Neocortical Changes Research Articles

Neocortical and Hippocampal Changes after Multiple Pilocarpine‐induced Status Epilepticus in Rats

Multiple episodes of pilocarpine-induced status epilepticus (SE) in developing rats (P7-P9) lead to progressive epileptiform activity and severe cognitive impairment in adulthood. The present work studied possible underlying abnormalities in the neocortex and hippocampus of pilocarpine-treated animals. Wistar rats were submitted to pilocarpine-induced SE at P7, P8, and P9, and were killed at P35. Immunocytochemistry was performed on 50-microm vibratome sections, by using antibodies against nonphosphorylated neurofilament (SMI-311), parvalbumin (PV), calbindin (CB), calretinin (CR), and glutamate decarboxylase (GAD-65). Ten-micron cryostat sections were processed for immunohistoblot by using antibodies against GluR1, GluR2/3, and GluR4 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits and NR2ab N-methyl-D-aspartate (NMDA) receptor subunit. Adult rats submitted to SE at P7-9 showed: (a) altered distribution of neocortical interneurons; (b) increased cortical and reduced hippocampal GAD-65 expression; and (c) altered expression of hippocampal AMPA and NMDA receptors. We conclude that multiple SE episodes during P7-9 generate long-lasting disturbances that underlie behavioral and electrographic abnormalities later in life.

In vivo study of acetylcholine esterase in basal forebrain, amygdala, and cortex in mild to moderate Alzheimer disease

It is currently unclear whether impairment of the cholinergic system is present in Alzheimer disease (AD) already at an early stage and to what extent it depends on degeneration of the nucleus basalis of Meynert (nbM). We examined acetylcholine esterase activity in vivo in the nbM, the amygdala, and cerebral neocortex. Measurements were performed in normal controls and in patients with mild to moderate AD with positron emission tomography (PET) and C-11-labeled N-methyl-4-piperidyl-acetate (MP4A) which is a specific substrate of AChE. AChE activity was reduced significantly in amygdala and cerebral cortex. In contrast, AChE activity and glucose metabolism appeared preserved or even increased in the nbM. The results support the concept that neocortical and amygdaloid functional changes of the cholinergic system are an early and leading event in AD, rather than the consequence of neurodegeneration of basal nuclei.

A longitudinal study of brain morphometrics using quantitative magnetic resonance imaging and difference image analysis

Serial quantitative magnetic resonance imaging (MRI) allows the detection of subtle volumetric changes in brain volume. We used serial volumetry and voxel-based difference image analysis to quantify and characterize longitudinal changes in the hippocampus, cerebellum, and neocortex in younger and middle-age individuals. Paired volumetric MRI brain scans 3.5 years apart were performed on 90 healthy subjects 14 to 77 years old. Quantitative assessment of registered images included hippocampal volumetry, cerebellar volumetry, and automatically determined regional brain volumes. Longitudinal volume changes in three age epochs (<35, 35–54, >54 years) were compared and neocortical changes beyond regions of interest were visualized using filtered difference images. Cross-sectional analysis revealed a significant association between age and reduction in all brain volumes except hippocampal volume. Changes in normalized hippocampal and white matter volume were significantly different among the three groups. Individual analysis revealed 5 subjects with significant longitudinal volume changes lying outside the normative range. Difference image analysis showed global involutional changes in the >54 age group. Our findings suggest that cross-sectional observations in intracranial volume, cerebellar volume, and gray matter volume are likely to reflect uniform rates of volume loss or secular changes. Accelerated brain atrophy was seen from the age of 35–54 and increased rates of hippocampal atrophy from the age of 54. Our findings emphasize the importance of controlling for age effects when studying pathological brain changes over a wide age range.

MRI studies. Do seizures damage the brain?

Methods to assess the development of cerebral damage need to be quantitative, reliable, reproducible and safe. They must be acceptable to patients and to a healthy control group, for repeated use and the acquisition and analytical methods must be stable over years. Longitudinal studies are necessary to determine whether secondary cerebral damage occurs as a consequence to the epilepsies. The principal aim of longitudinal studies is to detect physical evidence of brain damage when it occurs. Patient groups will be heterogeneous in this regard and analysis will need to be not only of changes in group means, but also of the number of patients who show significant changes in imaging parameters, that exceed the limits of test-retest reliability. MRI is attractive as a tool to evaluate the presence and development of cerebral damage in patients with epilepsy. MRI is readily available and non-invasive, making it acceptable to patients and controls. MRI volumetry is reliable and reproducible, but the sensitivity of the method to detect subtle abnormalities has not yet been established. Longitudinal studies are ongoing in patients with newly diagnosed and chronic epilepsy, with an inter-scan interval of 3.5 years, using complementary voxel-based and region-based methods that can detect changes in hippocampal and cerebellar volumes of 3% and neocortical volume changes of 1.6%. MR spectroscopy may be more sensitive for detecting abnormalities, but the test-retest reliability is less good. Other MRI tools, such as diffusion tensor imaging, may be useful methods for evaluating secondary cerebral damage acutely and chronically.

Temporal lobe epilepsy: a clinicopathological study with special reference to temporal neocortical changes.

The number of patients undergoing surgical treatment for pharmacoresistant temporal lobe epilepsy is rapidly increasing. While there have been many clinicopathological studies concerning the medial structures of the temporal lobe in temporal lobe epilepsy, its lateral structures have received little attention. To examine the nature and frequency of lateral temporal lobe abnormalities that occur in temporal lobe epilepsy, 22 patients who underwent standard anterior temporal lobectomy with hippocampectomy for intractable temporal lobe epilepsy were studied. The mean ages at the onset of seizure and at surgery were 15.9 years and 27.7 years, respectively. The electroclinically determined epileptogenic zones were the medial structures of the temporal lobe in 16 patients and the lateral in six. There was histologic evidence of hippocampal sclerosis in 12 of the 16 patients with medial onset seizures and in three of the six patients with lateral onset seizures. The lateral structures of the temporal lobe showed variable degrees of histological abnormalities in 21 patients. Among these abnormalities, heterotopic white matter neurons were observed in six of the 16 medial patients and in all the lateral patients. Glial changes were also common abnormalities, and often glial fibrillary acidic protein (GFAP)-positive astrocytes were present over the entire temporal lobe. In addition to hippocampal sclerosis, cerebral microdysgenesis and gliosis in the lateral structures of the temporal lobe may have a significant role in epileptogenesis of temporal lobe epilepsy.

Morphometric analysis of the temporal lobe in temporal lobe epilepsy.

Using high-resolution magnetic resonance imaging (MRI), we examined the temporal neocortex and the underlying white matter in patients with unilateral temporal lobe epilepsy (TLE) and in control subjects. The images of 27 patients and 42 control subjects were registered into stereotaxic space, corrected for image intensity inhomogeneity, and automatically segmented into gray matter, white matter, and cerebrospinal fluid (CSF) over a predetermined extent of the temporal lobe. The surface between the gray matter and CSF was extracted, indices of curvature (IOC) of the surface were calculated, and a frequency histogram of the IOC was obtained. There was significant bilateral reduction in the total volume of the temporal lobe and in the volume of gray matter. White matter volume was significantly reduced only in the temporal lobe ipsilateral to the seizure focus. There were significant changes in the position and amplitude of peaks in the frequency histogram of the IOC. The volume of gray matter was negatively correlated with duration of epilepsy, suggesting that neocortical changes may be a consequence of seizures. Changes in the frequency histogram of the IOC suggested an additional alteration in the surface morphology of the temporal lobe in TLE, possibly related to sulcal widening.

Neuropathologic Findings in Postmortem Studies of Sudden Death in Epilepsy

Death in patients with epilepsy may occur suddenly and unexpectedly. When no anatomic or chemically demonstrable cause for such a death is found at postmortem examination, the death may remain unexplained. Previous studies of general autopsy features in cases of sudden unexpected death in epilepsy (SUDEP) have reported increased lung and liver weights, pulmonary edema, hepatic fatty change, and small increases in heart weights. Neuropathologic findings include cerebral edema, lighter brain weights compared with age-matched controls, and various other structural brain lesions in 34% to almost 50% of cases. In an ongoing United Kingdom study, brains from 25 cases of SUDEP have been examined. Macroscopic abnormalities were identified in 70% of cases and included contusions, old infarcts, hippocampal sclerosis, cortical dysgenesis, vascular malformation, oligodendroglioma, neurodegenerative brain disease, and microcephaly. Histopathologic findings include evidence of acute neocortical and brainstem hypoxic neuronal changes. Similar changes in hippocampal and basal ganglia neurones have also been observed. These changes indicate a cerebral event occurring at least 4-6 h before death and are at odds with a "sudden" death which, by definition, occurs within 1 h. Because many SUDEP cases are unwitnessed, the exact time sequence of events is often unknown. This study confirms the high incidence of structural brain lesions in SUDEP cases.

Why there are complementary learning systems in the hippocampus and neocortex: insights from the successes and failures of connectionist models of learning and memory.

Damage to the hippocampal system disrupts recent memory but leaves remote memory intact. The account presented here suggests that memories are first stored via synaptic changes in the hippocampal system, that these changes support reinstatement of recent memories in the neocortex, that neocortical synapses change a little on each reinstatement, and that remote memory is based on accumulated neocortical changes. Models that learn via changes to connections help explain this organization. These models discover the structure in ensembles of items if learning of each item is gradual and interleaved with learning about other items. This suggests that the neocortex learns slowly to discover the structure in ensembles of experiences. The hippocampal system permits rapid learning of new items without disrupting this structure, and reinstatement of new memories interleaves them with others to integrate them into structured neocortical memory systems.

Longitudinal study of the early neuropsychological and cerebral metabolic changes in dementia of the Alzheimer type.

To examine the progression of neuropsychologic and metabolic changes in the early stages of dementia of the Alzheimer type (DAT), we studied 11 midly demented patients longitudinally. Three aspects of neuropsychological function were measured: memory, attention to complex sets and abstract reasoning, and lateralized functions, i.e., language and visuoconstruction. Regional cerebral metabolic rates for glucose were measured in frontal, parietal, and temporal association cortices. Our results show that, in general, memory deficits are the first neuropsychological impairments to occur in DAT, followed by problems with attention to complex cognitive sets and abstract reasoning, which are followed in turn by deficits in language and visuospatial abilities. In addition, neocortical metabolic abnormalities usually precede impairment of neocortically mediated attention and abstract reasoning by 8 to 16 months, and precede impairment of neocortically mediated language and visuospatial function by 12 to 37 months. These findings suggest that the first nonmnestic neuropsychological consequence of neocortical physiological dysfunction in DAT is a loss of attentional capacity. Since neocortical metabolic changes generally precede the appearance of neocortically mediated neuropsychological dysfunction, physiologic dysfunction may exist for some time before cognition is affected.

Neuronal changes in the aging mouse: Spinal cord and lower brain stem

In view of the marked changes which we have recently described in the Golgi-stained nerve cell bodies and dendrites of cerebral neocortex in senescent human subjects, we have attempted a similar study of the very old (26 to 30 months) mouse for comparative purposes. Although neocortical changes in this species seemed unimpressive, marked and apparently progressive agerelated changes were found in most neurons of spinal cord and lower brain stem. Early changes included irregular swelling and “lumpiness” of cell bodies and initial portions of the dendrites, followed by increasing nodularization of the dendrite tree and loss of whatever spines or postsynaptic specializations may have been present in the young adult. Zones of constriction along dendrite shafts seemed to result in complete breaks with loss of the distal segment and shrivelling of the proximal segment. Irregularly swollen neurons with “amputation stumps” replacing principle dendrites appeared the penultimate phase before eventual cell loss. The remarkably widespread occurrence of such changes throughout sensory and motor systems is considered in relation to the consequent loss of functional neuropil and the possible embarrassment of coping behavior in the senile mouse.

Effects of various psychotomimetic agents on the eeg and acetylcholine release from the cerebral cortex of brainstem transected cats

The effects of i.v. administration of Δ 9 THC, phencyclidine, the pyrrolidyl and piperidyl isomers of Ditran, and LSD-25 were determined on the spontaneous neocortical EEG and release of acetylcholine (ACh) from the somatosensory cortex of brainstem transected cats. Δ 9 THC was given in doses of 0.5–11 mg kg i.v. to animals with a pretrigeminal midpontine transection. Δ 9 THC produced neocortical high voltage EEG slow waves which were more prominent in the frontal areas of the brain. At the same time, arterial blood pressure and heart rate were reduced slightly. These effects were observable in doses of 0.5 mg kg , but were more obvious at larger doses. The administration of amphetamine promptly antagonized the EEG changes induced by Δ 9 THC. In doses of 0.5 mg kg , Δ 9 THC caused either no effect or a slight increase in the release of ACh from the cortex. Larger doses caused a progressive decrease in ACh release. The effects of Δ 9 THC were antagonized by the administration of (+)-amphetamine in doses of 2.5 mg kg i.v. Phencyclidine in doses of 1 mg kg i.v. caused marked EEG changes consisting of high voltage, slow wave burst patterns, especially in the frontal cortex. At this dose, a slight increase in the cortical release of ACh was observed. Larger doses of 5 mg kg which caused pronounced EEG changes did not significantly depress ACh release in contrast to pentobarbital (20 mg kg ) which dramatically reduced ACh release. Both isomers of Ditran caused EEG slowing in doses of 1 mg kg and a dramatic increase in the release of ACh from the cortex. They produced about a 200% increase in ACh release. In contrast, LSD-25 had no marked effect on ACh release. The effects were much less obvious and depended upon basal release levels. If basal release was low to moderate, LSD-25 in doses of 0.1 mg kg slightly increased ACh release, while larger doses caused no greater increase. If baseline release of ACh was high, the drug decreased release slightly. In such pretrigeminal midpontine transected cats, LSD-25 usually caused EEG high voltage, slow waves, and a decrease in arterial blood pressure. It is concluded that various hallucinogens differentially affect the neocortical release of ACh in pretrigeminal midpontine transected cats. Δ 9 THC caused a definite decrease in ACh release similar to anesthetic agents like pentobarbital. A dissociative anesthetic such as phencyclidine produced negligible effects. The isomers of Ditran caused a marked increased release of ACh while LSD-25 had negligible effects. Gross EEG neocortical changes were not directly correlated with the cortical release of ACh per se.

Hippocampal slow (“arousal”) wave activation in the rostral midbrain transected cat

The neocortical and hippocampal EEG changes of an acute rostral midbrain cat preparation (brain-stem section at the junction of the diencephalon and midbrain) are described. 1. 1. In the neocortex an alternation of very regular, large amplitude slow waves (0.5–1.5 c/sec) without prominent spindle bursts, with irregular high voltage slow waves with repetitive spindle bursts was seen. 2. 2. The hippocampal EEG showed a continuous pattern of irregular fast waves with occasional slow waves. Posterior hypothalamic stimulation elicited hippocampal “arousal” waves (1.5–3.5 c/sec) which lasted from 5 sec to 2 min after the cessation of the stimulus, while the neocortex did not show the EEG desynchronization which could be elicited before transection. Depending upon the intensity of the hypothalamic stimulus and the pattern of background activity before stimulation, the neocortex also showed some change, from slight to marked suppression of slow waves with enhancement of spindle burst. Desynchronization of the neocortex by hypothalamic stimulation was observed only briefly during extremely strong stimuli. 3. 3. Thalamic stimulation elicited phasic desynchronization in the neocortical EEG with a less marked change in the hippocampal EEG, whereas hypothalamic stimulation induced stronger regular slow wave activation in the hippocampus (hippocampal “arousal” waves) with a lesser change in the neocortex. 4. 4. In the classic cerveau isolé preparation, hypothalamic stimulation could elicit brief neocortical desynchronization as well as hippocampal “arousal”. With a more rostral transection (at the junction between diencephalon and mesencephalon), it was very difficult to produce neocortical desynchronization by posterior hypothalamic stimulation which, however, produced marked hippocampal “arousal” waves. 5. 5. It is concluded that for activation of the hippocampus, the hypothalamus is not only the primary pathway receiving impulses from the midbrain reticular formation, but it also possesses a sustained activating mechanism for the hippocampus. This tonic activating mechanism may influence the neocortex through the midbrain reticular formation. There seems to be no important direct activating pathway to the neocortex from the hypothalamus under the conditions of an acute experiment.

An animal model of light sensitive epilepsy

1. 1. Intermittent light stimulation (ILS) was found to elicit EEG and motor paroxysmal responses in baboons, Papio papio, originating from the Casamance area of Senegal. Extensive studies to characterize the EEG and motor patterns to 25/sec ILS indicated three types of stimulus-bound paroxysmal responses, more or less individually determined. In certain of the animals, self-sustained epileptiform discharges, divisible into four different patterns, followed termination of ILS. Polygraphic studies showed epileptiform activity to be present in the EEG before appearance of motor seizures, EMG paroxysms or oculo-motor movements. Stability of response varied with individual animals, some of which exhibited a constant, high level of sensitivity. The majority of the paroxysmal responses were elicited at 20–30/sec with 25/sec about optimal. Light source or presence of click stimuli were unimportant; the latter alone did not elicit paroxysmal activity. 2. 2. Night-long EEG and polygraphic recordings showed the least sensitive animals to differ from cat and especially man by the absence of very high voltage, slow sleep as muscle activity lessened and by much reduced REM sleep, both in period length and in total. The two most sensitive animals showed spontaneous paroxysmal activity resembling spike and wave discharges during their nocturnal sleep and no identifiable REM sleep. 3. 3. Evoked neocortical responses to 1/sec ILS, usually studied as summed potentials in groups of 30, differed with eyes open and closed and between animals. Animals usually displaying paroxysmal responses to 25/sec ILS had more widespread distribution of evoked neocortical responses and changes in their wave form compared to pattern seen in animals relatively insensitive to 25/sec ILS. 4. 4. Papio papio showed low thresholds to pentylenetetrazol-induced seizures in the presence of ILS. Chlorpromazine increased the responsiveness to ILS and altered the neocortical evoked potential pattern to one similar to that seen in the most seizure-prone individual animals. 5. 5. Anticonvulsant activity of phenobarbital, trimethadione and diazepam was demonstrated against ILS-induced epileptiform seizures in two animals displaying stable, daily severe paroxysmal responses to ILS. Neocortical evoked responses were modified differently by the different drugs. 6. 6. It is considered that a photo-sensitive epilepsy in Papio papio has been demonstrated which in a number of ways closely parallels that seen in man.