Brain imaging and memory systems in humans: the contribution of PET methods

The development of neuroimaging methods such as PET, has provided a new impulse to the study of the neural basis of cognitive functions, and has extended the field of inquiry from the analysis of the consequences of brain lesions to the functional investigations of brain activity, either in patients with selective neuropsychological deficits or in normal subjects engaged in cognitive tasks. Specific patterns of hypometabolism in neurological patients are associated with different profiles of memory deficits. [¹⁸F]FDG PET studies have confirmed the association of episodic memory with the structures of Papez's circuit and have shown correlations between short-term and semantic memory and the language areas. The identification of anatomo-functional networks involved in specific components of memory function in normal subjects is the aim of several PET activation studies. The results are in agreement with ‘neural network’ models of the neural basis of memory, as complex functions subserved by multiple interconnected cortical and subcortical structures.     

Multiple and interrelated functional asymmetries in rat brain.

Normal rats rotate (turn in circles) at night and in response to drugs (e.g. d-amphetamine) during the day. Rats with known circling biases were injected with [1,2-³H]-deoxy-d-glucose, decapitated and glucose utilization was assessed in several brain structures. Most structures showed evidence of functional brain asymmetry. Asymmetries were of three different kinds: (1) a difference in activity between sides of the brain contralateral and ipsilateral to the direction of rotation (midbrain, striatum); (2) a difference in activity between left and right sides (frontal cortex, hippocampus); and (3) an absolute difference in activity between sides that was correlated to the rate of either rotation (thalamus, hypothalamus) or random movement (cerebellum). Amphetamine, administered 15 minutes before a deoxyglucose injection in other rats, altered some asymmetries (striatum, frontal cortex, hippocampus) but not others (midbrain, thalamus, hypothalamus, cerebellum). Different asymmetries appear to be organized along different dimensions in both the rat and human brains.     

Morphometric study on the interhemispheric asymmetries in the Wistar rat and the effects of early experience.

Sixty male Wistar rats were used for this experiment and assigned at random to the control group or to the stimulation method. Control rats show cerebral asymmetry with right bias at the frontal and occipital lobes. In the case of stimulated rats the differences from the occipital zone increase while those from the frontal lobe disappear.     

Analysis of interhemispheric asymmetries in the space-time organization of human cortical potentials

The study of spatial organization of human cortical potentials with multichannel recording (48 leads) has shown, that different functional conditions of brain (quiet alertness, excitation after caffeine administration, intellectual strain, negative emotional shifts, inhibition after administration of neuroleptics) are accompanied by synchronization changes in the left and right hemispheres specific of each brain condition. Similar shifts may be recorded both in states similar by their phenomenological characteristics (after administration of caffeine and during intellectual strain) and during the opposite levels of alertness (emotional strain and administration of neuroleptics).     

Hemispheric asymmetries: a brain in two minds

The two cerebral hemispheres are specialised for different cognitive functions, and which hemisphere's strategy is superior depends on the nature of the task. A new study of split-brain patients has provided another unexpected insight: the two hemispheres use different strategies when performing a guessing task.     

An EMG study of functional cortico-motoneuronal connections in humans.

We set out to decompose the EMG signal into its constituent motor unit action potential components to track motor unit firing rates with a high degree of accuracy and extract their average firing rate. We were able to show that this average firing rate tracks the subject's force trajectory from beginning to end. We propose that this average firing rate is a volitional control signal pointing to the existence of a 'volitional unit'. This volitional unit has to do with the projection of a group of functionally related cortico-motoneurons on a group of spinal motoneurons in the motoneuronal pool of a muscle. Our study of motor unit firing patterns during their steady state showed that spinal motoneurons respond to a descending central input in a Gaussian manner. We have further shown that the central drive itself, as represented by the average firing rate of the active motor units, also displays a Gaussian firing behavior. We have also described the existence of a 'translation factor', highly correlated to the motor unit size, which is unique to each spinal motoneuron and determines the motoneuronal response, and its resulting firing rate, to the descending inputs. As for force generation, we have shown that expressing the twitch force of a motor unit in a dynamic fashion using the 'electrotwitch' concept of firing rate x macro area, approximates motor unit force output better and accounts for firing rate related force changes more effectively than force estimates based on the mechanical twitch.     

Muscle fiber size and function in elderly humans: a longitudinal study.

Cross-sectional studies are likely to underestimate age-related changes in skeletal muscle strength and mass. The purpose of this longitudinal study was to assess whole muscle and single muscle fiber alterations in the same cohort of 12 older (mean age: start of study 71.1+/-5.4 yr and end of study 80+/-5.3 yr) volunteers (5 men) evaluated 8.9 yr apart. No significant changes were noted at follow-up in body weight, body mass index, and physical activity. Muscle strength, evaluated using isokinetic dynamometry, and whole muscle specific force of the knee extensors were significantly lower at follow-up. This was accompanied by a significant reduction (5.7%) in cross-sectional area of the total anterior muscle compartment of the thigh as evaluated by computed tomography. Muscle histochemistry showed no significant changes in fiber type distribution or fiber area. Experiments with chemically skinned single muscle fibers (n=411) demonstrated no change in type I fiber size but an increase in IIA fiber diameter. A trend toward an increase in maximal force in both fiber types was observed. Maximum unloaded shortening velocity did not change. In conclusion, single muscle fiber contractile function may be preserved in older humans in the presence of significant alterations at the whole muscle level. This suggests that surviving fibers compensate to partially correct muscle size deficits in an attempt to maintain optimal force-generating capacity.     

Vervet monkeys and humans show brain asymmetries for processing conspecific vocalizations, but with opposite patterns of laterality

A robust finding in the human neurosciences is the observation of a left hemisphere specialization for processing spoken language. Previous studies suggest that this auditory specialization and brain asymmetry derive from a primate ancestor. Most of these studies focus on the genus Macaca and all demonstrate a left hemisphere bias. Due to the narrow taxonomic scope, however, we lack a sense of the distribution of this asymmetry among primates. Further, although the left hemisphere bias appears mediated by conspecific calls, other possibilities exist including familiarity, emotional relevance and more general acoustic properties of the signal. To broaden the taxonomic scope and test the specificity of the apparent hemisphere bias, we conducted an experiment on vervets (Cercopithecus aethiops)-a different genus of old world monkeys and implemented the relevant acoustic controls. Using the same head orienting procedure tested with macaques, results show a strong left ear/right hemisphere bias for conspecific vocalizations (both familiar and unfamiliar), but no asymmetry for other primate vocalizations or non-biological sounds. These results suggest that although auditory asymmetries for processing species-specific vocalizations are a common feature of the primate brain, the direction of this asymmetry may be relatively plastic. This finding raises significant questions for how ontogenetic and evolutionary forces have impacted on primate brain evolution.     

Reorganization of callosal interhemispheric connections in the adult cat: effects of monocular occlusion after chiasmotomy

Two groups of adult cats were chiasmotomized and their cortical receptive fields (17-18 boundary) were compared after a postoperative period of ca 6 weeks. In one group, binocular vision was maintained during that period, in the other one, one eye was sutured at the time of the chiasmotomy, depriving one hemisphere from patterned vision through the direct pathway. In monocular chiasmotomized animals, the receptive fields to stimulation of the contralateral eye were significantly larger than in the binocular ones.     

Participation of brain stimulation reward substrates in memory: anatomical and biochemical evidence.

On the basis of the pioneering leads provided by James Olds, brain stimulation reward has been shown to be a) derived from specific anatomical locations, b) influenced by psychotropic drugs, and c) functionally related to feeding behavior and sexual activity. These results recommend the view that it is worthwhile to understand, not necessarily the curious intracranial self-stimulation behavior itself, but the physiological function of the substrate revealed by the intracranial self-stimulation (ICSS) technique. I have suggested that certain components of the brain stimulation reward system may function as a memory consolidation system. In view of the biological specificity of brain reinforcement pathways, I suggest the hypothesis that activity in the mesocortical dopaminergic brain stimulation reward pathways participates in the memory consolidation process. Consequent to activity in such anatomical systems, phosphorylation of band F in the frontal cortex is altered. Thus, intracranial self-stimulation pathways are considered to play a role in memory formation by providing a biochemical residual following learning.     

Post-tetanic modification of the efficacy of excitatory transmission in neuronal networks with interhemispheric connections

The modifiable reciprocal transcallosal monosynaptic excitatory connections were for the first time detected in vivo experiments in rat motor cortex using multiunit recording and crosscorrelation analysis, It was shown that high-frequency microstimulation (MCS) of a small group of cortical cells of one hemisphere produces long-term changes in the efficacy of transcallosal excitatory connections, and also ipsilateral connections in both hemispheres. The posttetanic changes appear as long-term potentiation (LTP) and long-term depression (LTD). The bursting neurons were found to have more favorable conditions for the induction of LTP of most converging inputs (in contrast to cells with other discharge patterns). Both LTP and LTD could be simultaneously induced in synapses formed by axon collaterals of a callosal cell on several neurons. LTP and LTD could be simultaneously obtained at diverse synapses of the same cell. The number of spontaneously active callosal neurons as well as the number and efficacy of transcallosal connections increased after the MCS, whereas the number and efficacy of ipsilateral connections decreased. Basing on these data we assume that the ipsilateral inhibition is more effective than the transcallosal inhibition. MCS results in the modification of the pattern of initially existing connections between numerous neurons of an ensemble including cells of both hemispheres.     

Interhemispheric EEG asymmetries during unilateral bright-light exposure and subsequent sleep in humans

We tested whether evening exposure to unilateral photic stimulation has repercussions on interhemispheric EEG asymmetries during wakefulness and later sleep. Because light exerts an alerting response in humans, which correlates with a decrease in waking EEG theta/alpha-activity and a reduction in sleep EEG delta activity, we hypothesized that EEG activity in these frequency bands show interhemispheric asymmetries after unilateral bright light (1,500 lux) exposure. A 2-h hemi-field light exposure acutely suppressed occipital EEG alpha activity in the ipsilateral hemisphere activated by light. Subjects felt more alert during bright light than dim light, an effect that was significantly more pronounced during activation of the right than the left visual cortex. During subsequent sleep, occipital EEG activity in the delta and theta range was significantly reduced after activation of the right visual cortex but not after stimulation of the left visual cortex. Furthermore, hemivisual field light exposure was able to shift the left predominance in occipital spindle EEG activity toward the stimulated hemisphere. Time course analysis revealed that this spindle shift remained significant during the first two sleep cycles. Our results reflect rather a hemispheric asymmetry in the alerting action of light than a use-dependent recovery function of sleep in response to the visual stimulation during prior waking. However, the observed shift in the spindle hemispheric dominance in the occipital cortex may still represent subtle local use-dependent recovery functions during sleep in a frequency range different from the delta range.     

Caudate-cortical connections in the cat brain

By means of optical and electron microscopic methods, the cortical fields from the ipsilateral hemisphere was analysed in the cat after electrocoagulation of the dorsal part in the nucleus caudatus (NC). Degenerating axonal preterminals and terminals were detected in the preparations impregnated after Nauta--Gygax and Wiitanen's methods and in electronograms. To exclude degeneration of cortical and projective thalamic fibrillae from the great number of regenerated conductors, additional operations were performed on the same cats--thalamic and ventral NC nuclei were damaged and coagulative electrode was inserted into the dorsal NC a month before the last operation.     

Molecules involved in the formation of synaptic connections in muscle and brain.

Synapses are highly specialized structures designed to guarantee precise and efficient communication between neurons and their target cells. Molecules of the extracellular matrix have an instructive role in the formation of the neuromuscular junction, the best-characterized synapse. In this review, the molecular mechanisms underlying these instructive signals will be discussed with particular emphasis on the receptors involved. Additionally, recent evidence for the involvement of specific adhesion complexes in the formation and modulation of synapses in the central nervous system will be reviewed. Synapses are specialized junctions between neurons and their target cells where information is transferred from the pre- to the postsynaptic cell. At most vertebrate synapses, this transfer is accomplished by the release of a specific neurotransmitter from the presynaptic nerve terminal. The release of neurotransmitter is initiated by the action potential and the subsequent influx of Ca(2+) into the presynaptic nerve terminal. This results in the rapid fusion of vesicles with the nerve membrane and the release of the neurotransmitter into the synaptic cleft. The neurotransmitter then diffuses across the cleft and binds to specific postsynaptic receptors, resulting in a change in the membrane potential of the postsynaptic cell. This can result in the generation of an action potential. The high precision of synaptic transmission requires that pre- and postsynaptic structures are both highly organized and in juxtaposition to each other. In addition, alterations in synaptic transmission are the basis of learning and memory and are likely to be accompanied by the remodeling of synaptic structures (Toni et al., 1999). Thus, the study of how synapses are formed during development is also of relevance for the understanding of the cellular and molecular processes involved in learning and memory. This review focuses on the molecular mechanisms involved in the formation and the function of synapses.     

Variations and asymmetries in regional brain surface in the genus Homo

Paleoneurology is an important field of research within human evolution studies. Variations in size and shape of an endocast help to differentiate among fossil hominin species whereas endocranial asymmetries are related to behavior and cognitive function. Here we analyse variations of the surface of the frontal, parieto-temporal and occipital lobes among different species of Homo, including 39 fossil hominins, ten fossil anatomically modern Homo sapiens and 100 endocasts of extant modern humans. We also test for the possible asymmetries of these features in a large sample of modern humans and observe individual particularities in the fossil specimens.This study contributes important new information about the brain evolution in the genus Homo. Our results show that the general pattern of surface asymmetry for the different regional brain surfaces in fossil species of Homo does not seem to be different from the pattern described in a large sample of anatomically modern H. sapiens, i.e., the right hemisphere has a larger surface than the left, as do the right frontal, the right parieto-temporal and the left occipital lobes compared with the contra-lateral side. It also appears that Asian Homo erectus specimens are discriminated from all other samples of Homo, including African and Georgian specimens that are also sometimes included in that taxon. The Asian fossils show a significantly smaller relative size of the parietal and temporal lobes. Neandertals and anatomically modern H. sapiens, who share the largest endocranial volume of all hominins, show differences when considering the relative contribution of the frontal, parieto-temporal and occipital lobes. These results illustrate an original variation in the pattern of brain organization in hominins independent of variations in total size. The globularization of the brain and the enlargement of the parietal lobes could be considered derived features observed uniquely in anatomically modern H. sapiens.