A fundamental question about human memory is which brain structures are involved, and when, in transforming experiences into memories. This experiment sought to identify neural correlates of memory formation with the use of intracerebral electrodes implanted in the brains of patients with temporal lobe epilepsy. Event-related potentials (ERPs) were recorded directly from the medial temporal lobe (MTL) as the patients studied single words. ERPs elicited by words subsequently recalled in a memory test were contrasted with ERPs elicited by unrecalled words. Memory formation was associated with distinct but interrelated ERP differences within the rhinal cortex and the hippocampus, which arose after about 300 and 500 milliseconds, respectively. These findings suggest that declarative memory formation is dissociable into subprocesses and sequentially organized within the MTL.
Studies in rodents and nonhuman primates have linked the activity of N-methyl-D-aspartate (NMDA) receptors within the hippocampus to animals' performance on memory-related tasks. However, whether these receptors are similarly essential for human memory is still an open question. Here we present evidence suggesting that hippocampal NMDA receptors, most likely within the CA1 region, do participate in human verbal memory processes. Words elicit a negative event-related potential (ERP) peaking around 400 ms within the anterior mesial temporal lobe (AMTL-N400). Ketamine, an NMDA-receptor antagonist, reduces the amplitude of the AMTL-N400 (in contrast to other hippocampal potentials) on initial presentation, eliminates the typical AMTL-N400 amplitude reduction with repetition, and leads to significant memory impairment. Of the various hippocampal subfields, only the density of CA1 neurons correlates with the word-related ERPs that are reduced by ketamine. Altogether, our behavioral, anatomical, and electrophysiological results indicate that hippocampal NMDA receptors are involved in human memory. L ong-term potentiation (LTP) is a long-lasting increase in synaptic efficacy after high-frequency stimulation of afferent fibers. It depends on high levels of postsynaptic calcium. The primary source of the calcium influx during the induction of hippocampal LTP occurs through an ion channel that is coupled to the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor (1, 2). NMDA receptors are thus hypothesized to play a crucial role in the induction of associative LTP within the hippocampal CA1-region (3); this is viewed as a putative mechanism for Hebbian learning. This form of synaptic plasticity has been offered as a cellular model of memory processes in hippocampal slice preparations (4). Numerous studies in rodents and primates have linked hippocampal LTP with spatial learning and memory (5) although there are some contradictory results (6).NMDA receptors are also abundant within the human hippocampus (14, 15). NMDA receptor antagonists block LTP induction in surgically resected specimens from the human temporal cortex (16). The human mesial temporal lobe system is considered essential for declarative memory (7, 8), contributing to both encoding and retrieval (9-13). Despite the suggestive findings of animal studies, however, the question of whether hippocampal NMDA receptors contribute to human memory processes remains unsettled.The occasional need to place depth electrodes within the mesial temporal lobes during the presurgical evaluation of patients with pharmacoresistant temporal lobe epilepsy affords us the opportunity to record depth potentials directly from the human hippocampal formation. Analyses of limbic event-related potentials (ERPs) can contribute to the presurgical workup with respect to both the lateralization of the epileptogenic focus (17-19) and the prediction of surgical outcome (20,21). Limbic ERPs also offer unique opportunities for investigating the relationship between hippocampal structures ...
Surgical removal of the dominant medial temporal lobe regions runs a considerable risk of verbal memory deficits which may be compensated for postoperatively by corresponding regions in the non-dominant medial temporal lobe. We examined this possibility by recording event-related potentials (ERPs) to words from the medial temporal lobes of patients with left-sided temporal lobe epilepsy (TLE) undergoing presurgical evaluation. N400 amplitudes in the right anterior medial temporal lobe predicted the postoperative verbal recall performance of individual patients with surprising accuracy, indicating that intracranial recordings can be used to quantify the functional capacities of the right hemisphere that can compensate for the verbal memory deficits after loss of medial temporal lobe structures in the left hemisphere.
Limbic P300 potentials can be recorded within the mesial temporal lobes of patients with temporal lobe epilepsy (TLE). To delineate possible mechanisms of their generation and pathological alteration, we analysed limbic P300s in 55 TLE patients with and 29 without Ammon's horn sclerosis (AHS) and correlated their amplitudes with neuronal cell counts in 30 histopathological specimens. Limbic P300 amplitudes were reduced on the side of the epileptogenic focus only in patients with AHS. Moreover, in AHS patients, limbic P300 latencies were prolonged bilaterally; and in patients with left-sided AHS, amplitudes were reduced bilaterally. Both findings suggest bilateral functional deficits in TLE with unilateral AHS. Limbic P300 areas correlated significantly with neuronal densities of dentate gyrus granule cells but not hippocampal pyramidal cells in the CA1-4 (cornu ammonis) subfields. This finding points to a potential mechanism for the bilateral effects of unilateral AHS as both dentate gyri exhibit strong reciprocal contralateral connectivity.
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