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The purpose of this study was to compare the relative efficacy of two methods in assessing the location of the sources of the N100 and P200 components of evoked magnetic fields (EMFs) to transient tone stimuli. EMFs to left ear stimulation, containing both components, were recorded over the right hemisphere of six normal subjects. The magnetic scalp distributions calculated at several adjacent time points, covering the duration of each component's peak, were used to estimate the source parameters of each component. Good estimates of the source of both components were obtained from all magnetic field distributions. The averaged spatial parameters derived from all distributions of each component as well as the parameters derived from the distribution that gave the best source estimate for each component were projected onto magnetic resonance images of subject's head. It was found that the source of each component is located on the superior surface of the temporal lobe and that the source of the P200 component is anterior to the N100 source in all subjects using both procedures.

We are fortunate to be physicians at a time when the molecular pathogenesis of disease is being unraveled. Beginning with the discovery of the structure of DNA to the Human Genome Project, molecular biology over the past 45 years has revolutionized medicine. Neurosurgery has a strong scientific tradition, but to remain active participants in this new era of medicine, we must understand the science of pathology at the molecular level, applying our unique perspective to its advancement. We will review most of the current techniques used today by cell and molecular biologists. Interwoven with these descriptions will be a brief discussion of pertinent molecular and cell biology concepts, a full review being beyond the scope of this article.

To elucidate the clinical course of the vegetative state after severe closed-head injury, the Traumatic Coma Data Bank was analyzed for outcome at the time of discharge from the hospital and after follow-up intervals ranging up to 3 years after injury. Of 650 patients with closed-head injury available for analysis, 93 (14%) were discharged in a vegetative state. In comparison with conscious survivors, patients in a vegetative state sustained more severe closed-head injury as reflected by the Glasgow Coma Scale scores and pupillary findings and more frequently had diffuse injury complicated by swelling or shift in midline structures. Of 84 patients in a vegetative state who provided follow-up data, 41% became conscious by 6 months, 52% regained consciousness by 1 year, and 58% recovered consciousness within the 3-year follow-up interval. A logistic regression failed to identify predictors of recovery from the vegetative state.

PART I: HISTORY AND EPIDEMIOLOGY: Arthur L. Benton: Historical notes on post-concussion Jess F. Kraus & Parivash Nourjah: The epidemiology of mild head injury Bryan Jennett: Some international comparisons PART II: EXPERIMENTAL MODELS AND NEUROPATHOLOGY: John T. Povlishock & Thomas H. Coburn: Morphopathological change associated Ronald L. Hayes, Bruce G. Lyeth, & Larry W. Jenkins: Neurochemical mechanisms of mild and moderate head injury PART III: CLINICAL MANAGEMENT, NEUROPHYSIOLOGY AND NEUROIMAGING: Ralph G. Dacey: Complications after apparently mild head injury and strategies of neurosurgical management J.W. Snoek: Mild head injury in children Howard M. Eisenberg & Harvey S. Levin: Computed tomography and magnetic resonance imaging in patients with mild to moderate head injury Rudolf Schoenhuber & Massimo Gentilini: Neurophysiologic assessment of mild head injury PART IV: NEUROPSYCHOLOGICAL SEQUELAE: Dorothy Gronwall: Cumulative and persisting effects of concussion on attention and cognition Massimo Gentilini, Paolo Nichelli, & Rudolf Schoenhuber: Assessment of attention in mild head injury Ronald M. Ruff, Harvey S. Levin, Steven Mattis, Walter M. High, Jr., Lawrence F. Marshall, Howard M. Eisenberg, & Kamran Tabbador: Recovery of memory after mild head injury Harvey S. Levin, Linda Ewing-Cobbs, & Jack M. Fletcher: Neurobehavioural outcome of mild head injury in children PART V: POST-CONCUSSION SYMPTONS: William H. Rutherford: Post-concussion symptons: Relationship to acute neurologic indices, individual differences and circumstances of injury S.S. Dikmen, Nancy Temkin, & Gay Armsden: Relationship of psychosocial functioning and post-concussional complaints to neuropsychological recovery PART VI: DISABILITY AND REHABILITATION: Philip Wrightson: Management of disability and rehabilitation services after mild head injury Jeffrey T. Barth, Wayne Alves, Thomas V. Ryan, Stephen N. Macciocchi, Rebecca Rimel, John A. Jane, & William Nelson: Mild head injury in sports: Neuropsychological sequelae and recovery of function Laurence F. Marshall & Ronald M. Ruff: Neurosurgeon as a victim Wayne Alves: Facilitation of recovery by support, education and cognitive training.

Inconsistencies across studies concerning outcome after mild head injury may reflect differences in the diagnostic criteria used for selection of patients. Consequently, we compared the neurobehavioral outcome in three groups of consecutively hospitalized patients (aged 16 to 50 years) who sustained a closed head injury (CHI) and had a Glasgow Coma Scale (GCS) score in the 9 to 15 range. These groups included patients with uncomplicated CHI with mild impairment of consciousness as reflected by a GCS score in the 13 to 15 range (n = 78), patients with initially mild impairment of consciousness complicated by brain lesion or depressed skull fracture (n = 77), and patients with moderate CHI (n = 60). Tests of memory, information processing, and verbal fluency were administered within 1 to 3 months after injury, and the Glasgow Outcome Scale was completed at 6 months. Neurobehavioral functioning was impaired in the groups with complicated mild CHI and moderate CHI as compared to the group with uncomplicated mild CHI. Although moderate CHI produced longer durations of impaired consciousness and posttraumatic amnesia than complicated mild head injury, patients in these groups did not differ in neurobehavioral performance. Global outcome at 6 months was better in the patients with mild CHI than in patients with complicated mild and moderate injuries. Analysis of the various complications of mild CHI revealed that the presence of an intracranial lesion was related to more severe neurobehavioral sequelae than injuries complicated by a depressed fracture.

✓ In a prospective investigation of neurobehavioral functioning in young boxers, 13 pugilists and 13 matched control subjects underwent tests of attention, information-processing rate, memory, and visuomotor coordination and speed. The results disclosed more proficient verbal learning in the control subjects, whereas delayed recall and other measurements of memory did not differ between the two groups. Reaction time was faster in the boxers than in the control subjects, but no other differences were significant. Ten subjects in each group were retested 6 months later and exhibited improvement in their neuropsychological performance as compared to baseline measurements. However, there were no differences in scores between the boxers and the control subjects at the follow-up examination or in the magnitude of improvement from baseline values. Magnetic resonance imaging, which was performed in nine of the boxers, disclosed normal findings.

The recovery cycle and two variants of the habituation hypothesis invoked to explain the N1-P2 amplitude attenuation of evoked potentials (EPs) to the second tone in two-tone series, were investigated. Paired stimuli were presented with a constant 360 ms inter-stimulus interval (ISI), but with different, fixed inter-pair intervals (IPIs) of 800, 1 000 and 1 200 ms in addition to a variable IPI averaging 1 000 ms. Amplitude reduction of the second tone EP was present for only the 1 000 and the 1 200 ms IPI series. These data contradict the specific predictions of all three hypotheses, although one prediction of the recovery cycle hypothesis was supported, stating that for a given relation of IPI to ISI the second tone attenuation effect disappears. To account for all findings in this experiment, an alternative explanation is advanced incorporating the concept of recovery cycle and involving the effects of rhythmic stimulation, whereby tone pairs are processed as units whose perceptual cohesiveness determines the distribution of response resources to each tone.

The eye and orbit are excellent subjects for ultrasonic evaluation. Examination and interpretation are relatively simple procedures. The normal ultrasonic anatomy of the eye and orbit is presented. Some examples of ocular and orbital pathology are discussed also.

Evoked potentials (EPs) to a probe tone stimulus were recorded simultaneously at the temporal and parietal areas of the left and right hemisphere of dextral adults engaged in either an arithmetic or a visuospatial task. The probe EP amplitude was attenuated in the left temporal area during the arithmetic task and in the left temporal and both parietal areas, but significantly more in the right, during the visuospatial task, indicating distinct patterns of regional cerebral engagement for the two types of cognitive activity.

Having noticed a consistent activation of right frontal areas during several visuospatial tasks, we retrospectively examined data from 121 regional cerebral blood flow (rCBF) studies conducted under a variety of conditions involving different stimuli, response modes and task requirements. These were compared to scans conducted while subjects were at rest. Significant hemispheric differences were found for all tasks combined in the frontal regions, where right flow was greater than left, especially in more demanding tasks. This finding suggests a very general role for the right hemisphere in attention or vigilance.

The effects of apamin on local rates of glucose utilization in the brain and spinal cord were studied employing the quantitative autoradiographic deoxyglucose method. Forty-five to 60 min after administration of apamin the animals lost exploratory behavior, remaining completely immobile, with the 4 limbs overextended, unresponsive to auditory stimuli. Out of 30 neural structures examined, glucose utilization was significantly decreased in the cochlear n., superior olivary n., lateral lemniscus, inferior colliculus, medial geniculate body, fastigial n., globus pallidus, caudate-putamen, n. accumbens and the lumbar ventral horn of the spinal cord. These results show that apamin specifically affects the functional activity of the auditory and motor structures.

Studied 64 children and adolescents who sustained blunt trauma to the head and were admitted to a neurosurgical service. Ss were divided into 2 groups at the time of injury: (a) 22 6-12 yr olds and (b) 42 12-18 yr olds. Neuropsychological sequelae were pervasive in both groups when they were evaluated after cessation of posttraumatic amnesia. Impairment of long-term storage and retrieval processes in memory was found in about half of the total sample. Residual neuropsychological deficit was directly related to severity of acute injury as reflected by duration of coma and the Glasgow Coma Scale. Language: en

A male infant with communicating hydrocephalus and a position dependent obstruction in the posterior third ventricle is described. The apparent mass in the posterior third ventricle was seen only when the child was inverted. Possible factors relating to hydrocephalus which can cause the walls of the posterior third ventricle to come together and explain this unusual finding are discussed. These include dilated ambient cisterns and dilated posteriormedial aspects of the temporal horns.

Magnetic resonance imaging (MRI) was performed in a series of 21 children and adolescents who had been hospitalized after sustaining closed head injuries of varying severity at least 6 months previously. Areas of high intensity in the parenchyma were present in 8 of the 11 severely injured patients, whereas MRI findings were normal in all 10 patients with mild-to-moderate head injuries. Lesions involving the subcortical white matter were confined to severely injured patients whose clinical features were compatible with diffuse axonal injury. Neuropsychological assessment disclosed deficits primarily in the severely injured patients; these deficits were significantly associated with persistent lesions visualized by MRI. Serial MRI and neurobehavioral assessment following early injury may be useful in documenting cognitive impairment in relation to structural alterations of the young brain.

✓ A multi-center double-blind randomized clinical trial was conducted by the National Acute Spinal Cord Injury Study Group to examine the efficacy of high-dose methylprednisolone (1000-mg bolus and 1000 mg daily thereafter for 10 days) compared with that of a standard dose (100-mg bolus and 100 mg daily for 10 days). No significant difference was observed in neurological recovery of motor function, pinprick response, or touch sensation 1 year after injury between the two treatment groups, after adjustment for other potentially confounding factors. Analyses that specifically took into account the patients' total steroid dose and relative weight confirmed the lack of a steroid treatment effect. The case fatality rate was 10.7% during the 1st year after injury, and this was not associated with the steroid treatment protocol or the patient's gender. Deaths did occur significantly more frequently among patients who were completely (15.3%) and partially (8.6%) plegic than among those who were paretic (2.5%, p = 0.0005), and among patients aged 50 years or older (38.6%, p = 0.0001).

Ischemia due to middle cerebral artery occlusion was studied in 29 rats from 1 to 24 hours after occlusion using magnetic resonance imaging. Images were made before and after the injection of a superparamagnetic iron oxide compound, AMI-25. Subtraction images demonstrated the region of perfusion deficit as early as 1 hour after occlusion, earlier than conventional T2-weighted images. The area of altered perfusion detected by this technique (subtraction imaging after AMI-25 administration) correlated with that demonstrated by iodoantipyrine autoradiography. Since this magnetic resonance technique can be used to serially estimate the location and size of the ischemic area, the technique can be an important adjunct to metabolic studies of focal ischemia using magnetic resonance spectroscopy. The technique may have clinical applications as well.

✓ This paper describes the pilot phase of the National Traumatic Coma Data Bank, a cooperative effort of six clinical head-injury centers in the United States. Data were collected on 581 hospitalized patients with severe non-penetrating traumatic head injury. Severe head injury was defined on the basis of a Glasgow Coma Scale (GCS) score of 8 or less following nonsurgical resuscitation or deterioration to a GCS score of 8 or less within 48 hours after head injury. A common data collection protocol, definitions, and data collection instruments were developed and put into use by all centers commencing in June, 1979. Extensive information was collected on pre-hospital, emergency room, intensive care, and recovery phases of patient care. Data were obtained on all patients from the time of injury until the end of the pilot study. The pilot phase of the Data Bank provides data germane to questions of interest to neurosurgeons and to the lay public. Questions are as diverse as: what is the prognosis of severe brain injury; what is the impact of emergency care; and what is the role of rehabilitation in the recovery of the severely head-injured patient?

45 children and adolescents recovering from closed head injury underwent neuropsychological testing. Multiple indices were used to classify the severity of injury but most important in this study were the persistence of coma indexed by grades I–III and the Glasgow Coma Scale. Although the presence of early neuropsychological sequelae and long-term intellectual deficit was generally related to the severity of injury, residual impairment was also found in patients with relatively mild injuries. Analysis of memory and learning demonstrated disruption of both storage and retrieval processes.

Evoked Potentials (EPs) to a click stimulus were recorded at the temporal areas of both hemispheres of dextral subjects engaged in covert rehearsal of a verbal passage or in covert rehearsal of musical passages. A pattern of left hemisphere attenuation of the click EPs was observed in all subjects during speech rehearsal but not during music rehearsal. The implications of these findings for the issue of electroencephalographic localization of speech production mechanisms in the left hemisphere are discussed.

✓ A case of a symptomatic Rathke's cleft cyst in a 10-year-old boy is described. The importance of the intraoperative differentiation between this rare tumor and a craniopharyngioma is discussed.

Angiotensin II infused intravenously into sinoaortic-denervated rats induced drinking and increased glucose utilization in the subfornical organ and pituitary neural lobe in amounts not different from those observed in sham-operated animals. We suggest that inputs from baroreceptors have a negligible influence on glucose metabolism in the subfornical organ during infusion of angiotensin II.

Auditory brain stem evoked responses (BSERs) to repetitive clicks were recorded in subjects engaged in overt speech, whispering, silent articulation, and covert verbal rehearsal tasks and during a control condition of attending to the clicks. Overt speech and whispering resulted in a significant amplitude reduction of the fifth peak of BSERs without affecting the amplitudes or the latencies of the earlier peaks. These data strongly suggest efferent inhibition of irrelevant auditory input at the level of the upper brain stem.

Electrical stimulation of the proximal stump of the transected sciatic nerve increased glucose utilization in the ventral horn of the spinal cord, with the greater increase in Rexed's lamina IX. Antidromic stimulation of the ventral root, however, did not change glucose utilization in the ventral horn. These results suggest that the axon terminals and not the cell bodies are the sites of enhanced metabolic activity during increased electrical activity in these elements.

In comparison with age-matched groups who sustained mild to moderate head injury, children and adolescents with severe head injury initially exhibited memory deficit. Cognitive impairment persisted primarily in the severely injured children, whereas the follow-up performance of severely injured adolescents more closely approximated that of age-matched patients with mild or moderate head injury. The results suggest that young children are no less and may be even more vulnerable to the deleterious effects of diffuse injury on memory and cognition.

Alpha and beta content of spectrally analyzed EEG were used to assess differential hemispheric engagement during two linguistic tasks (semantic and phonetic) and one acoustic task involving detection of target items embeddded within the same stimulus series. Beta content of the EEG increased reliably in the left hemisphere during the linguistic tasks, whereas the expected attenuation or blocking of alpha did not occur reliably. These data suggest that left hemisphere beta enhancement rather than alpha blocking is a more efficient index of differential hemispheric engagement during language processing.

Brainstem auditory evoked potentials (BAEPs) were recorded from rats before and after injection with apamin, a polypeptide component of bee venom. Increased absolute and interpeak latencies were found in Peaks III-VII of the BAEP beginning about 30 minutes after apamin injection suggesting impaired auditory function. No change in BAEP was found when animals were injected with saline or during the baseline period before apamin administration. Results corroborate recent findings from our laboratories of decreased glucose metabolism in brainstem nuclei of the auditory system [3] after injection with the same dose of apamin.

The ventriculographic findings of a severe ascending transtentorial herniation that occurred after shunting in an infant with a posterior fossa tumour are described.

✓ With the use of a ventricular perfusion technique, a cerebrospinal fluid formation rate of 1.4 ml/min was determined in a 5-month-old child with a choroid plexus papilloma and hydrocephalus. This rate was slightly greater than four times the rate observed in normal children. The clinical course, as well as a measured absorption rate, indicated that the patient's capacity for absorption was normal.

The question whether stimuli forming temporal patterns are processed differently from identical stimuli belonging to irregular temporal aggregates was investigated. Tones forming either regular or irregular triads were presented to eight normal subjects. The N1-P2 amplitude of evoked potentials to tones forming temporal patterns were consistently lower than those to tones in the irregular aggregates. These data indicate that the perceptual phenomenon of subordination of constituent parts to a well-formed whole is demonstrable in electrophysiological terms.

To investigate the inter-rater reliability and validity of the Neurobehavioural Rating Scale at various stages of recovery after hospitalisation for closed head injury, we studied 101 head trauma patients who had no antecedent neuropsychiatric disorder. The results demonstrated satisfactory inter-rater reliability and showed that the Neurobehavioural Rating Scale reflects both the severity and chronicity of closed head injury. A principal components analysis revealed four factors which were differentially related to severity of head injury and the presence of a frontal lobe mass lesion. Although our findings provide support for utilising clinical ratings of behaviour to investigate sequelae of head injury, extension of this technique to other settings is necessary to evaluate the distinctiveness of the neurobehavioural profile of closed head injury as compared with other aetiologies of brain damage.

In order to investigate post-traumatic hemispheric disconnection effects, dichotic listening and intermanual tasks were administered to 69 patients who had sustained a closed head injury of varying severity. The manual tasks consisted of naming objects palpated in either hand, transfer of postures from one hand to the other and writing. Consistent with predictions, the degree of ear asymmetry in dichotic listening performance was directly related to the severity of the head injury as reflected by the degree of impaired consciousness. Depth and localisation of parenchymal lesion characterised by magnetic resonance imaging were also related to the degree of ear asymmetry. Parenchymal lesions situated in sites which could potentially interfere with callosal auditory or geniculocortical pathways produced a greater disparity in response to left versus right ear inputs as compared with parenchymal lesions in areas such as the frontal lobes which are purportedly unrelated to asymmetries in dichotic listening performance. The results provide further evidence for the effects of multifocal brain lesions involving the white matter on tasks which require intra and/or interhemispheric integration.

✓ A case is presented to illustrate the technique of combined posteroanterior approach to tumors of the cervical spinal foramen. The anterior approach offers a direct, feasible complementary route when this type of tumor cannot be completely excised through the conventional posterior approach.

✓ A series of 34 lumboperitoneal shunts performed at Children's Hospital Medical Center, Boston, for communicating hydrocephalus is reviewed. The ease of placement and revision of this shunt, the relatively benign complications that occurred, and the fact that 21 of these 34 patients are still using lumboperitoneal shunts with good control of the hydrocephalus have justified continuing use of this method as the initial bypass procedure in the treatment of communicating hydrocephalus.

SEVERAL studies have demonstrated the ability of experimentally induced seizures to increase the penetration of a variety of blood borne solutes into brain. 1-5 In general, this increase has been attributed to an alteration in the permeability of the blood-brain barrier, as indicated by the increased passage of albumin from blood to central nervous system (CNS). 2,3,6 Under normal conditions, little, if any, blood protein gains access to the CNS. 7 A recent report from this laboratory has shown that the increase in brain permeability to albumin labeled with iodine 131, associated with prolonged pentylentetrazol seizures, was predominantly restricted to the thalamus, reversible within minutes after arrest of the seizure, and accompanied by an appreciable increase in the total water content of the thalamus. 8 These features provided a useful model to assess the effectiveness of glucosteroids on altered brain permeability, since the alteration (1) has a specific localization

SUMMARY Much of what is accepted about the pathophysiology of hydrocephalus is dependent upon the results of experiments in which perfusion is carried out between the lateral ventricles. Superficially, the method seems to be merely a technical variation of ventriculo-cisternal perfusion, but in fact it involves new and incorrect assumptions about the system under study. Valid results are obtained by the method only when absorption is zero. RESUME Perfusion entre les ventricules lateraux dans l'hydrocephalie experimentale Beaucoup de ce que l'on connait et croit sur la physiopathologie de l'hydrocephalie depend du resultat d'experiences dans lesquelles une perfusion entre les ventricules lateraux est effectuee. Superficiellement, la methode semble une variation technique de la perfusion ventriculo-cisternale, mais en fait, elle entraine des affirmations nouvelles et incorrectes sur le systeme etudie. Des resultats valides ne peuvent etre obtenus par cette methode qu'en cas d'absorption nulle. ZUSAMMENFASSUNG Perfusion zwischen den Seitenventrikeln in einer Studie des experimentellen Hydrocephalus Vieles dessen, was uber die Pathophysiologie des Hydrocephalus gelehrt und geglaubt wird, ist abhangig von den Ergebnissen der Experimente, in denen eine Perfusion zwischen den Seitenventrikeln durchgefuhrt wurde. Oberflachlich gesehen scheint diese Methode einfach eine technische Variante der ventriculo-cisternalen Perfusion zu sein, tatsachlich aber bringt sie neue und unrichtige Annahmen uber das System mit sich wahrend der Studie. Verwertbare Ergebnisse erhalt man mit dieser Methode nur, wenn die Absorption null ist. RESUMEN Perfusion entre los ventriculos laterales en el estudio de la hidrocefalia experimental Mucho de lo que se ensena y se cree acerca de la fisiopatologia de la hidrocefalia depende de los resultados de las experiencias en las que se realiza una perfusion entre los ventriculos. laterales. Superficialmente el metodo parece ser meramente una variacion tecnica de la perfusion ventriculo-cisternal, pero de hecho incluye nuevas e incorrectas opiniones sobre el sistema estudiado. Los resultados validos con este metodo se obtienen unicamente si la absorcion es nula.

Brain stem evoked responses (BSERs) were obtained within the first 72 hours after hospital admission from 38 patients with closed head injuries whose Glasgow coma scale scores were 8 or less. Peak V latency differentiated patients with unfavorable outcomes (vegetative or dead) from patients with more favorable outcomes, but no features of the response could further discriminate good, moderate, and severe outcomes as assessed by the Glasgow outcome scale. These data provide further support that BSERs are generally resistant to central nervous system trauma but, when impaired, are prognostic of unfavorable outcome.

The activity of Na+, K+-activated adenosinetriphosphatase and the uptake of a potassium analog, rubidium, were found to be similar in cerebral microvessels and choroid plexus when measured in vitro. This similarity suggests that sodium and potassium concentrations in the nascent brain extracellular fluid are determined by the same active process that regulates their concentration in nascent cerebrospinal fluid. The brain microvessels may thereby play on active role in brain potassium homeostasis and brain extracellular fluid formation.

Hemispheric disconnection syndrome is a rarely reported sequela of aneurysm rupture. Serial neurobehavioral examinations of such a patient after clipping of a right pericallosal artery that had bled into a large portion of the corpus callosum disclosed defects in interhemispheric transfer of information and competitive movements between the left and right extremities. Although the patient's postoperative memory deficit subsequently resolved, his disconnection syndrome persisted and was primarily responsible for his disability despite otherwise normal neurological findings. We studied a second patient with a hematoma in the genu of the corpus callosum secondary to an arteriovenous malformation (AVM). Although the second patient also exhibited postoperative memory problems, her hemispheric disconnection symptoms were minimal and commensurate with a more circumscribed corpus callosum lesion. Neurobehavioral sequelae of aneurysm or AVM rupture involving the anterior circulation, which may be overlooked in the absence of a detailed examination, can produce persistent disability in many patients.

Serial computed tomographic scans in 39 closed head injury patients were measured by planimetry. The ventricle-brain ratio was computed, and the lateral ventricles were considered to be enlarged or normal based on measurements from a control group. Delayed ventricular enlargement was common after head injury producing low Glasgow Coma Scale scores and prolonged coma, whereas subarachnoid/intraventricular haemorrhage was more common with early enlargement. The degree of ventriculomegaly was related to neuropsychological test performance only when enlargement was delayed. It is postulated that diffuse axonal injury and hypoxic-ischaemic insult contributed to late ventricular enlargement, whereas a compensated obstruction of cerebrospinal fluid may be the predominant cause in the early group.