests that they affect different aspects of processing in the central nervous system. (C) 2003 Elsevier Inc. All rights reserved.

Spatio-temporal evaluation of neck muscle activation during postural perturbations in healthy subjects

The purpose of this study was to examine the spatio-temporal activation of the sternocleidomastoid (SCM) and cervical extensor (CE) muscles with respect to the deltoid muscle onset during rapid voluntary upper limb movement in healthy volunteers. The repeatability and reliability of the spatio-temporal aspects of the myoelectric signals were also examined. Ten subjects performed bilateral and unilateral rapid upper limb flexion, abduction and extension in response to a visual stimulus. EMG onsets and normalised root mean square (nRMS) values were calculated for the SCM and CE muscles. Subjects attended three testing sessions over non-consecutive days allowing the repeatability and reliability of these measures to be assessed. The SCM and CE muscles demonstrated feed-forward activation (activation within 50 ms of deltoid onset) during rapid arm movements in all directions. The sequence and magnitude of neck muscle activation displayed directional specificity, however, the neck flexor and extensor muscles displayed co-activation during all perturbations. EMG onsets demonstrated high repeatability in terms of repeated measure precision (nSEM in the range 1.9-5.7%). This was less evident for the repeatability of nRMS values. The results of this study provide a greater understanding of cervical neuromotor control strategies. During bilateral and unilateral upper limb perturbations, the SCM and CE muscles demonstrate feed-forward co-activation. It seems apparent that feed-forward activation of neck muscles is a mechanism necessary to achieve stability for the visual and vestibular systems, whilst ensuring stabilisation and protection of the cervical spine. (C) 2004 Elsevier Ltd. All rights reserved.

Feedforward activity of the cervical flexor muscles during voluntary arm movements is delayed in chronic neck pain

The objective of this study was to compare onset of deep and superficial cervical flexor muscle activity during rapid, unilateral arm movements between ten patients with chronic neck pain and 12 control subjects. Deep cervical flexor (DCF) electromyographic activity (EMG) was recorded with custom electrodes inserted via the nose and fixed by suction to the posterior mucosa of the oropharynx. Surface electrodes were placed over the sternocleidomastoid (SCM) and anterior scalene (AS) muscles. While standing, subjects flexed and extended the right arm in response to a visual stimulus. For the control group, activation of DCF, SCM and AS muscles occurred less than 50 ms after the onset of deltoid activity, which is consistent with feedforward control of the neck during arm flexion and extension. When subjects with a history of neck pain flexed the arm, the onsets of DCF and contralateral SCM and AS muscles were significantly delayed (p<0.05). It is concluded that the delay in neck muscle activity associated with movement of the arm in patients with neck pain indicates a significant deficit in the automatic feedforward control of the cervical spine. As the deep cervical muscles are fundamentally important for support of the cervical lordosis and the cervical joints, change in the feedforward response may leave the cervical spine vulnerable to reactive forces from arm movement.

Neck flexor muscle fatigue is side specific in patients with unilateral neck pain

Despite the evidence of greater fatigability of the cervical flexor muscles in neck pain patients, the effect of unilaterality of neck pain on muscle fatigue has not been investigated. This study compared myoelectric manifestations of sternocleidomastoid (SCM) and anterior scalene (AS) muscle fatigue between the painful and non-painful sides in patients with chronic unilateral neck pain. Myoelectric signals were recorded from the sternal head of SCM and the AS muscles bilaterally during sub-maximal isometric cervical flexion contractions at 25% and 50% of the maximum voluntary contraction (MVC). The time course of the mean power frequency, average rectified value and conduction velocity of the electromyographic signals were calculated to quantify myoelectric manifestations of muscle fatigue. Results revealed greater estimates of the initial value and slope of the mean frequency for both the SCM and AS muscles on the side of the patient's neck pain at 25% and 50% of MVC. These results indicate greater myoelectric manifestations of muscle fatigue of the superficial cervical flexor muscles ipsilateral to the side of pain. This suggests a specificity of the effect of pain on muscle function and hence the need for specificity of therapeutic exercise in the management of neck pain patients. (C) 2003 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.