How fibers subserve computing capabilities: similarities between brains and machines.

Can the principles underlying the design of computers help to explain the cognitive capabilities of the human brain? This chapter shows that these principles can provide insight into the capabilities of the human cerebellum, the internal structure of which bears a remarkable resemblance to the design of a versatile computer. In computers, information processing is accomplished both by the hardware in the system (its circuitry) and by the software (the communication capabilities inherent in its circuitry), which is combination can produce a versatile information-processing system, capable of performing a wide variety of functions, including motor, sensory, cognitive, and linguistic ones. Such versatility of function is achieved by computer hardware in which many modules of similar circuits are organized into parallel processing networks; this structural organization is exemplified in the cerebellum by its longitudinal modules of similar circuits, which are arrayed in parallel zones throughout the structure. On the basis of this known cerebellar "hardware," it is possible to investigate the "software" capabilities inherent in the circuitry of the modules. Each module in the lateral cerebellum seems able to communicate with the cerebral cortex by sending out signals over a segregated bundle of nerve fibers, which is a powerful way of communicating information. We show why this bundling of fibers can enable the cerebellum to communicate with the cerebral cortex (including the prefrontal cortex) at a high level of discourse by using internal languages that are capable of conveying complex information about what to do and when to do it. We propose that such communication activity is reflected in the activation obtained on functional imaging of the cerebro-cerebellar system during the performance by humans of complex motor, sensory, cognitive, linguistic, and affective tasks. Further, we propose a new way of analyzing such cerebro-cerebellar activation, in order to ascertain whether the cerebellar circuitry can (like the circuitry in a versatile computer) perform a wide repertoire of computations on this wide range of information. It seems important to ascertain whether cerebellar circuitry is versatile in its computing capabilities because the demonstration of such versatile capabilities would enable theorists to resolve many of the current controversies about cognitive processing in the mammalian brain.

Cognitive and language functions of the human cerebellum.

Traditionally, the human cerebellum has been regarded as a motor mechanism, but this view of its function is being challenged by a growing body of data on the non-motor functions of the cerebellum. Some of these data are presented in this article, which reviews neuroanatomical, neuroimaging and behavioral reports of cerebellar involvement in cognitive and language functions. The article proposes that this functional expansion is a consequence of specific cerebellar structural changes that evolved during hominid evolution and that could have been a prerequisite for the evolution of human language.

Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat.

Fragile X syndrome is associated with massive expansion of a CGG trinucleotide repeat within the FMR-1 gene and transcriptional silencing of the gene due to abnormal methylation. Partial cDNA sequence of the human FMR-1 has been reported. We report here the isolation and characterization of cDNA clones encoding the murine homologue, fmr-1, which exhibit marked sequence identity with the human gene, including the conservation of the CGG repeat. A conserved ATG downstream of the CGG repeat in human and mouse and an in-frame stop codon in other human 5' cDNA sequences demarcate the FMR-1 coding region and confine the CGG repeat to the 5' untranslated region. We also present evidence for alternative splicing of the FMR-1 gene in mouse and human brain and show that one of these splicing events alters the FMR-1 reading frame, predicting isoforms with novel carboxy termini.

Human genes containing polymorphic trinucleotide repeats.

Expansions of trinucleotide repeats within gene transcripts are responsible for fragile X syndrome, myotonic dystrophy and spinal and bulbar muscular atrophy. To identify other human genes with similar features as candidates for triplet repeat expansion mutations, we screened human cDNA libraries with repeat probes and searched databases for transcribed genes with repeats. From both strategies, 40 genes were identified and 14 characterized. Five were found to contain repeats which are highly polymorphic including the N-cadherin, BCR, glutathione-S-transferase and Na+/K+ ATPase (beta-subunit) genes. These data demonstrate the occurrence of other human loci which may undergo this novel mechanism of mutagenesis giving rise to genetic disease.

The human cerebro-cerebellar system: its computing, cognitive, and language skills.

In this review of the human cerebro-cerebellar system, the focus is on the possible contributions of the cerebellum to cognitive and language functions. The role of the cerebellum in these human functions has tended to be obscured by the traditional preoccupation with the motor functions of the cerebellum, which have been widely observed in other vertebrates as well. In the human brain, some phylogenetically new parts evolved and enlarged in the cerebellum, concomitantly with the enlargement of association areas in the cerebral cortex. Anatomical evidence and behavioral evidence combine to suggest that this enlarged cerebellum contributes not only to motor function but also to some sensory, cognitive, linguistic, and emotional aspects of behavior. The anatomical evidence derives from the modularity of the cerebellum, whose cortical nerve cells are organized into longitudinal micro-modules, which are arrayed perpendicular to the cortical surface and parallel to each other. The number of these micro-modules increased when the cerebellum enlarged, which enlarged the computing capabilities of the network. (From principles underlying the processing of information, it is known that when modules with modest processing capabilities are assembled in large numbers in parallel, the resulting network can achieve remarkably powerful computing capabilities.) Such cerebellar computing capabilities can be utilized in the different areas of the cerebral cortex to which the cerebellum sends signals. The cerebellar output connections convey signals through the thalamus to the cerebral cortex in segregated channels of communication, which preserve the modularity of the cerebellum. Through these channels, modules in the lateral cerebellum can send signals to new cognitive and language areas of the cerebral cortex, such as Broca's area in the prefrontal cortex. The anatomy of the human cerebro-cerebellar system therefore suggests that the cerebellum can contribute to the learning not only of motor skills but also of some cognitive and language skills. Supporting this anatomical evidence is the mounting behavioral evidence, obtained both in normal brains and in clinical studies, which indicates that the lateral cerebellum is indeed involved in some cognitive and language functions.

Reappraising the cerebellum: what does the hindbrain contribute to the forebrain?

Although the cerebellum has traditionally been regarded as a motor mechanism, recent behavioral evidence indicates that the human cerebellum is involved in a wider range of functions: in learning, in planning, in judging time, in some emotional and cognitive disorders such as autism, and in some normal mental activities such as the cognitive processing of words. This evidence suggests that the traditional view of cerebellar function now needs to be reassessed and enlarged to include nonmotor as well as motor functions in the human brain. Whereas the cerebellar connections to frontal motor areas enable the cerebellum to improve motor skills, cerebellar connections to adjacent association areas of the prefrontal cortex can enable the cerebellum to improve mental skills, and cerebellar connections to Broca's area can enable the cerebellum to improve language skills.

Cerebro-cerebellar learning loops in apes and humans.

In the cerebro-cerebellar system of anthropoid apes and humans, the cerebellum seems able to contribute not only to motor skills but also to mental and language skills. Anatomical evidence suggests that in these species the cerebellum can function at two different hierarchical levels. At a lower level, the cerebellum can supply signals to the frontal motor areas for effecting the manipulation of muscles. At a higher level, the cerebellum can supply signals to some prefrontal areas for effecting the manipulation of symbols. At both levels, the cerebellum can function in essentially the same way: when incoming information is processed repeatedly in the neural loops in which the cerebellum is embedded, the cerebellum can learn to generate new sequences of signals, which constitute new programs for carrying out learned procedures. If cerebellar programs are used in the frontal motor areas (area 4 and are 6), motor manipulations can be effected rapidly and skillfully. Similarly, if cerebellar programs are used in some prefrontal areas (e.g., area 8 and the inferior frontal convolution), mental and language manipulations could be effected rapidly and skillfully. The cerebellum, in its contributions to these mental and language functions, as in its contributions to motor function, could serve as an adaptive mechanism whose signals enable the frontal cortex to execute learned procedures optimally. In the absence of such cerebellar signals, the frontal cortex would have to perform these procedures less rapidly and fluently. Modern testing techniques can reveal such a subtle difference in performance. These techniques are therefore now being used to test human subjects, in an attempt to validate or refute this broadened concept of cerebellar function. If the new concept is validated, it can provide powerful explanations for some unresolved mysteries about the human brain.

Does the cerebellum contribute to mental skills?

Although it has been known for half a century that unique structures evolved in the cerebellum of anthropoid apes and became greatly enlarged in the human brain, the function of these structures still remains unknown. In an attempt to explain their function, a new concept of cerebellar capabilities is proposed, which is based both on neural evidence and on information-processing theory. The phylogenetically newest structures of the cerebellum may contribute to mental skills in much the same way that the phylogenetically older structures contribute to motor skills. In both cases, the cerebellum can send signals from the dentate nucleus to the cerebral frontal cortex via the thalamus. Signals from the older part of the dentate nucleus certainly help the frontal motor cortex to effect the skilled manipulation of muscles, and signals from the newest part of the dentate nucleus may help the frontal association cortex to effect the skilled manipulation of information or ideas. How such mental skills could have evolved in higher primates in the course of phylogenetic and ontogenetic development is shown. The validity of this new concept of cerebellar function can be tested on humans by means of tomographic brain scans.

Repopulation of lymph nodes and spleen in thymus chimeras after lethal irradiation and bone marrow transplantation: dependence on the age of the thymus.

CAP and Lewis rats were thymectomized and received a syngeneic thymus graft followed by lethal irradiation and syngeneic bone marrow transplantation. In three groups (A: recipient 15 months old, thymus graft 3 months old; B: recipient 3 months old, thymus graft 15 months old; C: recipient and thymus graft both 3 months old), we performed an immunohistologic analysis of the splenic white and red pulp and the paracortical zone of the lymph nodes. The repopulation of these regions was demonstrated with monoclonal antibodies that react with Thy-1 positive cells, peripheral T cells, T helper cells, and T non-helper cells. In the splenic red pulp, more Thy-1 positive lymphocytes were found in group B than in group C. The proportion of T lymphocytes and T helper lymphocytes in the region of the periarteriolar lymphocyte sheath of the splenic white pulp was higher when a young thymus was transplanted (groups A and C) than when an old one was (group B). In contrast, in the splenic red pulp, more T lymphocytes were found in group A than in groups B and C. In the paracortical zone of the lymph nodes, this was demonstrable only for group C versus group B. The proportion of T non-helper lymphocytes in the region of the splenic red pulp was higher in group B than in group C. These results indicate that the repopulation of lymph nodes and spleen after transplantation of an old thymus is delayed, quantitatively reduced, and qualitatively different (more T non-helper lymphocytes).