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The loss of dopamine in idiopathic or animal models of Parkinson's disease induces synchronized low-frequency oscillatory burst-firing in subthalamic nucleus neurones. We sought to establish whether these firing patterns observed in vivo were preserved in slices taken from dopamine-depleted animals, thus establishing a role for the isolated subthalamic-globus pallidus complex in generating the pathological activity. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) showed significant reductions of over 90% in levels of dopamine as measured in striatum by high pressure liquid chromatography. Likewise, significant reductions in tyrosine hydroxylase immunostaining within the striatum (>90%) and tyrosine hydroxylase positive cell numbers (65%) in substantia nigra were observed. Compared with slices from intact mice, neurones in slices from MPTP-lesioned mice fired significantly more slowly (mean rate of 4.2 Hz, cf. 7.2 Hz in control) and more irregularly (mean coefficient of variation of inter-spike interval of 94.4%, cf. 37.9% in control). Application of ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2-amino-5-phosphonopentanoic acid (AP5) and the GABA(A) receptor antagonist picrotoxin caused no change in firing pattern. Bath application of dopamine significantly increased cell firing rate and regularized the pattern of activity in cells from slices from both MPTP-treated and control animals. Although the absolute change was more modest in control slices, the maximum dopamine effect in the two groups was comparable. Indeed, when taking into account the basal firing rate, no differences in the sensitivity to dopamine were observed between these two cohorts. Furthermore, pairs of subthalamic nucleus cells showed no correlated activity in slices from either control (21 pairs) or MPTP-treated animals (20 pairs). These results indicate that the isolated but interconnected subthalamic-globus pallidus network is not itself sufficient to generate the aberrant firing patterns in dopamine-depleted animals. More likely, inputs from other regions, such as the cortex, are needed to generate pathological oscillatory activity.

In Parkinson's disease the neurones of the subthalamic nucleus show increased synchrony and oscillatory burst discharge, thought to reflect a breakdown of parallel processing in basal ganglia circuitry. To understand better the mechanisms underlying this transition, we sought to mimic this change in firing pattern within sagittal slices of rat midbrain. The firing patterns of up to four simultaneously extracellularly recorded subthalamic nucleus (STN) neurones were analysed using burst and oscillation detection programs, and correlated activity between pairs of neurones assessed. In control conditions all but 11 of 488 (2%) neurones fired in a predominantly tonic pattern (with mean oscillation frequency >3 Hz), with no significantly cross-correlated activity in any of 393 pairs of neurones. The glutamate antagonists DL-2-amino-phosphonopentanoic acid (APV), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6-methyl-2-(phenylethynyl)pyridine (MPEP) did not change the firing rate or pattern of these cells, providing no evidence for a role of glutamatergic collaterals within the STN under these conditions. The GABA(A) receptor antagonist bicuculline and GABA(B) receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl]phenylmethyl phosphinic acid (CGP 55845) were also without effect on firing rate or pattern in these cells, suggesting that there was no active input from other GABAergic basal ganglia nuclei in this slice. The dopamine receptor antagonist haloperidol caused no significant change to firing rate or pattern of firing in these cells, suggesting that there was no active dopaminergic input in this slice. Excitations of STN neurones by muscarine, (+)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD), N-methyl-D-aspartic acid (NMDA) or dopamine were all unaccompanied by a change in firing pattern or any significant correlated activity between STN neurone pairs. Burst firing could be induced in STN neurones with either the potassium channel blocker tetraethylammonium (TEA; 10 mM; in 100/138 [72%] of cells) or with a combination of NMDA and the calcium-activated potassium channel blocker apamin (in 101/216 [47%] of cells). Burst firing in TEA was unchanged by CNOX and APV, MPEP, CGP55845, haloperidol, dopamine, and ACPD, although muscarine produced a significant increase in oscillation frequency. Burst firing in NMDA and apamin was unchanged by CNQX and APV, dopamine, muscarine and ACPD, although bicuculline caused a significant increase in oscillation frequency. Such burst firing was not accompanied by synchrony in any condition, either alone, or during application of excitatory agents or glutamate or GABA antagonists. As the bursting seen here was unaccompanied by the synchronous activity that has often been observed (pathologically) in vivo, it probably reflects solely intrinsic STN neuronal properties, rather than network activity. No functional role was found for glutamatergic collaterals within the STN, either when cells are firing tonically or burst firing. The circuitry needed to produce synchrony in the STN is most likely not intrinsic to the STN itself, but requires connections with other basal ganglia nuclei, and/or the cortex, which are not present in this preparation.

What is the neuronal basis for whether an experience is recalled or forgotten? In contrast to recognition, recall is difficult to study in nonhuman primates and rarely is accessible at the single neuron level in humans. We recorded 128 medial temporal lobe (MTL) neurons in patients implanted with intracranial microelectrodes while they encoded and recalled word paired associates. Neurons in the amygdala, entorhinal cortex, and hippocampus showed altered activity during encoding (9%), recall (22%), and both task phases (23%). The responses of hippocampal neurons during encoding predicted whether or not subjects later remembered the pairs successfully. Entorhinal cortex neuronal activity during retrieval was correlated with recall success. These data provide support at the single neuron level for MTL contributions to encoding and retrieval, while also suggesting there may be differences in the level of contribution of MTL regions to these memory processes.

Monitoring physiological changes in the brain parenchyma has important applications in the care of neurosurgical patients. A technique is described for measuring extracellular neurochemicals by cerebral microdialysis with simultaneous recording of electroencephalographic (EEG) and single-unit (neuron) activity in selected targets in the human brain. Forty-two patients with medically intractable epilepsy underwent stereotactically guided implantation of a total of 423 intracranial depth electrodes to delineate potentially resectable seizure foci. The electrodes had platinum alloy contacts for EEG recordings and four to nine 40-microm microwires for recording single-unit neuron activity. Eighty-six electrodes also included microdialysis probes introduced via the electrode lumens. During monitoring on the neurosurgical ward, electrophysiological recording and cerebral microdialysis sampling were performed during seizures, cognitive tasks, and sleep-waking cycles. The technique described here could be used in developing novel approaches for evaluation and treatment in a variety of neurological conditions such as head injury, subarachnoid hemorrhage, epilepsy, and movement disorders.

The hippocampus and its associated structures play a key role in human memory, yet the underlying neuronal mechanisms remain unknown. Here, we report that during encoding and recognition, single neurons in the medial temporal lobe discriminated faces from inanimate objects. Some units responded selectively to specific emotional expressions or to conjunctions of facial expression and gender. Such units were especially prevalent during recognition, and the responses depended on stimulus novelty or familiarity. Traces of exposure to faces or objects were found a few seconds after stimulus removal as well as 10 hr later. Some neurons maintained a record of previous stimulus presentation that was more accurate than the person's conscious recollection. We propose that the human medial temporal lobe constructs a "cognitive map" of stimulus attributes comparable to the map of the spatial environment described in the rodent hippocampus.

1. Synchronous interactions between neurons in mesial temporal structures of patients with complex partial seizures were studied using cross-correlation analyses. We recorded spontaneous activity from 293 neurons in 24 patients during the interictal state. Patients had depth microelectrodes chronically implanted in amygdala, hippocampal formation, and parahippocampal gyrus to record epileptic activity. One hundred twenty-five cells were recorded from the temporal lobe commonly initiating seizures (ipsilateral temporal lobe), and 168 cells from the contralateral temporal lobe. Eight hundred forty-three cross-correlograms were constructed between all pairs of simultaneously recorded neurons. Cross-correlogram peaks or troughs that exceeded confidence limits within 200 ms of the origin were considered evidence of synchronous neuronal interaction. 2. Synchronous neuronal interactions were observed in 223 of 843 cross-correlograms. Eighty-six percent of these 223 cross-correlograms showed significant central peaks (peak interactions), suggesting excitatory interactions, whereas the remainder displayed significant central troughs (trough interactions), suggesting inhibitory interactions. 3. Cross-correlograms constructed using cells from the ipsilateral temporal lobe (ipsilateral cross-correlograms) were more likely to display significant central troughs (14/262) than cross-correlograms constructed using cells from the contralateral temporal lobe (6/376; contralateral cross-correlograms). Similarly, cross-correlograms constructed using one cell from each hemisphere (11/205; bilateral cross-correlograms) were also more likely to display significant central troughs (trough interactions) than contralateral cross-correlograms. Both ipsilateral (77/262) and contralateral cross-correlograms (102/376) were more likely to display significant central peaks (peak interactions) than bilateral cross-correlograms (13/205). 4. Cells from different structures in the ipsilateral temporal lobe were more likely to display significant trough interactions (10/ 114) than neurons in different contralateral structures. We also compared the proportion of significant peak interactions between cells within the ipsilateral and contralateral sides of each structure. Neurons in the contralateral entorhinal cortex were more likely to show peak interactions (21/55) than cells from the ipsilateral entorhinal cortex (3/31). Also, cells in the ipsilateral presubiculum showed a higher proportion of peak interactions (9/16) than their contralateral homologues (5/30). 5. Neuronal burst discharges were defined as three or more action potentials (or spikes) separated by interspike intervals of < or = 30 ms, or two spikes separated by an interval of < or = 15 ms. The contribution of burst discharge to synchronous peak interaction was compared between temporal lobes. Cells used to construct ipsilateral cross-correlograms displaying significant central peaks (n = 154) were found to have significantly reduced burst discharge contributions to the observed synchronous peaks in comparison with their contralateral homologues (n = 204). When cross-correlograms were separated by regions, burst discharge contributions to synchronous peak interactions between cells in the ipsilateral hippocampus (n = 72) were significantly smaller than the contributions from cells in the contralateral hippocampus (n = 44). 6. The results suggest that in the interictal state, synchronous neuronal burst discharge is not a distinguishing feature of epileptogenic regions of patients with complex partial seizures, but inhibitory neuronal interactions are increased in regions of seizure initiation. Increases in the strength and spread of local inhibition in seizure initiating regions in these patients may result in a greater proportion of inhibitory interactions and could also cause increased synchrony between isolated action potentials.(ABSTRACT TRUNCATED)

We recorded 259 single neurons from mesial temporal lobe structures of 21 patients with complex partial seizures. Interspike intervals within clusters of action potentials (clustered interspike intervals) recorded from cells in mesial temporal structures ipsilateral to seizure initiation were compared to clustered interspike intervals in the contralateral temporal lobe. 'Clusters' were defined as any group of three or more spikes separated by intervals of less than a defined maximum, or two spikes separated by less than half that maximum. The maximum interspike interval which defined a cluster was varied from 5 to 40 ms in 5-ms steps. Significantly smaller proportions of clustered spikes were discharged by neurons in the amygdala, hippocampus and entorhinal cortex from the temporal lobe commonly initiating seizures, compared to neurons in contralateral homotopic regions. When data from the same three structures were combined, significantly fewer cluster interspike intervals between 10 and 25 ms were recorded from cells on the side of seizure onset. Because clustered action potential discharge is a normal pattern of firing for cells that discharge endogenous bursts, the relative decrease in proportions of 10-25 ms clustered interspike intervals occurring in the temporal lobe initiating seizures might reflect a reduction in endogenous burst discharges from that side. Reduced endogenous bursting could be due to the loss of burst discharging neurons as a product of seizure-related excitotoxicity. The identification of decreased interictal single neuronal burst discharge in epileptogenic structures stresses the difference between the interictal and ictal states in patients with complex partial seizures, and the importance of the transition between those states.

Connections in the human mesial temporal lobe were investigated using brief, single pulses of electrical stimulation to evoke field potential responses in limbic structures of 74 epileptic patients. Eight specific areas within these structures were stereotactically targeted for study, including amygdala, entorhinal cortex, presubiculum, the anterior, middle and posterior levels of hippocampus and the middle and posterior levels of parahippocampal gyrus. These sites were studied systematically in order to quantitatively assess the response characteristics and reliability of responses evoked during stimulation of pathways connecting the areas. Specific measures included response probability, amplitude, latency and conduction velocities. The results are assumed to be representative of typical human limbic pathways since all recordings were made interictally and response probabilities across sites were not found to differ significantly between non-epileptogenic vs. identified epileptogenic regions. Field potentials ranging in amplitude from less than 0.1 to greater than 6.0 mV were evoked ipsilaterally, with mean onset latencies and conduction velocities ranging from 4.4 ms and 3.64 m/s in the perforant pathway connecting entorhinal cortex to anterior hippocampus to 24.8 ms and 0.88 m/s in the pathway connecting the amygdala and middle hippocampus. Stimulation of presubiculum and entorhinal cortex were most effective in evoking widespread responses in adjacent limbic recording sites, whereas posterior parahippocampal gyrus appeared functionally separated from other limbic sites since its probability of influencing ipsilateral sites was significantly lower than any other area. It was particularly noteworthy that stimulation did not evoke responses in any sites in contralateral hippocampal formation; even though a large number of sites were tested with bilateral implantation of homotopic electrodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Firing periodicity was examined in human hippocampal neurons using autocorrelation analysis. Extracellular single-unit activities were recorded from the anterior hippocampus through fine platinum microelectrodes, and the typical firing pattern in an entire recording period was reconstructed statistically in autocorrelograms (average number of firings analyzed: 5639.0 +/- 968.1 SE, range: 1158 to 31,203; number of single-unit trains was 57). Three types of periodic firing were identified as highly consistent. The first pattern consisted of a random recurrence of high-frequency action potentials (100 to 300 Hz) and was observed as an intermittent burst. In this burst, the first 10 to 30 ms after the onset of the burst was the patterned firing of several action potentials, suggesting that the generation of this stereotyped portion of the burst is primarily due to intrinsic membrane characteristics. The second pattern was the continuous rhythmical firing with a lower frequency ranging from 1 to 30 Hz. The third pattern was a clustered rhythmical firing in which a series of short rhythmical firings recurred with regular intervals; the frequency of short rhythmical firing varied from 6.7 to 17 Hz between neurons, and the interval of the regular recurrence of these rhythmical firings ranged from 0.5 to 10 s among neurons. These firing periodicities not only cover a cellular rhythm in the theta frequency reported in the lower mammalian hippocampus but also appear to be more diverse than those previously reported for hippocampal neurons in the animal literature.