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In patients undergoing pallidotomy for Parkinson's disease, we recorded extracellularly from single neurons in the two internal segments (GPii, GPie) and the external segment (GPe) of the globus pallidus (GP) in response to active (cued) movements of the contralateral wrist, elbow or ankle. The patterns of cell activity occurring both before and after movement onset were analysed using hidden Markov models (HMMs) and clustered by movement type using the generative topographical mapping algorithm. Cluster separation was quantified in order to measure a cell's ability to discriminate between movements. Statistical analysis of variance indicated a significant regional gradient (GPii > GPie > GPe) of movement discrimination, while cells in all regions differentiated better between movements of different joints (wrist, elbow or ankle) than between flexion and extension of the same joint. We found that GP cells generally showed distinguishable firing patterns corresponding to more than one type of movement per cell, in support of the hypothesis that cells in these regions of the basal ganglia are not involved in preparation or execution of a single type of movement but participate in many different movements, analogous to the hidden units of a neural network. Our results also indicate that cell activity both preceding a movement and during its execution may be modelled by HMMs with only a small number of states.

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It is unclear how the disordered activity of cells in the basal ganglia contributes to the symptoms of Parkinson's disease (PD). We recorded from single neurons extracellularly in 3 regions of the globus pallidus (GPe, GPie and GPii) in patients undergoing pallidotomy for PD. Movement-related cell firing patterns, analysed using hidden Markov models, were significantly correlated with patients' preoperative clinical scores (off drugs). Responses of cells in GPii correlated best with the scores for specific motor tasks, rather than general ones related to activities of daily living, but the reverse was true for responses from GPe. In both GPii and GPe, a higher score (i.e. greater parkinsonian severity) was associated with greater variability in cell firing rather than an increase in firing rate itself.

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We have studied the effects of unilateral ventral medial pallidotomy in 26 patients with medically intractable Parkinson's disease with marked drug-induced dyskinesias. Preoperatively, all patients were assessed during one 5-day admission according to the Core Assessment Programme for Intracerebral Transplantation (CAPIT) protocol, including rating in the 'practically defined off' and 'best on' states before and during a single-dose levodopa challenge. Motor performance was assessed with subset categories of the Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests and a standard dyskinesia rating scale. Pallidotomy was performed under stereotaxic CT guidance with intra-operative extracellular microelectrode recording made from the basal ganglia. All patients were re-assessed 3 months postoperatively and a subgroup (n = 9) have so far also been re-assessed after 1 year. Pre- and postoperative performance scores were compared in order to determine which categories of performance improved postoperatively. Significance was accepted at P < 0.005 in order to take into account the multiple number of comparisons performed. Patient medication was compared pre- and postoperatively and the morbidity associated with surgery was also recorded. The most significant improvement postoperatively was the diminution of 'on' dyskinesias contralaterally (67%, P = 0.0001); however, ipsilateral (45%, P = 0.0006) and axial (50%, P = 0.0008) dyskinesias also improved. Contralateral to pallidotomy, the median 'off' motor UPDRS score improved by 27% (P = 0.001) and a significant improvement was also observed in contralateral rigidity by 25% (P = 0.001). There were trends towards improvement in contralateral tremor (33%, P = 0.016) and bradykinesia (24%, P = 0.013) scores. Ipsilateral rigidity improved by 22% (P = 0.005), but other ipsilateral motor scores did not alter significantly. The 'off' gait/postural instability score and 'off' walking time showed marginally significant improvements by 7% (P = 0.007) and 29% (P = 0.014), respectively. On medication, no significant postoperative improvements in parkinsonism were detected. Anti-parkinsonian medication increased by 11% postoperatively. In the subgroup who were available for assessment 1 year postoperatively, responses were generally maintained. Two (7.7%) of the 26 patients had fatal complications (one cerebral haemorrhage and one haemorrhagic infarct) directly related to surgery. Among the remaining 24 patients, four (15.4% of the total 26) had major complications (two persisting and two transient). Ten patients (38.5%) had minor complications. The majority of the complications (major and minor) occurred in the earlier operated patients and the complication rate subsequently declined with increasing operative experience. The remaining 10 patients (38.5%) had no significant side-effects. One of these 10 patients died from an incidental malignant glioma 6 months postoperatively. These findings confirm that levodopa-induced dyskinesias are dramatically reduced following ventral medial pallidotomy and constitute the principal indication for pallidotomy. Improvements in underlying parkinsonism were of smaller magnitude. Pallidotomy may also offer some patients an opportunity to increase antiparkinsonian medication. Patient selection for medial pallidotomy should, therefore, be based largely on anticipated improvements in levodopa-induced dyskinesias, but this must be balanced against the associated morbidity and mortality.

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Both tumor metabolism and its response to cytotoxic drugs are intrinsic properties of tumor cells. It is therefore likely that there is a relationship between the two properties, however subtle and complex, wherein the metabolic characteristics of tumor cells can reflect the inherent response (resistance or sensitivity) of these cells to cytotoxic drugs. We used artificial neural network analysis to show that it is possible to distinguish, prior to treatment, between drug-resistant and drug-sensitive human glioma cell cultures from their metabolic profiles, as given by high-resolution proton nuclear magnetic resonance spectra of the cell extracts, and to predict their cellular response to the chemotherapeutic drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in vitro. The results suggest that neural network analysis of tumor nuclear magnetic resonance spectra has potential as a prognostic tool for determining treatment of gliomas, ultimately noninvasively, and may be used to provide information about the metabolic pathways involved in drug response that may be helpful in developing novel treatments for these tumors.

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We measured the increase of regional cerebral blood flow (rCBF) in the somatosensory cerebral cortex occurring in response to a standard stimulation of the L. side mystacial vibrissae (facial whiskers) in rats anaesthetised with halothane, in conjunction with blocking of activity in the R. side parasympathetic (PS) and sensory fibres innervating the cerebral vessels. Blocking was achieved reversibly and repeatedly by means of a cooling probe. When the PS fibres and the nasociliary nerve (NCN) were blocked together, but not when the NCN was blocked alone, the R. side rCBF increase occurring with whisker stimulation was significantly reduced. Our results indicate that, in addition to the intrinsic cortical factors demonstrated in earlier studies, the cerebrovascular PS innervation, but not the NCN, contributes to the increase in cortical rCBF associated with somatosensory cortical neuronal activation.

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In two groups of normotensive rats anaesthetised with halothane, either the nasociliary nerve (NCN) or the NCN and parasympathetic (PS) fibres together (NCN-PS) were functionally blocked at the right ethmoidal foramen. Blocking was achieved reversibly and repeatedly using a cooling probe. Cortical regional CBF (rCBF) was measured bilaterally using laser-Doppler probes. In Group 1, bilateral common carotid occlusion (CCO) was applied for 1 min both with and without block. In Group 2, CCO was applied permanently followed by stages of controlled haemorrhagic hypotension to deepen the ischaemia and the block applied at each stage. In Group 1, during CCO, rCBF was unaffected by blocking NCN-PS. However, during the transient postocclusive hyperaemia, blocking NCN-PS, but not NCN alone, significantly increased right side rCBF. In Group 2 and in Group 1 in the absence of CCO (normotension), rCBF was unaffected by blocking either set of fibres. We conclude that neither NCN nor PS fibres contribute to the tonic level of rCBF or to its autoregulatory control, but PS fibres conduct impulses tending to resolve postischaemic hyperaemia. We suggest that a subpopulation of PS fibres containing neuropeptide Y is activated under conditions of supernormal rCBF.

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The parasympathetic innervation to the cerebral vessels has only recently begun to be investigated in detail and to be understood in terms of the control of brain function. Much of the experimental work has been motivated by the potent vasoactive potential of the parasympathetic fibres, which can produce profound increases in cerebral blood flow (CBF) when electrically stimulated. This paper first outlines the principal anatomical and biochemical evidence for the origins and pathways of the parasympathetic fibres and the basis of their influence on CBF. Next, studies performed to elucidate their physiological function are reviewed, and finally their possible functional significance is discussed in relation to normal and pathophysiological brain function and their possible involvement in the trigeminovascular system.

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The direct cortical response (DCR) and associated local cerebral blood flow was recorded from the primate cerebral cortex during a period of focal ischaemia induced by middle cerebral artery occlusion (MCAO). The DCR was lost when local blood flow fell below 20 ml/100 g/min but began to recover as collateral flow increased. Hypercapnia demonstrated a loss of local vascular reactivity following MCAO, but isovolaemic haemodilution still proved effective in increasing blood flow to these areas. The reduction in blood oxygen content induced by haemodilution did not impair cerebral function but the reduction in whole blood viscosity did exacerbate cerebral susceptibility to hypercapnia-induced intra-cerebral steal.

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In 8 baboons maintained under propofol anaesthesia, transcallosal evoked responses were recorded from the primary motor cortex following electrical stimulation of the contralateral homotopic cortical surface. The corpus callosum was made ischaemic by transorbital occlusion of the common anterior cerebral artery; blood flow (measured by the hydrogen clearance method) in the stimulating and recording regions was not significantly affected by this procedure. The transcallosal responses from the normally perfused brain contained early positive (P1) and negative (N1) components. As stepwise ischaemia was produced in the corpus callosum, the amplitude of P1 initially increased up to 150% of control and the peak latency of P1 was significantly prolonged. At flows below 8 ml/100 g/min the amplitude rapidly decreased. Wave form changes and flow threshold of N1 were similar to those of P1. These results suggest that measurement of early transcallosal responses could be useful clinically as monitors of the ischaemic level in anterior cerebral artery territory.

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In 7 baboons maintained under propofol anaesthesia, pyramidal tract responses were related to the corresponding peripheral EMG evoked by electrical stimulation of the motor cortex under conditions of focal cortical ischaemia. Pyramidal responses were recorded epidurally at the C5 level and the EMG was recorded from the contralateral hand or foot muscle using subdermal needle electrodes. Cortical ischaemia was produced by transorbital occlusion of the common anterior cerebral artery, and regional cortical blood flow was measured by the hydrogen clearance method. In the normally perfused brain, the later I waves of the C5 response required a lower stimulus strength to elicit them than the earlier I1 wave. It was more difficult to record the EMG from the hand than from the foot following stimulation of the corresponding cortex even though the C5 responses were always obtained in both cases. With moderate ischaemia, the later I waves were selectively abolished, leaving the D and I1 waves. EMG amplitude was significantly correlated with cortical blood flow (r = 0.88, P less than 0.005), and the threshold of cortical flow for the EMG was 10-13 ml/100 g/min. Our results indicate that changes in amplitude of the late I waves and particularly of the EMG are sensitive indicators of cortical ischaemia.

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BACKGROUND AND PURPOSE: We developed a model of acute focal ischemia in the territory of the anterior cerebral artery in baboons to study the ischemic pattern following occlusion and changes in regional cerebral blood flow. METHODS: In nine anesthetized animals, a Scoville clip was placed on the proximal segment of the common anterior cerebral artery via a unilateral transorbital approach. Regional cerebral blood flow was measured by hydrogen clearance in the cortex and corpus callosum. Postexperimentally, arteries were selectively injected. RESULTS: The resulting ischemia involved both hemispheres symmetrically and the corpus callosum. Cortical flows were significantly reduced within a region 15 mm from the midline on each side (p less than 0.01). A gradient of cortical flow reduction was produced between 10 and 25 mm from the midline. This area defines the boundary region between the territories of the anterior and middle cerebral arteries, and is identified as the "penumbra" of the ischemic core, which itself lies within 10 mm of the midline. Blood flows in the corpus callosum decreased from an average of 21.0 to 6.7 ml/100 g/min in the body (p less than 0.01) and from 22.5 to 10.7 ml/100 g/min in the genu (p less than 0.05). CONCLUSIONS: This ischemic model has close physiological and morphological relevance to stroke-related clinical circumstances, in particular the acute conditions of focal cerebral ischemia associated with vascular surgery. It also provides a new framework for experimental investigation of the ischemic penumbra.

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A circular magnetic stimulator coil placed perpendicularly to the surface of a large uniform conductor induces surface charge. The resulting electrostatic field reduces the total electric field within the conductor to 58% of the value in the absence of surface charge. The properties of 3 kinds of probe for measuring the effect of a magnetic stimulator are considered. A short dipole electric field probe is the only one which correctly measures the total electric field, including the contribution from any surface charge. A search coil generally gives incorrect results, since it is insensitive to the electrostatic field.

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We related intracranial auditory brain-stem evoked potentials (BAEPs) to the surface BAEP using a model of focal brain-stem ischaemia. In 17 baboons anaesthetised with alpha-chloralose, BAEPs were recorded bilaterally at the mastoids and in the caudal lateral lemniscus (LL) and inferior colliculus (IC), in response to monaural click stimulation. Electrodes at these sites were each connected to the positive input of a differential amplifier, and one other electrode, placed at the vertex, was connected to all the negative inputs. Measurements of local cerebral blood flow (CBF) by hydrogen clearance were made at the LL and IC sites. The LL wave form contained 5-7 positive peaks, the second (B wave) being dominant and coinciding with the negative wave II of the surface BAEP. Following graded ischaemia, produced by basilar artery occlusion and controlled hypotension, the latency changes of these two peaks were significantly correlated, as were those of the third wave (C wave) of the LL response and the surface wave III. In the IC, the contralateral wave form contained 4 positive waves (A-D) and a later, dominant, slow negative wave; changes in its peak latency and those of the slow negative surface wave were similarly correlated. The thresholds of local CBF for increases in latency of waves B and C in the LL were similar (12-15 ml/100 g/min), but in the IC the thresholds were 20, 30-35 and 20-24 ml/100 g/min for the B, C and slow negative waves, respectively. Our data indicate that a gradient of sensitivity to ischaemia is present along the brain-stem auditory pathways; this could explain the earlier change of the late, rather than early, BAEP components as reported in clinical cases involving brain-stem lesions.

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In 29 anaesthetized baboons avulsion of a small intracranial artery was used to produce a subarachnoid haemorrhage, in a closed-skull situation. Intracranial pressure was measured by extradural transducers, and arterial pressure was also measured continuously, with periodic measurements of cerebral blood flow. After haemorrhage there was an immediate fall in cerebral perfusion pressure in nearly all cases, reaching zero in 9 animals. In 18 there was a significant pressor response in the systemic circulation, but perfusion pressure usually remained low in spite of this response. Perfusion pressure recovered after a few minutes in most cases. In the 19 cases where intracranial pressure was measured on both sides, differences occurred in 11, with the higher pressure always on the same side as the haemorrhage. The difference was evident very soon after haemorrhage in 9 cases, and lasted over half an hour in 5 of them. The mechanism of arrest of bleeding was, in most of this series, not that of a zero perfusion pressure. Explanations for this and for the occurrence of differential pressures are discussed.

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Acute subarachnoid haemorrhage was produced in baboons by a transorbital vessel avulsion technique. Half the animals were pretreated with an intravenous infusion of the calcium antagonistic nimodipine, in a dosage comparable with clinical levels. The severity of the haemorrhage, as measured by changes in intracranial pressure, cerebral perfusion pressure, cerebral blood flow and reactivity, and evoked potentials, was not greater in the group receiving nimodipine. Changes in extracellular K+ and pH were much less marked in animals receiving nimodipine. It is suggested that nimodipine (a) has a protective effect at a cellular level against the ionic changes of ischaemia, (b) does not alter the mechanical severity of subarachnoid haemorrhage.

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We studied the changes in amplitude of the first short latency positive potential (2.3 +/- 0.3 msec, mean +/- S.D.) of the direct cortical response (DCR) elicited by surface electrical stimulation of the motor cortex in anaesthetised baboons. Local cortical blood flow, measured by the hydrogen clearance method, was progressively reduced by acute middle cerebral artery occlusion and subsequent hypotension and was related to the amplitude of this potential. With flow levels greater than 25 ml/100 g/min the DCR was essentially unaffected, but it was lost with flows below 20 ml/100 g/min. These results indicate a threshold relationship between the generation of the electrical activity evoked in the cortical elements and local cortical flow, similar to that previously demonstrated for cortical somatosensory evoked potentials.

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The effect of graded ischaemia on intracranial nerve fibre conduction has not previously been studied quantitatively. We measured pyramidal tract (PT) discharges evoked by electrical stimulation of the ipsilateral motor cortex, together with local blood flow (by hydrogen clearance), in the internal capsule and ventral pons of baboons anaesthetised with alpha-chloralose. Changes in conduction time and amplitude of the motor volley were monitored over this PT segment as it was subjected to progressive ischaemia in controlled stages. Conduction time increased significantly, with attenuation of the volley, at average brain-stem tissue flows below 30 ml/100 g/min. Using paired stimuli, we demonstrated relative refractory and supernormal characteristics of PT conduction. In mild ischaemia, the conduction time of the test response decreased, much more than with single stimulation, and in denser ischaemia it increased, relatively more so at smaller inter-stimulus intervals. The data demonstrate the impairment of conduction in a population of CNS axons with reduced local blood flow and indicate that the transmission of relatively rapid sequences of impulses would be the first aspect of conduction to suffer in ischaemia prior to conduction block.

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Experiments have been performed to produce localized thalamic ischaemia in baboons anaesthetised with alpha-chloralose. Somatosensory evoked potentials to median nerve stimulation were recorded in the medial lemniscus, VPL of thalamus and the primary somatosensory cortex. Local blood flow was also recorded by the hydrogen clearance technique in these regions. The early potential recorded in thalamus has been shown to be generated from 3 sources: (i) a positivity generated outside the VPL, (ii) local wavelets, most likely from synaptic activity close to the recording electrode, and (iii) a local overall negativity. The first of these potentials alone remains after thalamic ischaemia. It arises below the level of the thalamus, being very likely generated by the afferent volley in the medial lemniscus, and is seen in the surface-recorded response as the early component P8 (corresponding to P15 in the human).

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