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Response habituation in unconscious patients
Neuropycholonia.
1972.
Vol.
RESPONSE
IO. pp.
313 to 320.
Pergamon
HABITUATION
Press.
Printed
in England
IN UNCONSCIOUS
PATIENTS*
GRETE BRYHN GULBRANDSEN and KRISTIAN KRISTIANSEN Department
of Neurosurgery,
Ulleval Hospital, Oslo, Norway
and HOLGER URSIN Institute of Physiology, University of Bergen, Bergen, Norway (Received 13 March 1972) Abstract-Reactivity and response habituation were studied in 42 unconscious patients. They were easily separable into six grades of unconsciousness by the types of stimuli they responded to. These grades were clinically describable as depth of unconsciousness. This provides a rapid technique by which even nonmedical personnel can classify unconscious patients. The four lightest grades responded to sound with a variety of responses: there was no typical pattern or gradation in the responses observed. However, all responses habituated in all patients, and only a few trials were required. The rate of habituation showed no significant relation to grade of unconsciousness. Sensitization was almost exclusively observed in the lightest grade. Savings from one day to the next were not related to grade of unconsciousness, but were positively related to prognosis. INTRODUCTION
paper attempts to contribute to a classification of unconscious states, and to investigate the behavioral plasticity of unconscious brain-damaged patients. Unconscious patients usually retain some reactivity. It varies from patient to patient and with the extent and type of the lesion. It also appears to wax and wane in the same patient. In a neurosurgical ward, observations by the nursing staff of the fluctuations of consciousness are of great importance, as they may indicate the need for immediate neurosurgical intervention. In this paper, we report attempts to standardize observation and stimulus procedures for such patients. Patients have been classified according to what kind of stimuli they respond to and what type of responses they retain. The possibility that plasticity remains in the unconscious human nervous system has also been investigated. Studies in comparative psychology have shown that even very simple nervous systems may be capable of a great deal of plasticity in their reactivity to external stimuli. Plasticity is also present in the isolated spinal medulla of cat and human [ 1, 21. It is therefore to be expected that some plasticity remains in brain-damaged, unconscious patients. If such plasticity exists in these reduced brains, it raises important practical and theoretical questions. Perhaps the simplest form of plasticity is habituation to a repeated stimulus [l]. When a novel stimulus is presented to a mammal with an intact brain, an orienting response is observed. When the stimulus is repeated the response gradually disappears. The orienting response and its habituation are well described both in man and animals [3, 41. Characteristic changes in many physiological systems accompany the overt response, and THE PRESENT
*Sponsored in part by the Norwegian Research Council for Science and the Humanities. requests should be addressed to Institute of Physiology, University of Bergen. Bergen, Norway. 313
Reprint
314
GRETE BRYHN GULBRANDSEN. KRISTIAN KRISTIANSEN
and
HOLCER URSIN
these have often been used as indicators of the activation. Such indicators include galvanic skin resistance and potentials, heart rate, blood flow, skin temperature, electromyogram (EMG) and electroencephalogram (EEG). In studies on orienting responses in man, polygraphic recordings of these changes have been preferred to observations of overt behavior. In the unconscious human we have not used such recordings. In these severely damaged brains the control mechanisms from many autonomic activities may be disturbed. Muscle activity was irregular and differed from patient to patient and within body regions of the same patient. The EEG was very pathological in our patients. Therefore, only observations of overt behavior have been used. MATERIAL
AND
METHODS
The material consists of 42 patients admitted to the Neurosurgical Department, UllevRI Hospital, for brain damage leading to unconsciousness. The neurosurgeon in charge selected the patients to be examined, and the criteria were various degrees of unconsciousness. If the patient was dying or if the situation was labile and changing rapidly, he was not referred to this examination. All patients were observed for their reactivity to various classes of stimuli following a standardized procedure. Patients that did not respond at all (N=3), or to pain stimulation only (N=5), could not be tested further. The rest of the material, 34 patients, was observed for type of responses and habituation of these responses, to a compound auditory stimulus (buzzer). The age distribution and the type of brain damage are evident from Table I. The classitication system for reactivity that was developed is evident from Table 2. Table 1. Diagnostic
groups in relation to age groups (only patients tested for habituation, Grades I-IV)
Diagnosis
Traumatic injuries (19) Cerebrovascular insults (8) Cerebral tumors (4) Miscellaneous (3)
5
N=34
5
Age groups 16-30 31-50 51-65 9 2 I
2 I
1
:
13
6
66-75
2 3 I
I 2
6
4
1
The patients were tested while in bed in their own room. The patient was first addressed by name. If he did not respond, he was shaken gently by the hand or arm, or his cheeks were slapped gently. lf still not responding, more painful stimuli were used, like pinching, forced flexion of the joint of the little finger, or deep pressure between the jaw and the mastoid process. If the patient did respond to his name, by opening his eyes, turning his head or any other motor movement, he was also tested for his ability to follow a moving object with his eyes, to obey simple and more complex commands. The habituation procedure then followed. A loud noise from a buzzer placed at the side of the bed lasted for 5 set or IO set; the same duration was always used in one given patient. The intertrial interval varied from I5 to 45 sec. All observable changes in behavior were noted for occurrence or nonoccurrence during and shortly after the stimulus presentation. The observed responses included eye opening, blinking, eye movements, head movements, gross movements of the body and the extremities, respiratory changes, chewing, arrest of ongoing activity, startle response and grimacing. Stimulations were repeated until no changes in behavior were observed for at least three consecutive trials. The number of trials required to reach the criterior. for habituation was noted (first trial in criterion run). In 12 patients, in which hospital routine permitted the procedure and the situation was stable over time, the habituation routine was given on three consecutive days to test possible savings. The same procedure was followed for all three days.
RESULTS 1. A classifcation qf unconsciousness The type of stimuli the patients responded to varied greatly from patient to patient, but the analysis of their reactivity showed clearly that there was a systematic rank order of the effective stimuli in the whole material. Patients that responded to touch and voice always
RESPONSE
HABITUATION
IN
UNCONSCIOUS
PATIENTS
315
responded to pain; if the patient was able to respond to a waving hand or simple commands he would also respond to pain, touch and sudden acoustic stimuli, and so on. Based on this analysis of the reactivity to the various classes of stimuli the six grades of unconsciousness were defined (Table 2). Table Grade
VI
Grade
II:
Grade
I:
2. Grades
of unconsciousness
:
Patient
:
Patient unconscious but reacts to pain, high sound and touch and/or sound of voice (N=7). Patient stuporous. In addition to reactivity to pain, high sound, touch and voice the patient may be aroused to respond to the sight of a waving hand or other moving objects, or to simple commands like “grip my hand” or “open your eyes” (N-8). Patient’s consciousness seriously reduced (soporose), responds as other grades but he may also be aroused to indicate “yes” or “no” correctly to simple questions like “have you had your dinner?“--“is it daytime now?‘, by blinking his eyes according to a predesigned code, or by nodding or shaking his head (N=7).
The 8 patients in the two deepest classes (Grades V and VI) could not be tested further and will not be dealt with in the following. The remaining 34 patients responded to sound with a great variety of responses. They also varied with regard to what other stimuli they responded to. All of them had varying degrees of reduced consciousness, as judged by the medical staff, even the patients in the lightest class (Grade I) that was able to react at least to some requests by indicating “yes” or “no” for instance by eye-blinking. In each patient there was some fluctuation of the level of unconsciousness, but the average level of unconsciousness might stay unaltered for several days, weeks or even months. No systematic evaluation of the validity of the reactivity classification has been obtained. However, it agrees well with the judgment of the department for each patient. All 34 patients included in Grades I-IV were rated by the head of the department (K.K.) into four rank order classes for the depth of coma at the time they had been tested. This grading was done without access to the data from the reactivity classification, and independent of the exact definition of the final classes. He based his retrospective judgment on all other data available from the files of the patient. There were quite a few disagreements, but most of these were limited to one grade, and the agreement was statistically significant (Pearson product-moment correlation coefficient = 0.49, p ~0.01). There was no systematic tendency in the sign of the differences. The responses also varied from patient to patient, both in the intensity as well as the number of components. The responses were analysed for frequency, patterning, and intensity, but no systematic trend was evident. Comparing the type of responses with the classification based on stimulus sensitivity, only a few findings were consistent. Only patients in the deep group (Grade IV) showed a startle response, and patients in the lightest group (Grade I) did not show eye-blinking, gross body movements or chewing. Eyeopening, eye movements, head movements and respiratory changes and arrest were observed in all groups with no predominance of any response in either group. *. 3
Habittrath
In all the patients who responded to sound stimulation by overt behavior, a change in reactivity was observed upon repeated stimulation. In the majority of the patients, this
316
GRLTE BRY~IN GUI.BRAW\EV,
KRISTIAV KRISTIASSEN and HM.~ER UF~IN
change occurred after a strikmgly low number of stimulations. Even in pattents m whom a very clear response was obtamed. this response sometrmes could not be ehcited after as few as two or three trial% When the patient was activated by another stimulus as loud shoutmg or shakmg him (dtshdbnuated), the response reoccurred. Habituatton tates dtd not doffer stgnificantly between grades. A curvthnear relattonshtp is suggested from Fig I ; Grade 111 patients tended to require more trtals to habituatton than Grades IV and II, but were not significantly different from Grade I. However, this relationship did not reach signtficance in an analysis of vnnance. TRIALS 10
tiABI’U4TION
15
I
10
m
--
5
--
IJl Grade
m
I ’
Grade
Iii (muddle1
lili -__
-...
.I_
IV fdctrp)
Grcde
11 (Ilgh?)
Grade
I
I
I (very
Ilght)
FIG I Tr~alr to habltuation of observed responses to auditory stimulation in 34 unconscious patients The result from each patient is represented by a vertical lme The mean for each grade of unconsctousncss IS indicated by a horizontal, dotted hne (III).
In the I2 pattents in wham habttuation data were obtamed for three or mare consecutive days, savings were observed in 5 patients In these patients there was a clear decline in habituation rate from day to dsy. There was no clear relationship between the presence of savings and the degree of coma as classified either by the reactivrty classrficatron or by the clinician According to the reactivity classification, there were 2 patients in Grade IV, 2 in Grade III, and 1 in Grade I showing savings. The 7 pattents showing no savings However, savings may were also evenly dtstributed among unconsciousness grades indicate a better prognosis (see later) The material was also analysed with regard to sensitization. If a patient showed a stronger orientation reaction to the stimulus after it had been presented a few times, this was noted as sensitizatton. A stronger orientation reaction could etthcr consist of more vigorous head turning, or mcreasmg unrest, or a more complex orientation reaction, for instance head turning being added to eye blinking. Defined this way, sensitization was observed m 9 pattents, and in 14 patients there was a clear lack of sensitization. In the rest
RCSPONSE HABITUATKIN
IN UNCONSCIOUS
PATIENTS
317
of the material it was too difficult to evaluate whether sensitization had occurred or not due to the response repertoire of the patients. The clear cases of sensitization and lack of sensitization are distributed evenly over grades, with one exception. Lack of sensitization was most frequently observed in the lightest group, Grade I, in which 6 of the 7 patients showed no sensitization (Table 3). Table 3.
Coma group
Sensitization
Sensitization
Lack of sensitization
Uncertain -
Grades Grade Grade Grade
IV 111 II I
N=34
(12) (7) (S) (7)
5 2 2 0
4 2 2 6
3 3 4
9
14
II
I
The prognosis was rather poor for all the patients included in the material. Satisfactory restitution was found in 8 patients, 14 patients did not show satisfactory restitution, and 12 of the patients died. The correlation between the reactivity classification and the prognosis does not reach significance (O.lO>p>O.O5, fourfold table chi square), but the clinical classification correlates significantly with the prognosis (p
DISCUSSION The aim of the study was (a) to contribute to a classification of unconscious states, and (b) to investigate the behavioral plasticity of unconscious brain-damaged patients. We have developed a procedure for reactivity evaluations of these patients that correlates satisfactorily with the clinical judgment. The advantages of the scoring procedure are that it gives a quick and reliable estimate of the state of unconsciousness of a given patient at a given time, it does not require any instrumentation, and it can be used by personnel not medically trained. The result from one test at one point in time does not give useful information on prognosis; the time course and the underlying pathology are decisive factors which must be taken into account. However, the presence or absence of savings is
318
GRATE
BRYHN
GULBRAXDSEN.
KRISTIANKRISTIAUENand HOLGERURSI\
an indicator of the prognosis. The possible usefulness the time course has not been explored further.
of the scoring
method
in following
In all examinations of these patients the surprising degree of remaining plasticity must be taken into account. All patients who responded to the buzzer, habituated to the stimulation. Since the reactivity reoccurred when activation was produced by another stimulus “dishabituation”, the phenomenon classifies as a true habituation phenomenon according to the criteria set forth by SHARPLESS and JASPER [3] and SOKOLOV [4]. The responses observed in our patients are a very heterogeneous group of muscular activities, varying from gross body movements to startle responses. Many of the responses like eye-opening, arrest of ongoing activity, movements of the eyes and the movements of the head may well be components of the orienting response. Some may be part of “defensive reflexes” observed to strong stimuli in intact mammals [4]. According to the the part of the central of stimulus patterns. of a tone which had This cognitive model unconscious patients. unconscious patients damaged brains.
Sokolov model habituation does not indicate a loss of sensitivity on nervous system. His theory involves a cognitive model of recognition He has demonstrated, for example, that if he decreased the intensity been given repeatedly to a subject, orienting or altering reoccurred. does not seem to be adequate for the habituation observed in the It seems unreasonable to account for the fast habituation rate in the by ascribing some superior discriminatory abilities to these severely
Very simple neuronal circuits like abdominal ganglias in aplysia [5, 6, 71. and the spinal cord of the spinal cat preparation [I] have been chosen in successful attempts to illustrate the cellular and synaptic changes taking place during habituation. These models make no assumption about consciousness, and may furnish us with a model for neuronal events taking place also in the unconscious patient. According to the dual-process theory of GROVES and THOMPSON [5], every stimulus evoking a behavioral response has two properties: It elicits a response mediated through a “S-R pathway,” and, secondly, a stimulus also influences a system of inter-neurons parallel to the S-R pathway. This “state system” affects the general level of excitation or “arousal”, and comprises all factors that affect the excitability of the nervous system. Habituation seems to be due to properties of some of the excitatory synapses in the S-R pathway itself, the so-called “habituating” type of synapses. These synapses have been shown to decrease in excitatory efficiency upon repeated firings. The nervous system also contains a second type of synapse, the sensitizing synapse, which is mainly found in the state system. These synapses increase in efficiency upon repeated firings. Groves and Thompson conclude that the strength of a behavioral response to a repeated stimulus is the net outcome of these two independent synaptic processes. The response observed in a brain-lesioned, unconscious patient follows some S-R pathway left intact in his brain. The habituation observed may be a natural consequence of the fact that most S-R pathways contain habituating synapses. The plasticity in his response, according to this model, is a function which is built irreversibly into the S-R pathway itself. If there is a response, there is also habituation. Our findings are, therefore, not surprising according to this model. In the lighter cases, more complex types of stimulus recognition may be involved, as they are in the normal, awake brain according to SOKOLOV [4]. The curvilinearity suggested by Fig. 1, if true, may derive from more complex mechanisms taking over in the less damaged brains.
RESPONSE HABITUATION IN UNCONSCIOUS PATIENTS
319
Sensitization, which may be due to synapses particular to the state system, did not However, lack of sensitization was correlate with any coma level or with the prognosis. found in almost all the patients in the lightest group (Grade 1). In spite of being unconscious, these patients are able to follow quite complex commands, and very complex S-R pathways must remain intact. Their pathology, therefore, may be limited mainly to the state system, showing a particular lack of sensitization according to the Groves and Thompson model. It remains to be seen it drugs increasing the excitability of the central nervous system like amphetamine may have more effect in this type of unconsciousness than in any of the other groups. Our findings do not agree with the generally held notion that brain lesions produce a reduction in the extent of behavioral response habituation [I, 41. Compared with habituation of galvanic skin response and heart rate changes to a mild auditory stimulus in normal subjects [9] the habituation shown by our patients is as fast or maybe faster. In patients with less serious neurological diseases there is also a fast habituation of cc-wave blockage [IO]. Further, it has been shown that rats with brain damage due to excess t_-phenylalsnine in the diet in early life have a behavioral deficit that is characterized by a defective arousal function and fast habituation [I I]. Therefore, general statements about brain lesions producing prolonged habituation rates are questionable. The habituating properties of the synapses in a S-R pathway cannot be changed by a gross brain lesion. If the S-R pathway is damaged itself, a longer and more complex route is probably necessary; this may, if anything, lead to faster habituation. Resistance to habituation may be produced by changing the excitability level in the pathway, by changing the state system or the stimulus identification processes, as when for instance lesions in the limbic structures interact with the habituation mechanisms [12, 131. Sleep seems to be a different state from the unconsciousness produced by brain lesions; in normal sleeping subjects there is little or no habituation [14].
REFERENCES I. 2. 3. 4. 5. 6. 7. 8. 9. 10.
II. 12. 13.
14.
THOMPSON, R. F. and SPENCER, W. A. Habituation: A model phenomenon subtrates of behavior. Psychol. Rev. 73, 1M3. 1966.
for the study
of neuronal
DIMITRIJEVIC, M. R. and NATHAN, P. W. Studies of spasticity in man. 5. Dishabituation of the flexion reflex in spinal man. Bruin 94, 77-90, 1971. SHARPLESS, S. and JASPER, H. Habituation of the arousal reaction. Brain, 79, 665-680, 1956. SOKOLOV, E. N. Perception and rhe Condiiioned Reflex, 309 pp. Pergamon Press, New York, 1963. PINSKER, H., KUPFERMANN, I., CASTELLUCCI, V. and KANDEL, E. Habituation and dishabituation of the gill-withdrawal reflex in aplysia. Science, N. Y. 167, 1740-1742, 1970. KUPFERMANN, I., CASTELLUCCI, V., PINSKER, H. and KANDEL, E. Neuronal correlates of habituation and dishabituation of the gill-withdrawal reflex in aplysia. Science, N, Y. 167, 1743-1745, 1970. CASTELLUCCI, V., PINSKER, H., KUPFERMANN,I. and KASDEL, E. R. Neuronal mechanisms of habituation and dishabituation of the gill-withdrawal reflex in aplysia. Science, N. Y. 167, 1745-1748, 1970. GROVES, P. M. and THOMPSON, R. F. Habituation: A dual-process theory. P.rychol. Rev. 77,419-450, 1970. ZAHN, T. P., ROSENTHAL,D. and LAWLOR, W. G. Electrodermal and heart rate orienting reactions in chronic schizophrenia. J. Psychiat. Res. 6, 117-134, 1968. WELLS, C. E. Response of alpha waves to light in neurological disease. Arch. neural. 6, 478-491, 1962. HOLE, K. Arousal defect in I_-phenylalanine-fed rats. Develop. Psychobiol. (In press) 1972. KIMBLE, D. P. Hippocampus and internal inhibition. Psycho/. Bull. 70, 285-295, 1968. BAGSHAW, M. H., KI.CIBLE, D. P. and PRIBRAM, K. H. The GSR of monkeys during orienting and habituation and after ablation of the amygdala, hippocampus and inferotemporal cortex. NeIfropsychologia II, 111-119, 1965. JOHNSON, L. C. A psychophysiology for all states. Psychophysiology 6, 501-516, 1970.
320
GHFTL
RRYHU
GL~LRRANDSFU.
KRISTI\X
KRISTIAXSEN
and
HOLCFR URSIV
Resume--On a titudie la reactivitc et I‘habituation de la reponse chez 42 malades inconzcients. On Ies regroupait aisemcnt selon 6 degres de troubles de la conscience d’apres les types de stimulus auxquels ils ripondaicnt. On pouvait dtcrire cliniquement ces degres comme temoignant de la profondeur du trouble de la conscience. Ainsi etait procuree une technique rapide grice h laquelle du personnel, mSme non medical, pouvait classer les malades selon les degres du trouble de la conscience. Les malades correspondant aux quatre degris les plus legers donnaient des rcponses de type varic aux differents sons. II n’y avait pas d’aspect typique ou de progression dans les reponses observees: cependant on constatait une habituation de la reponsc chez tous les malades, et cela apres seulement quelques essais. II n’y avait pas de relation signiticative cntre la vitcsse de I’habituation et le degre du trouble de la conscience. La scnsibilisation etait presqu’exclusivement observee dans les degres Its plus Iegers. La reduction de la vitesse de I’habituation d’un jour sur I’autre n’etait pas liie au degre du trouble de la conscience mais etait reliee de facon positive au pronostic.
Zusammenfassung-Reaktionsund Antwortverhalten wurde bei 42 bewufitseinsgestortcn Kranken gepriift. Den Reizantworten entsprechcnd war es leicht moglich. 6 graduell unterschiedliche Typen von BewuRtseinsstorungen aufzustellen. Klinisch entsprach dies der jeweils bcschriebenen Tiefe der RewuBtscinsstiirung. Auf diese Weise konnte die Anwendung technischer Verfahren vermieden ucrden, weil such nichtmedizinisches Personal die BewuDtseinsstorungen zu klassifizieren imstnnde ist. Die 4 leichtesten Grade entsprachen einer Reaktion auf Laute. Da&i wurden keine typischen Antwortformen beobachtet. Trotzdem wurden bei allen Patienten Reaktionen registriert, van dcncn nur eine kleine Anzahl gepriift wurde. Die Gewohnungsrate stand in keiner signifikanten Relation zum ArtsmalT dcr BcwuBtseinsstorung. Sensibilisierung wurde ausschliet3lich bci leichtesten Formcn nachpcwiesen. Besserungen von einem Tag auf den andercn korrelierten nicht zum Ausmai? dcr Bewul3tseinssti5rung. konnten aber beziiglich der Prognose positiv beurteilt wcrden.
1972.
Vol.
RESPONSE
IO. pp.
313 to 320.
Pergamon
HABITUATION
Press.
Printed
in England
IN UNCONSCIOUS
PATIENTS*
GRETE BRYHN GULBRANDSEN and KRISTIAN KRISTIANSEN Department
of Neurosurgery,
Ulleval Hospital, Oslo, Norway
and HOLGER URSIN Institute of Physiology, University of Bergen, Bergen, Norway (Received 13 March 1972) Abstract-Reactivity and response habituation were studied in 42 unconscious patients. They were easily separable into six grades of unconsciousness by the types of stimuli they responded to. These grades were clinically describable as depth of unconsciousness. This provides a rapid technique by which even nonmedical personnel can classify unconscious patients. The four lightest grades responded to sound with a variety of responses: there was no typical pattern or gradation in the responses observed. However, all responses habituated in all patients, and only a few trials were required. The rate of habituation showed no significant relation to grade of unconsciousness. Sensitization was almost exclusively observed in the lightest grade. Savings from one day to the next were not related to grade of unconsciousness, but were positively related to prognosis. INTRODUCTION
paper attempts to contribute to a classification of unconscious states, and to investigate the behavioral plasticity of unconscious brain-damaged patients. Unconscious patients usually retain some reactivity. It varies from patient to patient and with the extent and type of the lesion. It also appears to wax and wane in the same patient. In a neurosurgical ward, observations by the nursing staff of the fluctuations of consciousness are of great importance, as they may indicate the need for immediate neurosurgical intervention. In this paper, we report attempts to standardize observation and stimulus procedures for such patients. Patients have been classified according to what kind of stimuli they respond to and what type of responses they retain. The possibility that plasticity remains in the unconscious human nervous system has also been investigated. Studies in comparative psychology have shown that even very simple nervous systems may be capable of a great deal of plasticity in their reactivity to external stimuli. Plasticity is also present in the isolated spinal medulla of cat and human [ 1, 21. It is therefore to be expected that some plasticity remains in brain-damaged, unconscious patients. If such plasticity exists in these reduced brains, it raises important practical and theoretical questions. Perhaps the simplest form of plasticity is habituation to a repeated stimulus [l]. When a novel stimulus is presented to a mammal with an intact brain, an orienting response is observed. When the stimulus is repeated the response gradually disappears. The orienting response and its habituation are well described both in man and animals [3, 41. Characteristic changes in many physiological systems accompany the overt response, and THE PRESENT
*Sponsored in part by the Norwegian Research Council for Science and the Humanities. requests should be addressed to Institute of Physiology, University of Bergen. Bergen, Norway. 313
Reprint
314
GRETE BRYHN GULBRANDSEN. KRISTIAN KRISTIANSEN
and
HOLCER URSIN
these have often been used as indicators of the activation. Such indicators include galvanic skin resistance and potentials, heart rate, blood flow, skin temperature, electromyogram (EMG) and electroencephalogram (EEG). In studies on orienting responses in man, polygraphic recordings of these changes have been preferred to observations of overt behavior. In the unconscious human we have not used such recordings. In these severely damaged brains the control mechanisms from many autonomic activities may be disturbed. Muscle activity was irregular and differed from patient to patient and within body regions of the same patient. The EEG was very pathological in our patients. Therefore, only observations of overt behavior have been used. MATERIAL
AND
METHODS
The material consists of 42 patients admitted to the Neurosurgical Department, UllevRI Hospital, for brain damage leading to unconsciousness. The neurosurgeon in charge selected the patients to be examined, and the criteria were various degrees of unconsciousness. If the patient was dying or if the situation was labile and changing rapidly, he was not referred to this examination. All patients were observed for their reactivity to various classes of stimuli following a standardized procedure. Patients that did not respond at all (N=3), or to pain stimulation only (N=5), could not be tested further. The rest of the material, 34 patients, was observed for type of responses and habituation of these responses, to a compound auditory stimulus (buzzer). The age distribution and the type of brain damage are evident from Table I. The classitication system for reactivity that was developed is evident from Table 2. Table 1. Diagnostic
groups in relation to age groups (only patients tested for habituation, Grades I-IV)
Diagnosis
Traumatic injuries (19) Cerebrovascular insults (8) Cerebral tumors (4) Miscellaneous (3)
5
N=34
5
Age groups 16-30 31-50 51-65 9 2 I
2 I
1
:
13
6
66-75
2 3 I
I 2
6
4
1
The patients were tested while in bed in their own room. The patient was first addressed by name. If he did not respond, he was shaken gently by the hand or arm, or his cheeks were slapped gently. lf still not responding, more painful stimuli were used, like pinching, forced flexion of the joint of the little finger, or deep pressure between the jaw and the mastoid process. If the patient did respond to his name, by opening his eyes, turning his head or any other motor movement, he was also tested for his ability to follow a moving object with his eyes, to obey simple and more complex commands. The habituation procedure then followed. A loud noise from a buzzer placed at the side of the bed lasted for 5 set or IO set; the same duration was always used in one given patient. The intertrial interval varied from I5 to 45 sec. All observable changes in behavior were noted for occurrence or nonoccurrence during and shortly after the stimulus presentation. The observed responses included eye opening, blinking, eye movements, head movements, gross movements of the body and the extremities, respiratory changes, chewing, arrest of ongoing activity, startle response and grimacing. Stimulations were repeated until no changes in behavior were observed for at least three consecutive trials. The number of trials required to reach the criterior. for habituation was noted (first trial in criterion run). In 12 patients, in which hospital routine permitted the procedure and the situation was stable over time, the habituation routine was given on three consecutive days to test possible savings. The same procedure was followed for all three days.
RESULTS 1. A classifcation qf unconsciousness The type of stimuli the patients responded to varied greatly from patient to patient, but the analysis of their reactivity showed clearly that there was a systematic rank order of the effective stimuli in the whole material. Patients that responded to touch and voice always
RESPONSE
HABITUATION
IN
UNCONSCIOUS
PATIENTS
315
responded to pain; if the patient was able to respond to a waving hand or simple commands he would also respond to pain, touch and sudden acoustic stimuli, and so on. Based on this analysis of the reactivity to the various classes of stimuli the six grades of unconsciousness were defined (Table 2). Table Grade
VI
Grade
II:
Grade
I:
2. Grades
of unconsciousness
:
Patient
:
Patient unconscious but reacts to pain, high sound and touch and/or sound of voice (N=7). Patient stuporous. In addition to reactivity to pain, high sound, touch and voice the patient may be aroused to respond to the sight of a waving hand or other moving objects, or to simple commands like “grip my hand” or “open your eyes” (N-8). Patient’s consciousness seriously reduced (soporose), responds as other grades but he may also be aroused to indicate “yes” or “no” correctly to simple questions like “have you had your dinner?“--“is it daytime now?‘, by blinking his eyes according to a predesigned code, or by nodding or shaking his head (N=7).
The 8 patients in the two deepest classes (Grades V and VI) could not be tested further and will not be dealt with in the following. The remaining 34 patients responded to sound with a great variety of responses. They also varied with regard to what other stimuli they responded to. All of them had varying degrees of reduced consciousness, as judged by the medical staff, even the patients in the lightest class (Grade I) that was able to react at least to some requests by indicating “yes” or “no” for instance by eye-blinking. In each patient there was some fluctuation of the level of unconsciousness, but the average level of unconsciousness might stay unaltered for several days, weeks or even months. No systematic evaluation of the validity of the reactivity classification has been obtained. However, it agrees well with the judgment of the department for each patient. All 34 patients included in Grades I-IV were rated by the head of the department (K.K.) into four rank order classes for the depth of coma at the time they had been tested. This grading was done without access to the data from the reactivity classification, and independent of the exact definition of the final classes. He based his retrospective judgment on all other data available from the files of the patient. There were quite a few disagreements, but most of these were limited to one grade, and the agreement was statistically significant (Pearson product-moment correlation coefficient = 0.49, p ~0.01). There was no systematic tendency in the sign of the differences. The responses also varied from patient to patient, both in the intensity as well as the number of components. The responses were analysed for frequency, patterning, and intensity, but no systematic trend was evident. Comparing the type of responses with the classification based on stimulus sensitivity, only a few findings were consistent. Only patients in the deep group (Grade IV) showed a startle response, and patients in the lightest group (Grade I) did not show eye-blinking, gross body movements or chewing. Eyeopening, eye movements, head movements and respiratory changes and arrest were observed in all groups with no predominance of any response in either group. *. 3
Habittrath
In all the patients who responded to sound stimulation by overt behavior, a change in reactivity was observed upon repeated stimulation. In the majority of the patients, this
316
GRLTE BRY~IN GUI.BRAW\EV,
KRISTIAV KRISTIASSEN and HM.~ER UF~IN
change occurred after a strikmgly low number of stimulations. Even in pattents m whom a very clear response was obtamed. this response sometrmes could not be ehcited after as few as two or three trial% When the patient was activated by another stimulus as loud shoutmg or shakmg him (dtshdbnuated), the response reoccurred. Habituatton tates dtd not doffer stgnificantly between grades. A curvthnear relattonshtp is suggested from Fig I ; Grade 111 patients tended to require more trtals to habituatton than Grades IV and II, but were not significantly different from Grade I. However, this relationship did not reach signtficance in an analysis of vnnance. TRIALS 10
tiABI’U4TION
15
I
10
m
--
5
--
IJl Grade
m
I ’
Grade
Iii (muddle1
lili -__
-...
.I_
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Grcde
11 (Ilgh?)
Grade
I
I
I (very
Ilght)
FIG I Tr~alr to habltuation of observed responses to auditory stimulation in 34 unconscious patients The result from each patient is represented by a vertical lme The mean for each grade of unconsctousncss IS indicated by a horizontal, dotted hne (III).
In the I2 pattents in wham habttuation data were obtamed for three or mare consecutive days, savings were observed in 5 patients In these patients there was a clear decline in habituation rate from day to dsy. There was no clear relationship between the presence of savings and the degree of coma as classified either by the reactivrty classrficatron or by the clinician According to the reactivity classification, there were 2 patients in Grade IV, 2 in Grade III, and 1 in Grade I showing savings. The 7 pattents showing no savings However, savings may were also evenly dtstributed among unconsciousness grades indicate a better prognosis (see later) The material was also analysed with regard to sensitization. If a patient showed a stronger orientation reaction to the stimulus after it had been presented a few times, this was noted as sensitizatton. A stronger orientation reaction could etthcr consist of more vigorous head turning, or mcreasmg unrest, or a more complex orientation reaction, for instance head turning being added to eye blinking. Defined this way, sensitization was observed m 9 pattents, and in 14 patients there was a clear lack of sensitization. In the rest
RCSPONSE HABITUATKIN
IN UNCONSCIOUS
PATIENTS
317
of the material it was too difficult to evaluate whether sensitization had occurred or not due to the response repertoire of the patients. The clear cases of sensitization and lack of sensitization are distributed evenly over grades, with one exception. Lack of sensitization was most frequently observed in the lightest group, Grade I, in which 6 of the 7 patients showed no sensitization (Table 3). Table 3.
Coma group
Sensitization
Sensitization
Lack of sensitization
Uncertain -
Grades Grade Grade Grade
IV 111 II I
N=34
(12) (7) (S) (7)
5 2 2 0
4 2 2 6
3 3 4
9
14
II
I
The prognosis was rather poor for all the patients included in the material. Satisfactory restitution was found in 8 patients, 14 patients did not show satisfactory restitution, and 12 of the patients died. The correlation between the reactivity classification and the prognosis does not reach significance (O.lO>p>O.O5, fourfold table chi square), but the clinical classification correlates significantly with the prognosis (p
DISCUSSION The aim of the study was (a) to contribute to a classification of unconscious states, and (b) to investigate the behavioral plasticity of unconscious brain-damaged patients. We have developed a procedure for reactivity evaluations of these patients that correlates satisfactorily with the clinical judgment. The advantages of the scoring procedure are that it gives a quick and reliable estimate of the state of unconsciousness of a given patient at a given time, it does not require any instrumentation, and it can be used by personnel not medically trained. The result from one test at one point in time does not give useful information on prognosis; the time course and the underlying pathology are decisive factors which must be taken into account. However, the presence or absence of savings is
318
GRATE
BRYHN
GULBRAXDSEN.
KRISTIANKRISTIAUENand HOLGERURSI\
an indicator of the prognosis. The possible usefulness the time course has not been explored further.
of the scoring
method
in following
In all examinations of these patients the surprising degree of remaining plasticity must be taken into account. All patients who responded to the buzzer, habituated to the stimulation. Since the reactivity reoccurred when activation was produced by another stimulus “dishabituation”, the phenomenon classifies as a true habituation phenomenon according to the criteria set forth by SHARPLESS and JASPER [3] and SOKOLOV [4]. The responses observed in our patients are a very heterogeneous group of muscular activities, varying from gross body movements to startle responses. Many of the responses like eye-opening, arrest of ongoing activity, movements of the eyes and the movements of the head may well be components of the orienting response. Some may be part of “defensive reflexes” observed to strong stimuli in intact mammals [4]. According to the the part of the central of stimulus patterns. of a tone which had This cognitive model unconscious patients. unconscious patients damaged brains.
Sokolov model habituation does not indicate a loss of sensitivity on nervous system. His theory involves a cognitive model of recognition He has demonstrated, for example, that if he decreased the intensity been given repeatedly to a subject, orienting or altering reoccurred. does not seem to be adequate for the habituation observed in the It seems unreasonable to account for the fast habituation rate in the by ascribing some superior discriminatory abilities to these severely
Very simple neuronal circuits like abdominal ganglias in aplysia [5, 6, 71. and the spinal cord of the spinal cat preparation [I] have been chosen in successful attempts to illustrate the cellular and synaptic changes taking place during habituation. These models make no assumption about consciousness, and may furnish us with a model for neuronal events taking place also in the unconscious patient. According to the dual-process theory of GROVES and THOMPSON [5], every stimulus evoking a behavioral response has two properties: It elicits a response mediated through a “S-R pathway,” and, secondly, a stimulus also influences a system of inter-neurons parallel to the S-R pathway. This “state system” affects the general level of excitation or “arousal”, and comprises all factors that affect the excitability of the nervous system. Habituation seems to be due to properties of some of the excitatory synapses in the S-R pathway itself, the so-called “habituating” type of synapses. These synapses have been shown to decrease in excitatory efficiency upon repeated firings. The nervous system also contains a second type of synapse, the sensitizing synapse, which is mainly found in the state system. These synapses increase in efficiency upon repeated firings. Groves and Thompson conclude that the strength of a behavioral response to a repeated stimulus is the net outcome of these two independent synaptic processes. The response observed in a brain-lesioned, unconscious patient follows some S-R pathway left intact in his brain. The habituation observed may be a natural consequence of the fact that most S-R pathways contain habituating synapses. The plasticity in his response, according to this model, is a function which is built irreversibly into the S-R pathway itself. If there is a response, there is also habituation. Our findings are, therefore, not surprising according to this model. In the lighter cases, more complex types of stimulus recognition may be involved, as they are in the normal, awake brain according to SOKOLOV [4]. The curvilinearity suggested by Fig. 1, if true, may derive from more complex mechanisms taking over in the less damaged brains.
RESPONSE HABITUATION IN UNCONSCIOUS PATIENTS
319
Sensitization, which may be due to synapses particular to the state system, did not However, lack of sensitization was correlate with any coma level or with the prognosis. found in almost all the patients in the lightest group (Grade 1). In spite of being unconscious, these patients are able to follow quite complex commands, and very complex S-R pathways must remain intact. Their pathology, therefore, may be limited mainly to the state system, showing a particular lack of sensitization according to the Groves and Thompson model. It remains to be seen it drugs increasing the excitability of the central nervous system like amphetamine may have more effect in this type of unconsciousness than in any of the other groups. Our findings do not agree with the generally held notion that brain lesions produce a reduction in the extent of behavioral response habituation [I, 41. Compared with habituation of galvanic skin response and heart rate changes to a mild auditory stimulus in normal subjects [9] the habituation shown by our patients is as fast or maybe faster. In patients with less serious neurological diseases there is also a fast habituation of cc-wave blockage [IO]. Further, it has been shown that rats with brain damage due to excess t_-phenylalsnine in the diet in early life have a behavioral deficit that is characterized by a defective arousal function and fast habituation [I I]. Therefore, general statements about brain lesions producing prolonged habituation rates are questionable. The habituating properties of the synapses in a S-R pathway cannot be changed by a gross brain lesion. If the S-R pathway is damaged itself, a longer and more complex route is probably necessary; this may, if anything, lead to faster habituation. Resistance to habituation may be produced by changing the excitability level in the pathway, by changing the state system or the stimulus identification processes, as when for instance lesions in the limbic structures interact with the habituation mechanisms [12, 131. Sleep seems to be a different state from the unconsciousness produced by brain lesions; in normal sleeping subjects there is little or no habituation [14].
REFERENCES I. 2. 3. 4. 5. 6. 7. 8. 9. 10.
II. 12. 13.
14.
THOMPSON, R. F. and SPENCER, W. A. Habituation: A model phenomenon subtrates of behavior. Psychol. Rev. 73, 1M3. 1966.
for the study
of neuronal
DIMITRIJEVIC, M. R. and NATHAN, P. W. Studies of spasticity in man. 5. Dishabituation of the flexion reflex in spinal man. Bruin 94, 77-90, 1971. SHARPLESS, S. and JASPER, H. Habituation of the arousal reaction. Brain, 79, 665-680, 1956. SOKOLOV, E. N. Perception and rhe Condiiioned Reflex, 309 pp. Pergamon Press, New York, 1963. PINSKER, H., KUPFERMANN, I., CASTELLUCCI, V. and KANDEL, E. Habituation and dishabituation of the gill-withdrawal reflex in aplysia. Science, N. Y. 167, 1740-1742, 1970. KUPFERMANN, I., CASTELLUCCI, V., PINSKER, H. and KANDEL, E. Neuronal correlates of habituation and dishabituation of the gill-withdrawal reflex in aplysia. Science, N, Y. 167, 1743-1745, 1970. CASTELLUCCI, V., PINSKER, H., KUPFERMANN,I. and KASDEL, E. R. Neuronal mechanisms of habituation and dishabituation of the gill-withdrawal reflex in aplysia. Science, N. Y. 167, 1745-1748, 1970. GROVES, P. M. and THOMPSON, R. F. Habituation: A dual-process theory. P.rychol. Rev. 77,419-450, 1970. ZAHN, T. P., ROSENTHAL,D. and LAWLOR, W. G. Electrodermal and heart rate orienting reactions in chronic schizophrenia. J. Psychiat. Res. 6, 117-134, 1968. WELLS, C. E. Response of alpha waves to light in neurological disease. Arch. neural. 6, 478-491, 1962. HOLE, K. Arousal defect in I_-phenylalanine-fed rats. Develop. Psychobiol. (In press) 1972. KIMBLE, D. P. Hippocampus and internal inhibition. Psycho/. Bull. 70, 285-295, 1968. BAGSHAW, M. H., KI.CIBLE, D. P. and PRIBRAM, K. H. The GSR of monkeys during orienting and habituation and after ablation of the amygdala, hippocampus and inferotemporal cortex. NeIfropsychologia II, 111-119, 1965. JOHNSON, L. C. A psychophysiology for all states. Psychophysiology 6, 501-516, 1970.
320
GHFTL
RRYHU
GL~LRRANDSFU.
KRISTI\X
KRISTIAXSEN
and
HOLCFR URSIV
Resume--On a titudie la reactivitc et I‘habituation de la reponse chez 42 malades inconzcients. On Ies regroupait aisemcnt selon 6 degres de troubles de la conscience d’apres les types de stimulus auxquels ils ripondaicnt. On pouvait dtcrire cliniquement ces degres comme temoignant de la profondeur du trouble de la conscience. Ainsi etait procuree une technique rapide grice h laquelle du personnel, mSme non medical, pouvait classer les malades selon les degres du trouble de la conscience. Les malades correspondant aux quatre degris les plus legers donnaient des rcponses de type varic aux differents sons. II n’y avait pas d’aspect typique ou de progression dans les reponses observees: cependant on constatait une habituation de la reponsc chez tous les malades, et cela apres seulement quelques essais. II n’y avait pas de relation signiticative cntre la vitcsse de I’habituation et le degre du trouble de la conscience. La scnsibilisation etait presqu’exclusivement observee dans les degres Its plus Iegers. La reduction de la vitesse de I’habituation d’un jour sur I’autre n’etait pas liie au degre du trouble de la conscience mais etait reliee de facon positive au pronostic.
Zusammenfassung-Reaktionsund Antwortverhalten wurde bei 42 bewufitseinsgestortcn Kranken gepriift. Den Reizantworten entsprechcnd war es leicht moglich. 6 graduell unterschiedliche Typen von BewuRtseinsstorungen aufzustellen. Klinisch entsprach dies der jeweils bcschriebenen Tiefe der RewuBtscinsstiirung. Auf diese Weise konnte die Anwendung technischer Verfahren vermieden ucrden, weil such nichtmedizinisches Personal die BewuDtseinsstorungen zu klassifizieren imstnnde ist. Die 4 leichtesten Grade entsprachen einer Reaktion auf Laute. Da&i wurden keine typischen Antwortformen beobachtet. Trotzdem wurden bei allen Patienten Reaktionen registriert, van dcncn nur eine kleine Anzahl gepriift wurde. Die Gewohnungsrate stand in keiner signifikanten Relation zum ArtsmalT dcr BcwuBtseinsstorung. Sensibilisierung wurde ausschliet3lich bci leichtesten Formcn nachpcwiesen. Besserungen von einem Tag auf den andercn korrelierten nicht zum Ausmai? dcr Bewul3tseinssti5rung. konnten aber beziiglich der Prognose positiv beurteilt wcrden.