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Some TMS studies suggest that siently expanded the representation for the premotor cortex and SMA provide bilateral lower face into the hand representation 150 mg cleocin sale skin care books, but his output projections to spinal motoneurons and lower chin moved in synchrony with move- contribute to movement of the affected hand ments of the paretic thumb discount cleocin 150 mg with amex acne excoriee. These contralesional cortical neurons cortex cheap cleocin 150mg with visa acne pictures,70a which may hark back to prenatal ac- may be more excitable when they are less in- tivity-dependent connectivity created by the hibited by callosal inputs that no longer pro- fetal thumb-in-mouth position. Functional imaging studies can costriatal fibers that initially caused the hand only point to this possibility. Opposition of the fingers of the normal Representational Plasticity left hand activated the right insula, anterior cin- In a series of groundbreaking studies by gulate, striatum, and the lateral prefrontal, Weiller and colleagues, PET was performed in premotor, and inferior parietal (area 40) cor- normal control subjects and patients who re- tices more than normal. Mild impairment of covered hand function after a striatocapsular movements of the ipsilateral upper extremity infarction. The mo- the experiments also showed that the lateral tor task with either hand activated the con- prefrontal and cingulate cortices and the angu- tralateral motor cortices and ipsilateral cere- lar gyrus were activated by a simple task after bellum to the same degree as in healthy the stroke. Subjects with recovered hand func- lective attention and intention come into play tion had greater rCBF compared to the con- when an automatic movement reorganizes. These nonprimary corti- and activation of distributed pathways that cal motor areas apparently served a substitutive would not ordinarily have been as metabolically function. The imaging studies were not designed explain the associated or mirror movements in to determine whether representational changes the left hand that often accompanied a right- and the recruitment of remote regions played handed task. Sites of activation differed in relationship to Imaging with fMRI has been remarkably the precise localization of the subcortical le- successful, given the complexity of the tech- sion. The small number of cases in each with lesions limited to the posterior limb of the study, the wide variations in the type and lo- internal capsule showed a 1 cm extension of ac- cation of stroke, differences in clinical out- tivation in S1M1 of the affected hemisphere. These investigations have whose fMRI study is shown in Color Figure yielded some additional insights into plasticity Functional Neuroimaging of Recovery 173 after stroke, especially in regard to S1M1. Con- Although the hippocampus and association tralesional S1M1 is the most common region cortices such as the posterior parietal, inferior of interest to rapidly reveal an increased num- temporal, and prefrontal regions are most of- ber of activated voxels during movement of the ten thought of as storage areas for sensory in- affected hand. Retraining a skill yielded other instances of shifts in neuronal may, then, require optimizing the sensory feed- networks, especially in primary sensory and as- back for the desired task-related movement, sociation cortex. These movements of the cen- which integrates sensorimotor contributions for ter of activation are most evident as the paretic the movement. Success in accomplishing a skill subject carries out and monitors difficult mo- may be reflected by serial functional imaging tor activities. The impact of sen- time-dependent change in the effective con- sory inputs that are relevant to carrying out a nectivity of interacting regions that drives task should not be underestimated. Primary motor cortex the degree of representational plasticity is that acts to bring together functionality across the the size of a functional unit for performing a joints of a limb. Primary somatosen- imal regional activation is required under dif- sory cortex cannot. On the other hand, M1 may enlarge from input MIRROR MOVEMENTS IN about a movement coming from S1, then CEREBRAL PALSY shrink toward normal as the skill is reacquired. When the sensory inputs and motor outputs Attempts at unilateral or isolated movements came closer to normal, S1 may also shrink to may produce contralateral mirror movements normal. Imaging studies af- stimulation evoked larger motor responses in ter stroke have attempted to understand the abdominal muscles rostral to a thoracic whether or not these movements, which are of- spinal cord lesion and from a greater number ten transient in adults, represent a phase of re- of scalp positions than were evoked in the ab- organization. The investiga- tion has been especially apparent in infants and tors could not exclude a change at the level of children after hemispherectomy for epilepsy126 the affected spinal motoneurons, such as an in- and after early stroke (Color Figure 12–3 in crease in their excitatory response to a de- separate color insert). Ipsilateral cortical effer- scending volley or to sprouting of corticospinal ent pathways can come to subserve hand move- axons. The cortex through age 15, prior to the natural, investigators found enhanced bilateral activity perhaps activity-dependent regression of neu- in the thalamus and cerebellum and expansion rons and synapses in the developing brain. They have tor potential, suggesting plasticity-related so- generally not been observed after adult onset matosensory cortex adaptation to deafferenta- hemiparesis. The cortical activation for the tongue branched from the normal hemisphere to bi- shifted medially and superiorly about 13 mm, lateral homologous spinal motoneuron pools compared to healthy subjects. No shift was found, surprisingly, for the lem in sensorimotor integration in subjects wrist representation. An active and tent with other studies revealing that a discon- passive movement fMRI study and TMS pro- nected, but available cortical representation duced contralateral activation for the unaf- may come to cofunction with neighboring fected hand in seven subjects. Twelve subjects who had a mild TBI 1 month SPINAL CORD INJURY before testing were compared to controls in the Paraplegic and tetraplegic subjects reorganize auditory n-back task (see Experimental Case their primary sensorimotor cortical represen- Study 3–1) for assessing working memory (see tations for movements. Activity in the bilateral dorsolateral (Tower of London task), switching from one prefrontal and superior parietal cortices was aim to another during a task (Stroop Test), as- similar for the 0-back (simple vigilance) com- pects of memory,141,142 expectation and receipt pared to 1-back (low demand) condition. A of rewards,143 and emotional responses to stim- much more extensive activation was found in uli144 can be used to compare normal subjects these regions on the right in patients with TBI to people who remain disabled by the typical for the 1-back to 2-back comparison, although sequelae of TBI (see Chapter 11). Both groups had a lying hypothesis is that patients process infor- similar magnitude of task-related increase in mation less efficiently after TBI. In addition, activation when the 0-back and 2-back were the effects of repetition and priming on mem- compared. Functional imaging, then, revealed ory processing can be monitored by functional a difference in the ability of the TBI subjects imaging, which may aid the development of to modulate or allocate resources with an in- cognitive rehabilitation approaches. The clin- ical symptoms of the patients suggested diffi- MULTIPLE SCLEROSIS culties in the maintenance and manipulation of verbal information. A study of patients who the partial remissions after exacerbations of were recovering from more severe TBI used multiple sclerosis (MS) and the progression the paced auditory serial addition test to assess over long periods of time lead to the specula- working memory (see Chapter 7). Compared tion that partial restitution and substitution to healthy subjects, the patients made more er- may evolve from lesion-induced and practice- rors and the pattern of cerebral activations was related network and representational plasticity, more dispersed and lateralized to the right improved axonal conduction,146 remyelination, frontal lobe. By the same logic, exhaus- impaired network may require larger or more tion of reorganizational plasticity as the burden widespread network activity to successfully of axonal lesions grows may contribute to func- carry out cognitive tasks. Another PET activation study examined one An fMRI study employed simultaneous flex- of the consequences of diffuse axonal injury. Perseverative errors were higher ipsilateral activation accompanied significantly and inversely related to metabo- greater functional impairment in patients com- lism in the right, but not the left dorsolateral pared to controls. This re- weighted MRI lesion load of MS plaques, the lationship was independent of any individual center of the activation shifted posteriorly in differences in global brain metabolism, general the sensorimotor representation contralateral cognitive ability, or overall performance on the to the hand that moved, especially as the vol- test. No relationship was found between per- ume of the MS lesions increased within the severative errors and the presence of prefrontal corticospinal projection. Functional imaging tests of tion moved approximately 8 mm, from the pos- this frontal-subcortical circuit, then, may help terior wall of the precentral gyrus to the ante- clinicians measure the impact of diffuse axonal rior wall of the postcentral gyrus in 15 of 24 injury in frontal white matter and serve as phys- subjects. As in the studies of patients with iologic markers for the evaluation of cognitive stroke described earlier, this posterior migra- and pharmacologic interventions aimed at tion may point to a greater representational modulating the circuit. A study of 176 Neuroscientific Foundations for Rehabilitation patients with primary progressive MS who had sentational changes as assessed by TMS, MEG, normal function of an upper extremity also re- PET, and fMRI. Transcranial magnetic stimu- vealed a different pattern of cortical activation lation reveals a lower threshold, greater num- than healthy control subjects during flexion- ber of stimulation sites, and higher evoked am- extension movements of the unaffected plitude for the muscles most proximal to the hand. In addition, functional imaging TRAINING-INDUCED has revealed evidence for motor reorganization REORGANIZATION after a single bout of MS148a and adaptive changes during a sustained attention task in pa- Although the number of pilot studies of pa- tients who performed normally. Nine patients with CADASIL, for the ideal serial study compares perform- example, were more likely to have bilateral ance-related activations before, during, and af- S1M1 activations on an fMRI task of hand tap- ter completion of training.
Forexample buy cheapest cleocin skin care brand names,despite the amplitude of the reﬂex response produced by the extra 0 cheap 150mg cleocin with mastercard acne 30s female. Accordingly buy discount cleocin 150mg line acne gel prescription, it has been corresponds to the simultaneous arrival of the two arguedthatdifferencesinthebehaviourofHandten- volleys at spinal level (Chapter 5). This is due to two don jerk reﬂexes reﬂect the involvement of drive in reasons. Thisbeliefhas been called into question because H and tendon jerk reﬂexes differ in a number of other respects, as dis- PSPs in individual motoneurones cussed in detail in Chapter 3. Ofgreater importance the rise time of the EPSP is sufﬁciently long that the could well be the effects on the spindle response to dischargeofthelastrecruitedmotoneuronesevoked percussion of the thixotropic properties of intrafusal by the monosynaptic input will not occur before the ﬁbres (see Chapter 3). Thisissoeventhoughthe synaptic delay at the interneurone delays the onset of the IPSP by 0. In addition, an EPSP elicited by a condi- In most investigations, the monosynaptic reﬂex is tioning volley entering the spinal cord after the test used as a test reﬂex to assess the effect of condition- volley may summate with the decay phase of the test ing volleys on the motoneurone pool. Control and conditioned reﬂexes should Motoneurones do not discharge at the same time be randomly alternated, because: (i) this avoids the in the test reﬂex possibility of the subject voluntarily or involuntarily predicting the reﬂex sequence; and (ii) regular alter- Eveninthecatthereis0. Thus, a disynaptic IPSP elicited by a conditioning volley entering the spinal cord at the same time as the test monosynaptic Ia volley may inhibit the last spikes (thin interrupted lines) contributing to the monosynaptic reﬂex discharge, while the ﬁrst spikes (thick continuous lines) are not modiﬁed. Adapted from Matthews (1972)(a), and Araki, Eccles & Ito (1960)(b), with permission. There are differences in the rise- the recovery cycle of the H reﬂex times of mechanically and electrically evoked EPSPs (∼10 ms for tendon percussion; ∼2msfor the elec- the recovery cycle of the H reﬂex investigates the trically evoked volley), but this is not obvious in the time course of the changes in the H reﬂex after a reﬂex EMG potentials because the axons of the last conditioningreﬂexforconditioning-testintervalsup recruited motoneurones have a more rapid conduc- to 1–2 s. Such studies were in vogue in the 1950– tion velocity than those ﬁrst recruited. Chapter8),afterhyperpo- There are advantages with threshold tracking over larisation and recurrent inhibition of motoneurones amplitude tracking for H reﬂex studies. Chapter 4), muscle spindle receptor unloading (i) the results are less variable (cf. Chapter 3), Golgi (ii) the recorded response involves a constant tendon organ activation by the conditioning twitch population of motoneurones, and clamping the (cf. Chapter 6), and effects mediated by long loops reﬂex response to a ﬁxed size avoids the problem (Taborıkova&S´ ´ ´ ax, 1969). There is an initial period of be reﬂected in the size of the test response. These changes in the intensity of the afferent volley must be altered, excitability are those of the stimulated peripheral and this could introduce inaccuracies, because the nerve axons (Chan et al. By con- Amplitude and threshold tracking of the trast, with amplitude tracking, changes in reﬂex compound H reﬂex excitability produce instantaneous changes in the reﬂex response. With threshold tracking, test stimuli are varied auto- matically by computer, much as in conventional threshold tracking (Bostock, Cikurel & Burke, 1998), Limitations related to mechanisms acting to maintain a constant compound H reﬂex, the cur- on the afferent volley of the reﬂex rent being then referred to as the threshold for the Hreﬂex. Reﬂex facilitation will produce a decrease the pathway of the monosynaptic reﬂex is not as in the required current, and reﬂex inhibition will simpleasitatﬁrstseems. The recovery cycle of the H reﬂex following a single subthreshold conditioning stimulus. The soleus H reﬂex was conditioned by a weak stimulus to the posterior tibial nerve (65% of the unconditioned test stimulus, subthreshold for the H reﬂex during contraction). Data representing the deviation from the unconditioned value (horizontal dashed line), using threshold tracking (a) and amplitude tracking (b)atrest(❍) and during tonic soleus voluntary contractions (●)are plotted against the conditioning-test interval. In (a) the intensity of the test stimulus was altered to keep the test H reﬂex constant: an increase in excitability would therefore require less current. In (b), the test stimulus was constant: an increase in excitability would therefore increase the amplitude of the test H reﬂex. The extent of hyperpolarization depends on the impulse load, but can be prominent. Repetitiveactivationofcutaneousafferents(Kiernan For example, with motor axons, contractions last- etal. Post-activation depression produced by different ways of activating the Ia afferent-MN synapse repetitively. Several methods have been devel- tant for group Ia afferents and the H reﬂex, because oped to assess presynaptic inhibition of Ia termi- the excitability of the afferents will decrease dur- nals in human subjects, as described in detail in ing a voluntary contraction if there is a fusimotor- Chapter 8. As a result, the reﬂex response to a ﬁxed stimulus could change, independently of the Post-activation depression othercontraction-relatedchanges(presynapticinhi- A different presynaptic mechanism limiting bition of Ia afferents, post-activation depression, monosynaptic reﬂexes is post-activation depression motoneuroneexcitability). Additionally,thecontrac- at the Ia ﬁbre-motoneurone synapse, probably due tion will activate Ib afferents and thereby reduce to reduced transmitter release from active Ia affer- theirexcitabilitytoelectricalstimulation. Thiswould ents, a phenomenon which is described in detail reduce the number of Ib afferents in the afferent in Chapter 2 (pp. Post-activation depres- volley and the extent to which they limit the size of sion occurs when (and only when) the conditioning the H reﬂex (see pp. Hreﬂexdepression Presynaptic inhibition of Ia terminals has been reported to occur following a preceding H Ia terminals mediating the afferent volley of the reﬂex (Magladery & McDougal, 1950), a subliminal monosynaptic reﬂex are subjected to presynaptic tendon tap (Katz et al. Changes in presynaptic inhibition contraction of soleus or stretch of soleus produced ofIaterminalscancausemajorchangesintheampli- by contraction of tibialis anterior (Crone & Nielsen, tude of the H reﬂex, and the possibility that a change 1989; see also Wood, Gregory & Proske, 1996). The in presynaptic inhibition accounts for a change in effects of this phenomenon can be profound, as the amplitude of the H reﬂex must therefore always illustrated in Fig. In all cases, there was dramatic reﬂex group I EPSP underlying the H reﬂex is so short depression at short intervals (1–2 s), with gradual (some 1–2 ms) that the monosynaptic Ia compo- recovery over 10 s. The depressive effects of the nent of the EPSP must be curtailed by oligosynap- stimulus rate on reﬂex size are generally taken tic inhibition, and that this would help limit the size into consideration in reﬂex studies, but the same of the H reﬂex (Burke, Gandevia & McKeon, 1984). It is likely ways could truncate the monosynaptic Ia excitation: that misinterpretations have arisen because this (i)Ibinhibitoryinterneuronesactivatedbythegroup phenomenon was neglected in studies comparing I test volley produce autogenetic inhibition with an changes in the test reﬂex during or after a voluntary onset ∼0. In addition, when the effects of a to the group Ia monosynaptic EPSP in motoneu- conditioning volley are compared at rest and during rones (Pierrot-Deseilligny et al. Contribution of oligosynaptic pathways Disynaptic limitation of the group Ia excitation to the H reﬂex Recent experimental evidence for a disynaptic lim- Limitation of the size of the H reﬂex itation of the group Ia excitation that is the basis In soleus, when the intensity of the test stimulus is of the H reﬂex has been provided for the quadri- increased, the amplitude of the H reﬂex commonly ceps (Marchand-Pauvert et al. The evidence reachesitspeakbeforetheantidromicvolleysetupin is as follows. At rest and during weak contractions of motor axons collides with and annihilates the reﬂex quadriceps stimulation of the deep peroneal nerve response (see p. Thus, there is a limitation to the produces a late facilitation of the quadriceps H size of the H reﬂex independent of the collision with reﬂex with a central delay of 6–12 ms. Taborıkova&´ ´ ´ D), but this is suppressed during a contraction Sax(1968)demonstratedthat,innormalsubjects,the of 10–20% maximum voluntary contraction (MVC) percentage of soleus motoneurones activated in the. However, HreﬂexbymaximalstimulationofIaafferentsranges thecorrespondingfacilitationoftheon-goingEMGis from 24 to 100, usually ∼50%. Such a discrepancy soleus, this implies the existence of factors limiting raises the possibility of an inhibitory mechanism ga- the size of the reﬂex. Curtailment of the compound EPSP by an Panel (c) shows the peak of homonymous group I oligosynaptic IPSP excitation evoked by femoral stimulation, panel (d) the ﬁrst motoneurones discharging in the H reﬂex the weak facilitation at around 27 ms elicited by sep- do so at a latency consistent with a monosynaptic arate stimulation of the deep peroneal nerve, and pathway (Magladery et al. However, based (e)thesigniﬁcantreductionofthefemoralexcitation on estimates from post-stimulus time histograms oncombinedstimulation. Suppressiononcombined (PSTHs) of the discharge of single motor units, it stimulationwhenthestimulibythemselvesproduce the monosynaptic reﬂex 15 (a) 3 (c) FN 0.
If the patient withdrew from the study before of the four treatments buy discount cleocin 150 mg line skin care 4men palm bay, simple mean values are the 90th treatment day buy cleocin online now acne 7-day detox, the mean of the last expected to produce a bias towards no effect discount cleocin 150 mg with amex acne wiki. At three recorded days is extended from the least when comparison is done to placebo: in this last recorded day plus one to day 90 post- group there were more withdrawals and many of randomisation. This will introduce a selection bias subtract that from all daily means. The way this mean is computed for the run-in period, which is is done is as follows: used as a baseline, and then for the treatment period (from the day of randomisation and 1. The change from baseline is used as all missing values between the ﬁrst and the last effect variable, and the analysis is an ANOVA recorded day for each patient. The following table shows the no asthma symptoms and no rescue medication adjusted mean values for the effect variable was needed. The percentage of such days is for the four treatment groups, adjusted to a often a useful variable, at least in studies on common baseline value (the mean over the full mild–moderate asthmatics. Another approach to diary card data is to mea- 95% Conﬁdence sure time to ﬁrst exacerbation. In a population Treatment Mean SEM limits like this, this is not expected to produce better placebo −10. Morning or evening PEF should be more than data, the explanatory power of the analysis is 20% below the period mean during run-in. The patient woke up during night-time and by ﬁrst computing individual period means. Symptom scores and rescue medication are however variables for which the average value By scanning the diary cards we can, for each is not necessarily easy to interpret. Symptom patient, compute the time to ﬁrst exacerbation, if scores are really ordered categorical data, and there is one, otherwise the patient is censored. We see a picture similar to rescue medication, the problem is mainly that that conveyed by the period means. Statistically we use the mean as a measure of location for we can compare groups either by log-rank tests a distribution which, for some patients, might be or semiparametric Cox regression. Also the distribution of period means over below treatments are compared to placebo based patients may well be skew. At ratio limits p-Value least the former is often for mild patients a A 200 µgvs 0. This idea can be carried one step placebo further: we can introduce the concept of an B 200 µgvs 0. Kaplan–Meier plot of the time to a mild exacerbation We see that the hazard for a mild exacerbation to the last one). As expected in this Such a study needs a detailed deﬁnition of what patient group, the results are, from a statistical is meant by asthma control. There is no such point of view, somewhat weaker than the ones universal deﬁnition, but lack of asthma control is obtained from the analysis of period means. So the working deﬁnition above could be used, and the algorithm is to step A Dose Reduction Study down until a mild exacerbation occurs. To compare the efﬁcacy of two GCSs, a ran- In such a study the diary card variables per se domised, double-blind parallel group study with are not of independent use, they should not be two treatment arms (one for each GCS) was compared between groups, except possibly the designed. Instead it is expected tive dose potency by starting each arm on a high that the mean values are similar in the two dose of the GCS, treating for some weeks, step- arms over the treatment period, what varies is ping down the dose and treating for some weeks, the underlying dose producing those effects. This is done until effect variable of interest is the MED, which is the asthma is no longer controlled. On the one hand RESPIRATORY 391 it will be rather discrete in nature, with only a Moderate: the patient has breathlessness on few possible levels. On the other hand the most exertion and FEV1 in the range 40–60% of informative way of expressing the result is to predicted normal. The most appropriate way into two groups: symptomatic effects and disease to do this is to regard the data as interval censored modifying effects. This decline in lung function dose–response studies, it is informative for the leads to progressive symptoms and diminished interpretation of the results to relate the observed exercise endurance. This to the alleviation of symptoms and improvement can be done within a study, so that the patients of quality of life, whereas disease modifying are put on a heavy treatment, consisting of a effects are effects that lessen the decline rate in high dose of a GCS and a long-acting β2-agonist lung function. It during run-in, in a period after a run-in period should lead to improved symptoms, fewer exacer- or by adding on a period at the end of the bations and better performance on exercise tests. The purpose of Many drugs that were originally anti-asthma this is to be able to quantify the response in drugs have been tried, and licensed, for the terms of what can actually be achieved in the COPD indication. If we put this reference be due to the reversible component that many period at the end of the study, we must make COPD patients have in their disease – in other certain that all patients, including withdrawals, words an anti-asthma effect within the COPD. In pass it in order to avoid having problems with order to claim effects above this, studies have a selection bias. If we put this reference period been performed in which one tries to exclude before randomisation, we might have carry-over patients with reversible components by using effects into the randomised treatments with their exclusion criteria on patients with a reversibility potential problems. To claim that short- as reference often helps in the interpretation of term effects seen in the population are due to the results. However, regula- the patient has FEV1 > 60% of predicted tory requirements make FEV1 the primary efﬁ- normal, no breathlessness and is in general cacy variable in COPD studies – at least as of unknown to the health care system. In fact the intensity of the rhinitis is dependent on pollen CPMP guidelines require two primary efﬁcacy counts in the air, and lack of treatment effects variables in COPD studies – one should be FEV1 can well be due to insufﬁcient pollen exposure. Prevention of exacerbations is perhaps the most One of the challenges for drug development is important aspect of COPD treatment, so a 6- to prove that a new treatment is therapeutically month study is the minimum. In the area of A COPD drug which claims disease modifying respiratory diseases this problem appears in two properties has a heavier burden of proof on different settings – when we want to register a it. The effect of disease modifying is that the new formulation, most often a new inhaler, and rate of decline in lung function is reduced. The statistical analysis should focus on the rate of decline, Bioequivalency of Two Devices which could be done using a linear mixed Bioequivalency refers to a speciﬁc problem. Assume that a drug is delivered as a tablet or in some other form, such that it must pass through Rhinitis Trials the bloodstream before reaching its site of action. Classiﬁcation of rhinitis patients into groups Then the plasma concentration proﬁles of the according to severity is lacking. This reasoning division is between occasional and continuous is the rationale for the bioequivalence concept: expression of symptoms, i. The rhinitis lent, show that the plasma concentration proﬁles symptoms are the same, so the measurements, are sufﬁciently similar. As already logically infer that the therapeutic effects are suf- indicated symptoms are often recorded in diary ﬁciently similar to have the same therapeutic cards for blockage, runny nose, sneezing/itchy effect. This is in general a rather straightfor- and eye symptoms, and the sum of the ﬁrst three ward problem, requiring only small pharmacoki- make up the Combined Nasal Symptom score netic studies. We reduce the general question of similar rhinitis lies more in the study design/conduct. For plasma concentration curves to key measures of perennial rhinitis the situation is similar to that rate and extent of absorption, including AUC.
I have changed the names of the patients and certain other details to preserve their anonymity order cleocin paypal acne treatment for sensitive skin. When I graduated from medical school in 1955 buy cleocin 150 mg on line acne quitting smoking, I adopted the model of disease then prominent order generic cleocin from india acne popping, if not exclusive, in U. Each case (as I encountered the person and the facts) began to unravel my rigid views about disease and illness. Eventually, I found the biomolecular model of disease applicable only to a narrow segment of patients who seek medical care. We need to draw clear distinctions between the reductionist research model and the need for an ex- panded clinical model that encompasses the psychological and social aspects of human beings. Human biology and clinical med- icine overlap, but they are also quite different and are too often confused. When I did, I was heavily inﬂuenced by his writings and began to understand some of the clinical problems I was encountering. Balint studied general practitioners for several years in the United Kingdom as if they were pharmacologic agents. He was examining the correct dos- age, underdosage, overdosage, and duration of action of physicians themselves as a drug. Balint developed the term apostolic function of a physician to describe the beliefs and teachings of physicians as these affected their relationships with their patients. Of the apostolic function, Balint (1955, 684) writes: We meant that every doctor has a set of fairly ﬁrm beliefs as to which illnesses are acceptable and which are not; how much pain, suffering, fears, and deprivations a patient should tolerate, and when he has the right to ask for help and relief: how much nuisance the patient is allowed to make of himself and to whom, etc. Tese beliefs are hardly ever stated explicitly but are nevertheless very strong. They compel the doctor to do his best to convert all of his patients to accept his own standards and to be ill or to get well according to them. The effect of the apostolic function on the ways the doctor can administer himself to his patients is fundamental. Abram and I jointly published a chapter in his book Basic Psychiatry for the Primary Care Physician. It is this narrow version under which I had attempted to function during the early years after I graduated from medical school. The hypothetical statement says: I believe my job as a physician is to ﬁnd and classify each disease of my patient, prescribe the proper medicine, or recommend the appropriate surgical procedure. Medical disease (real or organic disease) is caused by a single physi- cochemical defect such as by invasion of the body by a foreign agent (virus, bacterium, or toxin) or from some metabolic de- rangement arising within the body. It was only by an accumulation of confounding clinical expe- riences, described in the early chapters of this book, that I came to reject the narrow model. When I was in full-time private practice in Selma, Alabama, in the early 1960s, the senior partner in my practice group got pneu- monia. For about three months, I saw all of his patients in addition to my own growing practice. I was surprised to ﬁnd that many of his patients carried diagnoses of diseases they did not have. Upon my return to Birmingham and full-time academic life in 1963, I continued to encounter patients who carried diagnoses of nonexistent disease. I wrote a satire called the Art and Science of Nondisease and published it in the New England Journal of Medi- cine (Meador 1965). I thought of it as a tongue-in-cheek poke at the foibles of medical practice. The continued responses to that article tell me that I hit on some deep nerve in the way medicine is prac- ticed—that I uncovered some fundamental problem. I remained puzzled by what to make of this seemingly com- mon error in medical practice until I began to write this book. It is now clear to me that making a false diagnosis of a disease is a con- sequence of adhering rigidly to the narrow biomolecular model. This view of diseases says, If a patient has symptoms in the body, then there must be a disease of the body. However, there is not a de- ﬁnable medical disease behind every physical symptom. In this book, I tell the stories of a series of patients who had symptoms in their bodies but who had no demonstrable medical disease to explain them. Additionally, I raise and explore answers Introduction xiii to a set of questions about patients who carry diagnoses of diseases they do not have: 1. If the patient does not have the disease diagnosed, then what does he or she have? What harm can come from having a diagnosis of a disease that is not present? Why has this error been almost completely ignored in the medical literature? In the later chapters, I present patient stories, ﬁndings, and out- comes that came from my adoption of a broader model of disease and illness. Many patients were referred to me by physicians who knew of my interest in problem patients and particularly in patients who carried diagnoses of diseases they did not have. In the last chapters of the book, I present applications of a broader paradigm of disease that was proposed by George Engel, which may be a step in this new direc- tion. Abram and I formulated the following hypothetical statement to deﬁne this broader biopsychosocial model: I do not believe in a single causation for most diseases. I be- lieve the symptoms of disease arise in a highly complex mix of genetic weakness, psychosocial events and stresses, physico- chemical abnormalities, and a host of other factors. I see pa- tients as people with problems who may or may not also have a demonstrable physicochemical defect. If the defect is deﬁn- able, I prescribe medication aimed at correcting the physio- xiv Symptoms of Unknown Origin logic abnormality or I recommend a surgical procedure. I also listen to the patient in a manner that will permit him to bring up whatever is bothering him. I am impressed with the fre- quency with which my patients can tell me what happened in their lives just before getting sick. I recount my time with Carl Rogers at the Center for the Study of the Person in La Jolla, California, and with Joseph Sapira, a mas- ter clinician at the University of Alabama in Birmingham, and with Stonewall Stickney, one of my mentors in psychiatry at the Univer- sity of South Alabama School of Medicine in Mobile. I am suggesting the term symptoms of unknown origin, or SUO, for all patients who do not have a ready or immediate medi- cal explanation for their physical symptoms. This approach also avoids the use of more pejorative terms like crock, shad, or turkey. We really do not know what the origin of any symptom is when we ﬁrst meet a patient. My plea is to stay in that mode until the level of certainty of the diagnosis is compelling. Most important, this term enlists the patient in inspecting his or her life to ﬁnd the variables that may be triggering or even causing the symptoms. Several colleagues have suggested that the clinical methods de- scribed here need a unifying name.