Surgical resection for intractable epilepsy in "double cortex" syndrome yields inadequate results.

PURPOSE: To analyze the results of surgical treatment of intractable epilepsy in patients with subcortical band heterotopia, or double cortex syndrome, a diffuse neuronal migration disorder. METHODS: We studied eight patients (five women) with double cortex syndrome and intractable epilepsy. All had a comprehensive presurgical evaluation including prolonged video-EEG recordings and magnetic resonance imaging (MRI). RESULTS: All patients had partial seizures, with secondary generalization in six of them. Neurologic examination was normal in all. Three were of normal intelligence, and five were mildly retarded. Six patients underwent invasive EEG recordings, three of them with subdural grids and three with stereotactic implanted depth electrodes (SEEG). Although EEG recordings showed multilobar epileptic abnormalities in most patients, regional or focal seizure onset was recorded in all. MRI showed bilateral subcortical band heterotopia, asymmetric in thickness in three. An additional area of cortical thickening in the left frontal lobe was found in one patient. Surgical procedures included multiple subpial transections in two patients, frontal lesionectomy in one, temporal lobectomy with amygdalohippocampectomy in five, and an additional anterior callosotomy in one. Five patients had no significant improvement, two had some improvement, and one was greatly improved. CONCLUSION: Our results do not support focal surgical removal of epileptogenic tissue in patients with double cortex syndrome, even in the presence of a relatively localized epileptogenic area.

From healthy aging to early Alzheimer's disease: in vivo detection of entorhinal cortex atrophy.

Using quantitative structural MRI protocols, we examined the effects of age on alterations in entorhinal cortex (EC) volume. The left EC was found to be smaller than the right in both young and healthy aged subjects. More importantly, the right EC, but not the left, was significantly smaller in elderly participants compared to young controls. In an attempt to determine the earliest sites of involvement in mild and incipient Alzheimer's disease (AD), we compared entorhinal and hippocampal volume in (1) healthy elderly controls, (2) patients with very mild AD, and (3) elderly patients who were evaluated for cognitive complaints, but did not meet criteria for dementia. Both patient groups differed from controls in EC volume, but not from each other. In contrast, the two patient groups differed in hippocampal volume from controls, as well as from each other, with the mild AD cases showing the greatest atrophy. These results suggest that degeneration of the EC and hippocampal formation occurs before the onset of overt dementia. In fact, follow-up clinical evaluations available on 23 of 28 nondemented patients indicated that 12 of 23 had converted to AD. Converters could be best differentiated from nonconverters on the basis of entorhinal volume.

Hemispheric differences in hippocampal volume predict verbal and spatial memory performance in patients with Alzheimer's disease.

Atrophy of the hippocampal formation, a region important for the acquisition of new declarative knowledge, has been well-documented in Alzheimer's disease (AD), although the relation of such atrophy to the extent of memory dysfunction in these patients has been less clear. In the present study, 18 patients with a clinical diagnosis of probable AD were studied with a high-resolution, quantitative magnetic resonance imaging (MRI) protocol, as well as the verbal and spatial versions of the Buschke controlled learning task. The volumes of the hippocampal formation and, as a control for generalized atrophy, parahippocampal gyrus and temporal neocortex were computed from gapless coronal slices taken perpendicular to the long axis of the hippocampus. To correct for individual differences in brain size, volumes of regions of interest were divided by total intracranial volume. Separate stepwise regression analyses (with age, right and left hippocampal, parahippocampal gyrus, and temporal lobe volumes as the independent variables) showed that left hippocampal volume was the best predictor of free recall and delayed free recall of verbal information (P = 0.0042 and P < 0.0001, respectively). Recall and delayed recall of the spatial location of verbal items were best predicted by right hippocampal volume (P = 0.0054 and P = 0.0118, respectively). Memory scores did not correlate either with parahippocampal gyrus or temporal lobe volume. Furthermore, the relation between hippocampal volume and memory function observed in cases with AD did not hold for healthy aged control subjects.

Landau-Kleffner syndrome. Treatment with subpial intracortical transection.

Landau-Kleffner syndrome (LKS) is an acquired epileptic aphasia occurring in childhood and associated with a generally poor prognosis for recovery of speech. It is thought to be the result of an epileptogenic lesion arising in speech cortex during a critical period of development. Utilizing a new surgical technique designed to eliminate the capacity of cortical tissue to generate seizures while preserving the normal cortical physiological function, we have treated 14 children with aphasia, seizures and a severely abnormal EEG by multiple subpial transection of the epileptogenic cortex. Seven of the 14 patients (50%) have recovered age-appropriate speech, are in regular classes in school and no longer require speech therapy. Four of the 14 (29%) have shown marked improvement, are speaking and understanding verbal instruction but are still receiving speech therapy. Thus, 11 of the 14 (79%), none of whom had used language to communicate for at least 2 years, are now speaking--a rate of sustained improvement considered unusual in this disorder. This study documents the value of a treatment modality not previously used in LKS. Success depends on selection of cases having severe epileptogenic abnormality that can be demonstrated to be unilateral in origin despite a bilateral electrographic manifestation.

Synapses on dendritic shafts exhibit a perforated postsynaptic density.

Synapses on dendritic shafts were examined in electron micrographs of serial sections obtained from the molecular layer of the rat dentate gyrus. Some of these synapses have been found to exhibit profiles of a discontinuous postsynaptic density (PSD). PSD reconstructions from serial sections were performed in a plane perpendicular to that of the sections. The results obtained indicate that profiles of discontinuous PSDs observed in random sections of dendritic shaft synapses are generated by sectioning of PSD plates that contain 1-3 holes or perforations. Earlier serial section studies of osmicated material have demonstrated that a proportion of axospinous synapses also exhibit a perforated PSD. It appears, therefore, that the presence of PSD perforations is a general phenomenon shared by subpopulations of different types of synapses, both those involving dendritic shafts and those involving dendritic spines.

Axospinous synapses with segmented postsynaptic densities: a morphologically distinct synaptic subtype contributing to the number of profiles of 'perforated' synapses visualized in random sections.

Axospinous synapses were examined in the molecular layer of the rat dentate gyrus. Serial section analysis of synapses, which exhibited a discontinuity of the postsynaptic density (PSD) in at least one consecutive section, was performed. Reconstruction of each discontinuous PSD was made in a plane perpendicular to that of serial sections. The results obtained confirm earlier observations that profiles of 'perforated' synapses visualized in random sections of osmicated material are produced by sectioning of synapses with perforated and horseshoe-shaped PSDs. Additionally, it has been found that two other synaptic subtypes, namely synapses with notched and segmented PSD, contribute to the number of profiles of 'perforated' synapses. Synaptic contacts with notched PSD are characterized by an indentation of an otherwise continuous PSD, relatively small dimensions and simple shape. They appear to be unrelated to the category of synapses with discontinuous PSD. Synaptic contacts with segmented PSD are distinguished by the presence of 2-5 discrete PSD segments at the interface between a presynaptic axon terminal and a postsynaptic dendritic spine. Some PSD segments exhibit 1-3 perforations, while others are horseshoe-shaped. It is postulated that the segmented PSD may evolve through the stages of perforated and horseshoe-shaped PSD to form a specialized synaptic contact of an unusually high efficacy. Every PSD segment is a component of a separate synaptic complex, each one comparable to that of a small, simple-shaped synapse. A concerted activation of several synaptic complexes belonging to a single synaptic junction may provide a mechanism for an amplification of synaptic transmission.

Aged rats need a preserved complement of perforated axospinous synapses per hippocampal neuron to maintain good spatial memory.

Spatial working memory, which crucially depends on the structural integrity of the hippocampal formation and its afferent connections, is impaired in the most, but not all, of aged rats. This study was designed to verify whether aged animals that do not exhibit the spatial memory deficit are the ones in which the hippocampal synaptic connectivity remains preserved with advancing chronological age. Young adult rats with good spatial memory, aged rats with impaired spatial memory and equally aged rats with intact spatial memory were compared. The number of synapses per neuron was estimated in the hippocampal dentate gyrus. The most important results were obtained when axospinous synapses were divided into perforated and non-perforated ones according to the appearance of their postsynaptic density. A significant decrease in the number of perforated synapses was found in memory-impaired aged rats as compared to either young adults or aged animals without memory deficits. The number of non-perforated synapses per neuron was diminished in memory-deficient aged rats relative to young adults, but not to memory-intact aged rats. However, it was only the loss of perforated synapses which correlated with the degree of spatial memory impairment. Thus, aged rats need a preserved complement of hippocampal perforated synapses to maintain good spatial memory.

Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats.

Most, but not all, aged rats exhibit a profound deficit in spatial memory when tested in a radial maze--a task known to depend on the integrity of the hippocampal formation. In this study, animals were divided into three groups based on their spatial memory capacity: young adult rats with good memory, aged rats with impaired memory, and aged rats with good memory. Memory-impaired aged animals showed a loss of perforated axospinous synapses in the dentate gyrus of the hippocampal formation in comparison with either young adults or aged rats with good memory. This finding suggests that the loss of perforated axospinous synapses in the hippocampal formation underlies the age-related deficit in spatial memory.

Age-dependent deficits in spatial memory are related to impaired hippocampal kindling.

Fischer 344 rats, 3 and 26 months of age, were first tested in an eight-arm spatial maze to assess memory function behaviorally. The same animals were then subjected to hippocampal kindling to examine alterations in neuronal plasticity as a function of aging. The results indicated that spatial memory was poorer and hippocampal kindling slower in aged rats than in young ones. Furthermore, there was a striking positive relation between performance in the eight-arm spatial maze and speed of kindling. This finding suggests that age-related deficits in spatial memory and hippocampal kindling reflect decreased efficacy of synaptic transmission in a common neuroanatomical substrate.

Pentoxifylline reverses age-related deficits in spatial memory.

Pentoxifylline, a phosphodiesterase inhibitor, produces a marked reversal of an age-dependent spatial memory deficit in Fischer 344 strain male rats. Performance of 26-month-old animals treated chronically with pentoxifylline approached that of 3-month-old controls. The effect was not dependent upon concurrent administration of the acetylcholine precursor choline chloride. It is concluded that the pentoxifylline-induced reversal of the age-dependent memory decline is not dependent on any presumed facilitation of acetylation and utilization of exogenously supplied transmitter substrate.

Conditioning of single units in visual association cortex: cell-specific behavior within a small population.

These experiments examine the interrelationships between the activity of adjacent neurons during learning. Does learning depend on coherent behavior in a population of neurons or does it depend on particular neurons engaging in a particular activity at specific times? A second purpose was to examine specificity in response modification as a function of reinforcement contingency. Cells from visual association cortex of locally anesthetized, paralyzed cats and rabbits were studied with extracellular microelectrodes capable of recording single and multiunit activity, as well as local field potentials. Multiunit records were fractionated by amplitude "windows" discrimination. Pavlovian discriminative conditioning procedures were used to evaluate selective plasticity. Cells that were activated by at least two different visual stimuli were selected. Only one of the effective stimuli was paired with foot-shock (reinforcement). Of the 180 cells or cell clusters studied, 27% exhibited conditioned modification to the reinforced stimulus (CS+) and 19% changed their response pattern to the unreinforced stimulus (CS-). None of the well isolated cells showed conditioning to both CS+ and CS-. Thus, cellular plasticity was specific to reinforcement contingency. These results provide a first demonstration of reinforcement-dependent functional distinctiveness at the neuronal level. Some cells showed no alteration of response pattern despite a most prolonged conditioning procedure. Neighboring cells, responsive to the same stimuli, revealed increases or decreases in firing rate, selective changes in the latency or amplitude of single response peaks, or the appearance of one or more new peaks as a function of conditioning. Rarely did adjacent cells show the same type of alteration when alteration occurred; there was no general tendency toward coherent firing patterns as conditioning proceeded.

Conditioned inhibition: selective response of single units.

Single cell activity and local field potentials in parastriate cortex of cats and rabbits were studied during a Pavlovian discrimination procedure. Cell activity was selectively modified; conditioned changes occurred in response either to the reinforced stimulus or to the unreinforced one, but not to both. Cells exhibiting conditioned alteration in response to the unreinforced stimulus are thought to participate in specialized circuits mediating conditioned inhibition.