Received October 7, 1997; revised February 3, 1998; accepted March
20, 1998. From the Veterans Affairs Medical Center and Western Psy- chiatric Institute and Clinic, Pittsburgh, Pennsylvania. Address cor- respondence to Dr. Keshavan, Western Psychiatric Institute andClinic, 3811 OHara Street, Pittsburgh, PA15213; e-mail: keshavan@pitt.edu Copyright 1998 American Psychiatric Press, Inc. The Neurologic Examination in Adult Psychiatry: From Soft Signs to Hard Science Richard D. Sanders, M.D. Matcheri S. Keshavan, M.D. Of the proliferating approaches to neuropsychiat- ric assessment, a relatively neglected technique is the venerable, accessible, noninvasive, and inex- pensive neurologic examination. This article or- ganizes and synthesizes the literature on neuro- logical ndings in adult psychiatric patients. Problems in conducting and interpreting research in this area are examined, clinically pertinent em- pirical ndings are surveyed, and directions for future investigation are outlined. Most of the soft signs can be reliably evaluated, and many have been validated against other techniques. Sev- eral psychiatric diagnoses are associated with im- paired neurologic performance. Prognosis and treatment selection may also be informed by neu- rologic ndings. The neurologic exam should be regarded as a collection of neurobiologic probes rather than as a single irreducible variable. Future work must better establish interrater and test- retest reliability of individual elements of the neu- rologic exam in psychiatric populations and focus on developing the clinical utility of individual and combined elements of the neurologic exam. (The Journal of Neuropsychiatry and Clinical Neurosciences 1998; 10:395404) T he neurologic examination has two general func- tions in psychiatry. The rst, screening for major neurological disease, is accomplished with an exami- nation emphasizing such hard or major signs as re- ex and motor asymmetry and the Babinski reex. The results of each component of the screening examination can be described dichotomously as normal or abnormal. These results reect the presence or absence of neuro- pathology, particularly that which is focal and acquired later in development. This article deals with the second objective of the psychiatric neurologic exam: evaluating performance decrements in psychiatric patients without identiable neurologic disorders. This evaluation may be accomplished with an extended exam, which in- cludes assessment for soft signs such as inaccurate motor sequencing and bilateral dysgraphesthesia. Such assessments may be described in terms of degree of per- formance decrement, rather than by the presence or ab- sence of abnormality. These evaluations are often per- formed by physicians but are also represented in some neuropsychological batteries. Although these two func- tionsscreening and evaluationare conceptually dis- tinguishable, the examinations serving these ends over- lap substantially, and ndings with signicance in either context are hereafter referred to inclusively as neurologic exam abnormalities (NEA). Classic descriptions of the psychiatric disorders often 396 VOLUME 10 NUMBER 4 FALL 1998 NEUROLOGIC EXAMINATION IN PSYCHIATRY included neurological exam ndings. Thus, insane temperament, 1 hysteria, 2 schizophrenia, 3,4 mood dis- orders, 5,6 and obsessive-compulsive disorder 7 were each thought to have characteristic NEA. By mid-century the American psychiatric literature rarely mentioned neu- rologic ndings. NEA research in child psychiatry then expanded as the concepts of soft neurological signs 8 and minimal brain dysfunction 9 became popular in the 1960s. This trend led to large pediatric studies 10,11 and to much conceptual and methodologic clarica- tion. 1215 Studies of NEA in adolescent 16,17 and then adult 18,19 psychiatric patients followed. Studies of NEA in adult psychiatric patients have increased in quantity and quality in recent years; recent texts again include NEA in descriptions of psychopathology. 20,21 Since its use by Bender in 1947 to describe ndings suggesting possible neurologic disease, the term soft signs has had other connotations, including a lack of di- agnostic or anatomic specicity, a lack of reliability, and evanescence. Also soft are the boundaries of the cate- gory, considered by some to include such variedfeatures as sinistrality, electroencephalographic dysrhythmias, and learning disabilities, as well as the more widely in- cluded NEA. 22 Not surprisingly, some view the topic with derision: The use of the terms soft signs and minimal brain damage is diagnostic of soft thinking. 23 However, summarily dismissing a heterogeneous col- lection of simple, noninvasive, and inexpensive assess- ment tools on the above bases could also be regarded as diagnostic of soft thinking. First, although anatomic specicity is uniquely valued in neurology, it may not be as important in psychiatry, in which localization is less central to diagnosis. Second, although the terms hard and soft imply that the former are reproducible and the latter not, the data suggest otherwise. Third, al- though some of the soft NEA may be evanescent, the extent of this has not been determined in adult psychi- atric patients. Because state variation is common in psy- chiatric syndromes, temporal variability in neurological measures may offer some advantages; variability in per- formance may itself be an important parameter in psy- chiatry. 24 The term neurological soft signs thus has multiple mis- leading meanings. Although it may be useful to char- acterize a set of data as hard or soft evidence of major neurologic disease, we suggest that the term not be used to describe individual signs. The potential for the neurologic examination to add to diagnosis, prognosis, and treatment selection in an era of increasing scal limitations warrants an exami- nation of the signicance of NEA in adult psychiatry. This article, written primarily for researchers, summa- rizes the current knowledge base on the bedside neu- rologic examination in adult psychiatry, focusing on methodological issues and on enhancing the clinical relevance of work in this eld. Although the boundaries blur between this and such related areas as neurophys- iology and neuropsychology, we address techniques that can be readily applied in clinical settings and that would not be considered part of the routine mental status exam. RELIABILITY AND VALIDITY Components of the Examination Psychiatric research on NEA has employed collections of neurologic examination items culled fromclinical tra- dition or previous research (Table 1). Some batteries are partly or entirely drawn from general neurology texts, 2527 and some are selected fromfamiliar neuropsy- chological batteries. 28,29 Several scales were developed for use with children in the heyday of research into neu- rological aspects of pediatric psychiatry 1012,30,31 and have found application in adult populations. The Neurological Evaluation Scale (NES), 32 based on a review of NEA in schizophrenia, 33 is the most fully described and widely employed instrument in adult psychiatry. 32,3439 Convit et al. 40 also developed a com- posite examination, the Quantied Neurological Scale, which has been used mostly within that group. Chen et al. 41 recently published, for use in adult psychiatry, a heterogeneous inventory of NEA and behavioral obser- vations, with administration guidelines and reliability data for some of the inventory. Some scales 31,40,41 addi- tionally include items usually used to screen for frank neurologic disease but not frequently seen in psychiatric patients. The primitive (release, frontal release) reexes are often dealt with separately. 42 Rudimentary sensory function, extrapyramidal motor function, spontaneous abnormal movements, and blink rate are not generally included in these neurologic examination schedules. Thus, the available scales tap into somewhat different yet overlapping aspects of neurologic performance. It is important to note this when comparing studies of NEA, particularly when only summary scores are presented. Each of the instruments referenced in Table 1 provides directions for administration, as well as some reliability and validity data. These instruments are best viewed as collections of individual examinations that need not be adopted in toto. It may often be more suitable to con- sider the items individually for inclusion in a clinical or research examination. Reliability Numerous threats to the reliability of NEA are worth considering. Many examination items, such as motor JOURNAL OF NEUROPSYCHIATRY 397 SANDERS AND KESHAVAN TABLE 1. Elements of the neurological examination pertinent to adult psychiatry Element NES PANESS QNS CNI Motor (station and gait) Casual gait X X Stressed gaits X Tandem gait X X X X Hopping X X Romberg X X X Complex movements Fist-ring X X Fist-edge-palm X X X Alternating st-palm X X X Diadochokinesis X X Finger-thumb opposition X X X Rhythm tapping X X X Synchronous tapping X Tap production X Extraocular movements Visual tracking X X Convergence X Gaze persistence X X Other motor Drift X Motor persistence X X Finger-nose X X X Heel-shin X Muscle tone X Mirror movement X X X Synkinesis of head X X Tremor X X Choreoathetotic movements X X Sensory Audiovisual integration X Stereognosis X X X X Graphesthesia X X X X Face-hand/extinction X X X X Face-noise test X Two-point discrimination X Right-left orientation X X X Primitive reexes Glabellar X X Snout X X Palmomental X Grasp X X Suck X Note: NESNeurological Evaluation Scale; 32 PANESSPhysical and Neurological Examination for Soft Signs; 30 QNSQuantied Neurological Scale; 41 CNICambridge Neurological Inventory. 42 overow, require subjectivity in rating, defying quanti- cation unless special instruments are employed. Inter- rater agreement is more difcult to achieve when the abnormal response is merely an exaggeration of a nor- mal phenomenon (e.g., tremor and postural sway). Sub- jectivity can also falsely elevate local agreement (attrib- utable to the shared experience of examiners, as opposed to communicable standards 13 ) and predispose to drift (weakening of interrater reliability over time 15 ). Because of the difculty of directly quantifying some NEA, these studies tend to collapse all data into ordinal or dichotomous formats for uniformity. This practice complicates the statistical approach to reliability assess- ment of individual exam items, reducing power and producing data that fall in the gray zone between what is suitable for intraclass correlation and what is suitable for the kappa statistic. 43 Empirical data nevertheless suggest that interrater re- liability is generally quite acceptable. 13 It is compro- mised primarily in the more subjectively assessed NEA 10,36,4446 and in those requiring discriminations be- tween normal and slightly abnormal. 10,47 Establishing reliability with some of the hard NEA, most strikingly muscle stretch reexes, may be at least as problematic as it is with psychiatrically signicant NEA. 10,44,46,4850 For example, reliability estimates in the Isle of Wight study 10 were higher for measures of coordination and developmental abnormalities than for muscle stretch reexes. In studies of neurology inpatients, 25% 50 and 43% 49 of routinely assessed NEA fell belowthe common reliability threshold of kappa0.4; in two populations of psychiatric patients, the corresponding percentages were 22% and 11%. 36 A clearer understanding of how to conduct the examination improves reliability. 42,44,48 Clinicians might require additional training to assess some of these signs as reliably as in research settings. Such training could be facilitated by video technology. Less attention has been paid to test-retest reliability. Prospective studies of patients, involving repeated ex- aminations, 28,29,5153 are required to clarify the state or trait aspects of NEA in psychiatric patients. Interpreting changes in performance over repeated neurologic exams in patients as a function of state change, though, will require data on the stability of NEA in the absence of potentially relevant state changes. Summary indices of NEAare stable in chronic schizophrenia. 32 However, the test-retest reliability of individual NEA has rarely been examined in adult psychiatric populations. Using kappa greater than 0.4 as a threshold, and restricting analysis to items with adequate interrater reliability, two small studies have found that 33% 36 and 44% 54 of NEA could be consistently reproduced. Thus, temporal stability of NEA in adult psychiatric patients remains uncertain. Determining which of the NEA are replicable over time in stable patients is critical for interpreting longitudinal studies of state-related inuences on neurologic func- tioning in psychiatry. Groupings of Neurologic Exam Elements Some studies ignore the heterogeneity of NEA, deriving a summary score to represent the overall severity of neu- rologic dysfunction or the total number of abnormal signs. 26 At the opposite extreme, analyzing NEA indi- vidually has limitations due to limited statistical power 398 VOLUME 10 NUMBER 4 FALL 1998 NEUROLOGIC EXAMINATION IN PSYCHIATRY with ordinal and categorical data, variable reliability among individual items, and problems attendant on multiple tests of signicance. Assigning NEA to sub- scales might allow one to exploit the heterogeneity of NEA while avoiding the limitations of item-by-item analysis. Some studies have grouped items on the basis of their presumed neuroanatomic substrates. 25,41,55,56 This grouping is debatable in psychiatric patients without fo- cal lesions: NEA do not necessarily have localizing sig- nicance in these populations. Rather than anatomical regions, NEA batteries could be indexed in terms of dis- tributed neuroanatomical or neurochemical systems. Others 15,22 categorize individual NEA as signs repre- senting developmental delay, signs consistent with ac- quired focal brain injury, and subtle variants of focal signs. Many other variables might dictate the associa- tion of individual exam items, including their depen- dence on general intelligence, sustained attention, or motivation. Five adult psychiatric studies, all involving schizo- phrenic patients, have used factor analytic techniques to derive item clusters for the neurologic exam, 34,37,51,57,58 with inconsistent results. Further study of the natural organization of NEA in adult psychiatric patients, with adequate numbers of subjects, using appropriate statis- tics and limiting entered data to reliably assessed NEA, should help to establish defensible subscales. Relationships With Other Neurologic Tests A variety of neurophysiologic techniques have been used to characterize phenomena seen in the clinical neu- rologic exam. Smooth pursuit eye movements (SPEM), 59 visual xation, 60 and extrapyramidal motor dysfunc- tion 61 have been studied instrumentally, and the pal- momental reex has been quantied following electrical elicitation. 62 These relatively noninvasive and inexpen- sive methods can obviously help validate the bedside exam, but they have yet to be applied to most NEA. Neurophysiologic methods may also be used to explore biological correlates of NEA; two studies 63,64 found re- lationships between EEG dysrhythmias and NEA, but others 16,19,65 have not. SPEM dysfunction has been re- lated to NEA among psychotic patients 39,66 and nonpa- tients. 67 Startle habituation has been related to global neurologic performance. 34 Functional neuroimaging parameters seem to be un- related to NEA in resting patients. 56,68 However, less ac- tivation of the appropriate cortical regions is seen dur- ing motor tasks in schizophrenia and dementia patients than in comparison subjects. 6971 Further application of functional imaging and other neurophysiologic meth- ods will be needed to clarify the mechanisms of NEA in patients without acquired focal lesions. CLINICAL UTILITY Differential Diagnosis Diagnostic comparisons of NEAhave mostly focusedon dementia and the psychotic disorders. The neurologic exam could signicantly clarify psychiatric differential diagnosis, particularly when the available history is lim- ited. We survey ndings to date in dementia and in psy- chotic, mood, and anxiety disorders (Table 2, rst col- umn). Dementia has been studied with respect to differential diagnosis and severity. In contrast with normal control subjects, Alzheimers disease patients have excesses of astereognosis, agraphesthesia, cerebellar ndings, olfac- tory decits, primitive reexes, hyperreexia, abnormal plantar responses, and extrapyramidal ndings. 72,73 Fo- cal NEA, gait abnormalities, and dysarthria are associ- ated with multi-infarct dementia, as opposed to other dementias. 74,75 Early extrapyramidal ndings may sug- gest dementia of the Lewy body type. 76 Dementia sec- ondary to alcoholism was strongly associated with ataxia and polyneuropathy in one study. 77 Several other forms of dementia may be related to specic NEA. 78 Primitive reexes, 72,79 olfactory decits, 80 and pyrami- dal, 72 extrapyramidal, 81,82 and other motor abnormali- ties 79,81 are associated with the cross-sectional severity of dementia; this factor thus needs to be controlled for when comparing NEA across dementias. Potentially, in addition to helping to identify focal and multifocal le- sions in patients with dementia, NEA might be found to distinguish between different types of primary de- generative dementia and between dementia and de- pressive pseudodementia. The primary psychoses, particularly schizophrenia, are much investigated with respect to NEA (see re- views 33,82 ). Many NEA, notably abnormalities of motor sequencing, coordination, and higher order sensory function, 33 are more common in schizophrenic than in healthy subjects even when only neuroleptic-naive pa- tients are included. 27,35,56 Parkinsonian ndings have also been described in neuroleptic-naive patients. 60,83 Most data suggest that schizophrenic patients have more neurologic dysfunction than nonpsychotic pa- tients, but the evidence is more mixed when comparing psychotic patients with different diagnoses. 33,8487 Some longitudinal data suggest an improvement in neurolog- ical performance with improvement in clinical state and/or treatment with antipsychotic medication. 51,53 Variation in NEA due to clinical state or medications JOURNAL OF NEUROPSYCHIATRY 399 SANDERS AND KESHAVAN TABLE 2. Clinical utility of the neurologic examination in psychiatry: current status Areas of Clinical Utility Disorder Differential Diagnosis Treatment Selection Prognosis Dementia Alzheimers vs. normal (S) 72,73 Ischemic vs. other (S) 74,75 Lewy body variant (W) 76 Alcohol-induced (W) 77 Treatment of cardiovascular risk factors (S) 74,75 Select cases for more aggressive treatment (N) Predict onset (W) 113 Rapid decline (S) 114116,118,119 Psychotic disorders Psychotic vs. normal (S) 27,35,56 Psychotic vs. nonpsychotic but psychiatrically ill (W) 88,9093 Primary psychotic disorder vs. psychiatric disorder complicated by psychosis (W) 8587,90,92 Choice of antipsychotic agent (N) EPSE prophylaxis (N) Long-term poor prognosis (W) 83,121,122 Persisting negative symptoms (W) 40 EPSE (W) 83,129 TD (N) Mood disorders Mood disorders vs. normal (W) 88,89 Psychotic mood disorder vs. primary psychosis (W) 8587 Choice of medication (N) Choice of psychotherapy (N) Predict relapse in bipolar (W) 123 Anxiety disorders OCD vs. normal (S) 96100 PTSD vs. normal (W) 102 SP vs. normal (W) 103 OCD, PTSD, SP vs. other psychiatric groups (W) 97 Choice of medication (N) Choice of psychotherapy N) Short-term poor prognosis (W) 124,125 Note: Sstrong evidence (replicated at least once, minimal conicting data); Wweak evidence (no replications, or signicant conicting evidence); Nno evidence to date; EPSEextrapyramidal side effects; TDtardive dyskinesia; OCDobsessive-compulsive disorder; PTSDposttraumatic stress disorder; SPsocial phobia. may thus obscure comparisons of diagnostic groups. Signicant clinical benets might be realized if NEA could distinguish between psychotic disorders, but fur- ther studies comparing diagnoses while controlling for treatment and clinical status will rst be necessary. Mood disorders have been neglected in NEAresearch. Abnormalities exceeding those of normal comparison subjects have been found in manic 88 and mixed manic and depressed patients. 89 Differences were found in mo- tor control and sequencing, stereognosis, and graphes- thesia. In studies comparing mood-disordered with schizophrenic patients, global NEA were fewer and/or milder in mood disorders, 18,9092 although two stud- ies 88,93 found few differences. Consistent with early de- scriptions of melancholia suggesting extrapyramidal dysfunction, 5,6 depression and extrapyramidal dysfunc- tion are related in Alzheimers disease. 81,94 There are few differences in NEA between unipolar and bipolar pa- tients. 25,29,89,92 The prevalence and diagnostic specicity of NEA in mood disorders remain unclear. The strong effects of psychiatric state on general functioning in the mood disorders, along with the mood-relatedvariability of neurologic functioning evidenced in psychiatric pa- tients, 29,52 suggest that phase of illness will need to be considered. Diurnal variation may also have a signi- cant impact on neurologic function in the mood disor- ders. 95 Anxiety disorders have scarcely been investigated, with the exception of obsessive-compulsive disorder (OCD). NEA are more frequent in OCD patients than in normal comparison subjects, 9699 although this nding was not replicated in female OCD patients. 100 Specic ndings include poor motor coordination, 97,98 disinhi- bited motor activity, 96,98,99 impaired balance, 97 an excess of left-sided dysfunction, 96,98,99 and extrapyramidal mo- tor ndings. 7,101 Difculties with motor control and with presumably right-hemisphere tasks are fairly consistent ndings in this body of work. The diagnostic specicity of these ndings to OCD remains unclear. 97 More NEA are seen in posttraumatic stress disorder patients 102 than in control subjects, with signicantly greater abnormal- ity in motor sequencing and the palmomental reex. So- cial phobia patients had marginally more NEAthan nor- mal control subjects in a small study. 103 Further work is needed to address the specicity of these ndings to anxiety disorders generally and to specic anxiety dis- orders, while considering the possible effects of state anxiety and medication. Treatment Selection and Prognosis To the extent that they are static or trait-like, NEAmight be expected to predict such aspects of psychopathology as illness onset, outcome, and complications of treat- ment. These are areas in which the neurologic exam has clear potential for complementing clinical assessment of psychiatric patients. These areas of clinical utility are represented in the last two columns of Table 2. Onset Prediction: Follow-up of subsamples from the National Collaborative Perinatal Project foundthat NEA at age seven, particularly motor abnormalities, predict depression, 14,104 anxiety, 14,104 and delinquency 105 in ad- 400 VOLUME 10 NUMBER 4 FALL 1998 NEUROLOGIC EXAMINATION IN PSYCHIATRY olescence and also predict criminality 105 and perhaps anxiety 106 in adulthood. Motor dysfunction and general neurological impairment in preadolescence predicted psychiatric morbidity in the New York schizophrenia high-risk project. 107 Children with motor impairments are more likely to develop schizophrenia by adult- hood, 108110 and sensory decits may also enhance vul- nerability to psychosis in youth 111 as well as in old age. 112 In elderly persons, extrapyramidal ndings may predict the onset of dementia. 113 Outcome Prediction: Neurologic ndings with possible prognostic value in Alzheimers disease include extra- pyramidal signs, 114116 myoclonus, 114,117 parietal signs, 114,117119 and primitive reexes. 115 In schizophre- nia and mood disorders, NEA at baseline may not pre- dict short-term amelioration of psychiatric symp- toms. 33,53,89,120 However, negative symptoms persisting after treatment with conventional antipsychotic medi- cation were predicted by baseline NEA. 40 Long-term global outcome in schizophrenia was also anticipatedby NEA, including motor sequencing and extrapyramidal dysfunction. 83,121,122 Stable, medicated bipolar patients with neurologic ndings were more likely to relapse during follow-up. 123 NEA predicted a poor response to medication in one of two studies of obsessive- compulsive disorder. 124,125 Thus, neurologic signs may have prognostic importance in a variety of psychiatric contexts, with implications for treatment selection. Predictions of Treatment Complications: Although NEA might predict neurologic side effects from a variety of psychiatric medications, the only data known to us per- tain to typical antipsychotic agents. Tardive dyskinesia, noted to coincide with motor and sensory ndings and primitive reexes, 126128 may also be predicted by such ndings: withdrawal-emergent dyskinesia was pre- dicted by the number of NEA in one study. 26 Low blink rate 129 and other parkinsonian signs 83 predict parkin- sonism after treatment with conventional antipsychotic drugs. Baseline neurological data may help to inform choices regarding antipsychotics and prophylactic anti- parkinsonian agents. CONCLUSIONS Psychiatry is progressively informed by the brain sci- ences, but it is constrained in applying this knowledge to the clinical assessment of the individual patient by the high cost of the technologies applied in neuropsy- chiatric research. The neurologic examination is inex- pensive and available to all physicians, and thus it has the potential to bridge the gulf between neurobiologic research and clinical practice. It has shown promise as an aid in differential diagnosis, prognosis, and treat- ment selection in a variety of psychiatric conditions. The neurologic examination also has important limi- tations. It offers only indirect reections of the salient properties of the brain, and it is presumably inferior to such approaches as functional imaging and histopa- thology in characterizing specic neural systems or in elucidating the neurobiologic bases of psychiatric dis- orders. Some may thus nd it less intellectually exciting than many other techniques, and its utility may lie in more immediately clinical questions. A second limita- tion is that an extended neurologic exam requires time to complete. Clinicians tend to avoid devoting time to evaluative activities that shed only ambiguous light on the case at hand and thus may be reluctant to perform entire exam schedules routinely. Any extension beyond the traditional cursory rule out examination will be adopted only to the extent that it has clear implications for patient care. The limitations on reliability, although neither trivial nor entirely determined (especially in the case of test-retest reliability), appear to be comparable to those of the conventional neurologic exam. Establishing efcient applications of the neurologic exam for specic clinical questions will require consid- erable renement of the knowledge base. As Table 2 il- lustrates, many potential clinical applications have been investigated insufciently, if at all. First, it must be clearly established, for a given clinical population, which examination items are frequently enough abnormal to be of interest and can be readily assessed with adequate interrater reliability. Batteries must be developed that are limited to such items. The reliability and validity of individual and aggre- gate neurologic tests should be assessed as methodically as are neuropsychological tests. These tests will require further validation against other measures, particularly those measuring regional brain function, so that we may better understand the nature of the abnormalities and explore the possibility that these tests offer more ef- cient alternative routes to similar information yieldedby these less accessible methods. We need comprehensive developmental and norma- tive assessments of such examinations, especially before they are otherwise used in studies involving elderly sub- jects. The exams should be applied to large samples of diagnostically heterogeneous patients to clarify their value in differential diagnosis; to longitudinal studies to clarify their value in prognosis; and to therapeutic trials to clarify their value in treatment selection. The current tendency toward descriptive studies will have to give way to the testing of more specic hypotheses. JOURNAL OF NEUROPSYCHIATRY 401 SANDERS AND KESHAVAN Much of the promise of the extended neurological ex- amination lies in its heterogeneity. Its numerous ele- ments individually have potential utility that may well be lost when they are combined into summary indices of soft signs or neuromotor dysfunction. Their po- tential may be realized only through item-by-item anal- yses. This approach is more feasible if these measures are continuous, rather than categorical or ordinal. Com- binations of items should be empirically rather than in- tuitively determined; this might be done through a quantitative distillation such as factor analysis. Bringing neurobiological knowledge to bear on clini- cal psychiatry is a task that can differ conceptually and methodologically from the more vigorously pursued task of uncovering the neurobiological bases of psychi- atric disorders. 130 If pursued with comparable fervor to that aroused by the more fundamental questions, such work could have a substantial impact on the practice of clinical psychiatry. The neurological examination offers promising avenues for the reintegration of neurobiology into psychiatric assessment. The authors thank Joseph Pierri, M.D., for his comments on this manuscript, Melissa Knox for library assistance, and Tamera McLaughlin for secretarial support. 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