|Home | About | Journals | Submit | Contact Us | Français|
This Special Topic “Cortical white matter: beyond the pale” includes 10 articles from 32 authors. These articles in this offer a summary of some of the current thinking regarding myelin, and the associated cellular populations in the white matter. The articles range from the micro–level of ultrastructure and molecular factors, to populational organization, and cognitive effects. All the articles devote at least some discussion to myelin in psychiatric conditions, raising the prospect of new paradigms of investigation and treatment. In this article the main conclusions, and some of what the host editors (Kathleen Rockland and Javier DeFelipe) consider the most interesting remarks, have been extracted from each of the individual articles. These commentaries are not necessarily directly derived from the original work of the authors, and may be the result of the collective work of several different laboratories. This is followed by a section dedicated to more general comments and a discussion of the issues raised. The authors who have participated in this article are listed in alphabetical order.A Commentary On Neurons in the white matter of the adult human neocortex by Suarez-Sola, M., Gonzalez-Delgado, F. J., Pueyo-Morlans, M., Medina-Bolivar, O. C., Hernandez-Acosta, N. C., Gonzalez-Gomez, M., and Meyer, G. (2009). Front. Neuroanat. 3:7. doi: 10.3389/neuro.05.007.2009.
Comment on points 4 and 13:
Are there studies that address the issue of synaptic connections of IN? studies on what is the proportion of these neurons that project over long distances?
Response to DeFelipe's comment:
Some articles in the next Special Topic (Cortical GABAergic neurons: stretching it) will talk about synaptic inputs, but I believe less is known about the output. I do not believe we have numbers yet about proportion. In part because there are multiple target structures, retrograde tracers are only partly useful in addressing this question.
Comment on points 2 and 5, and in general:
It may be worth remarking that “layer VIB” is used here to denote deep layer VI. This is not to be confused with “layer VIB” in rodents, sometimes also called “layer VII” and which constitutes a separate population. Questions of nomenclature are likely to be taken up in a subsequent Special Topic, as referenced above.
As these authors remark (points 6 and 7), the subplate neurons perform multiple functions developmentally, and themselves constitute a heterogeneous group. It is interesting to consider this in conjunction with Friedlander and Torres-Reveron, who emphasize the multiple and changing roles of WM neurons over a lifetime.
Comment on interstital neurons, the nomenclature and species differences:
Suárez-Sola et al. discuss the so-called “interstitial neurons” (IN) of the WM of the adult human cortex, which are located directly subjacent to the cortical gray matter and are found in high numbers especially in the prefrontal cortex. Initially they were regarded as remnants from the subplate during neurodevelopment, however in primates, IN rather seem to belong to a distinct neuronal system that carries out activities pertinent to the subcortical WM.
Interestingly, some species have in adult stage large numbers of WM neurons, in particular large-brained mammals such as artiodactyls and cetaceans (Hof et al., 1999), while they are only rudimentary in the brain of non-primate mammals. As the authors indicate, such species differences may reflect a correlation between the size of the cortical gray matter, the amount of WM interconnecting the neocortex, and the number of IN. The higher number of IN in large-brained animals may possibly support one of the proposed functions of the IN, which is coordination of activity among neocortical regions.
These comparative differences may also possibly be indicative of species-specific importance, similar to other specialized neuron types (such as spindle “von Economo” neurons in the anterior cingulate and frontoinsular cortices, Betz cells in M1, or Meynert cells in V1). However, the IN are a very heterogenous population of neurons, some pyramidal-like and covered with spines, thus presumably glutamatergic, while others are multipolar or bipolar and express GABA and a variety of neuronal markers (such as CB, CR, neuropeptide Y, somatostatin, and NOS). One of the proposed functions of the IN involves the coordinating of regulation of blood flow. Particularly in view of the presence of NO in some IN (as visualized by the presence of NADPH-d/nNOS+), and their close association with blood vessels, the IN have been suggested to be involved in the regulation of blood flow and neurovascular coupling. In addition, the expression of NPY, a powerful vasoconstrictor, could potentially antagonize the vasodilating effect of NO. Interestingly, comparable functions have been reported for select classes of neocortical interneurons characterized by their content of neuropeptides and particular morphologies (Cauli et al., 2004). If the IN have a role in blood flow regulation, it remains to be clarified however why are there fewer IN in visual cortex but higher numbers in frontal cortex, and also why they appear only rudimentary in smaller mammals such as rodents.
In the human, abnormalities of the IN in the frontal lobe have been observed in schizophrenia, although reports from different investigators are conflicting (summarized by Eastwood and Harrison, 2005). As the authors indicate, it is important to differentiate between early-born IN (probably related to transient roles of the subplate) and later-appearing resident cells, which may not be important for development but rather involved in activities proper to the adult WM.
Authors and commentators discussed the significance of the prominence of subplate zone and neurons, and of the large numbers of interstitial neurons in the primate brain and particularly in human. The answer may be in the obvious fact that subplate prominence and number of interstitial neurons is related to the enormous increase of cortico-cortical connectivity in human (Kostovic and Rakic, 1990). The increase of complexity of cortico-cortical connections requires a prolonged existence of the subplate zone as well as prolonged developmental function of subplate neurons (Kostovic and Judas, 2006). This is also consistent with the increased number of gyri and gyral white matter in human and primates (remark 2).
In respond to Rockland comments about synaptic inputs, I also refer to the next special topic “Cortical GABAergic Projection Neurons” and in particular to the article “Subplate cells: amplifiers of neuronal activity in the developing cerebral cortex” of Luhmann, Kilb and Hanganu-Opatz. Without endogenous activity of the subplate neurons, cortex can not properly develop. Here we emphasize prolonged coexistence of subplate circuitry with the gradual formation of adult-like thalamo-cortical and cortico-cortical circuitry (Kostovic and Judas, 2006). Thus, the subplate zone should always be defined as a synaptic layer.
The glutamatergic component of subplate zone factor Tbr1 (remark 8) is recognized as a useful marker. There are several other specific markers found in the subplate zone, such as CplX3, CTGF, Nurr-1/Nr 4a2, Mox D1, CTGF and F-spondin (Ayoub and Kostovic, 2009).
Involvement of white matter neurons in neurological and psychiatric disorders (remarks 16 and 17) may have a developmental interpretation: selective vulnerability of the subplate zone and neurons during development. This may be a crucial factor in pathogenesis of several neurological mental and cognitive disorders (Kostovic and Judas, 2006).
Response to the comments by Höistad and Hof regarding the number of interstitial neurons (IN) in different species. They argue that large brains have in general large amounts of cortical gray matter, accompanied by large numbers of cortical association fibers and thus an increased volume of cortical white matter, requiring large numbers of IN. The question is why the visual cortex has relatively few IN. I think that the connections of the primary visual cortex – Brodmann’s area 17- are well defined and highly specific. On the one hand, area 17 itself is a narrow koniocortex, and the proportion of intracortically projecting neurons higher than in other cytoarchitectonic areas. On the other hand, callosal fibers are sparse if not absent in most of area 17, and they only increase toward the 17/18 border, the representation of the vertical meridian. Area 17 is thus lacking a substantial component of the cortical white matter tracts, and in fact, macroscopic observation of the human striate area shows that the amount of white matter is smaller than in the nearby occipital association areas. By contrast, prefrontal areas have many and varied fiber connections which contribute to the huge volume of the underlying white matter. A possible additional function of IN may be that they serve as guideposts for distinct fiber fascicles, perhaps by establishing synaptic contacts. The primary visual cortex may thus not be the best model for studying IN, the more so since also during development subplate neurons below area 17 play important roles in specific visual functions, such as the establishment of ocular dominance columns. Studies on subplate neurons in primate cortex development should also include frontal and parietal association areas where IN are known to be very numerous in the adult.A Commentary On The changing roles of neurons in the cortical subplate by Friedlander, M. J., and Torres-Reveron, J. (2009). Front. Neuroanat. 3:15. doi: 10.3389/neuro.05.015.2009.
As the authors point out (point 9 and elsewhere), the terminology for subgriseal and white matter neurons is not standardized. Even in rodent, the same neuron population can be called “layer 6B,” “layer 7,” or subgriseal. This important issue is likely to be more extensively addressed in the following Special Topic, on GABAergic cortical projection neurons.
The possibility of pleiotropy of cellular function in the temporal domain – serial lifespan related and/or short-term (activity related?) neuronal multi-plexing – is provocative (points 2, 5, and elsewhere). In further investigations of this point, the sparseness of this population may actually be advantageous, if cell-type specific markers can be functionally exploited.
The authors very legitimately note that strength is not always in numbers (point 15), and that this relatively sparse population may still be exerting a significant influence.
It is interesting that subplate neurons form a well delineated cyto-architectonical layer in rodent brain-a compressed band along the bottom of layer 6 (remark 6). This cyto- architectonical correlate of the subplate feature may be explained by major differences in organization of white matter between rodents and primates: simplified corona radiata and absence of gyri in rodents. However, this also indicates a more uniform population of subplate neurons and a restricted developmental origin in rodents. The article makes very good points about the changing role and different function of subplate neurons over the course of the lifespan (remark 5), and the involvement of the subplate in the generation of action potentials. These factors will elaborate the explanation of the developmental roles, as will be presented in the next Specific topic “Cortical GABAergic Projection Neurons”A Commentary On Individual differences in distinct components of attention are linked to anatomical variations in distinct white matter tracts by Niogi, S., Mukherjee, P., Ghajar, J., and McCandliss, B. D. (2010). Front. Neuroanat. 4:2. doi: 10.3389/neuro.05.002.2010.
In regard to point 12, a recent fMRI study (Fan et al., 2008) using the ANT and examining physiological response of several brain regions in terms of interactions between conflict processing and activity of the anterior rostral cingulate cortex, and the effective connectivity between it and other cortical domains using psychophysiological interaction analysis and dynamic causal modeling showed a significant integration of the anterior cingulate with the caudal cingulate zone of the ACC and the lateral prefrontal, primary, and supplementary motor areas above and beyond the main effect of conflict and baseline connectivity. The intrinsic connectivity from the anterior to the caudal cingulate cortex was modulated by the context of conflict, indicating that conflict processing is associated with the effective contribution of the rostral cingulate to the neuronal activity of the caudal cingulate cortex, as well as other cortical regions.A Commentary On The effects of normal aging on myelinated nerve fibers in monkey central nervous system by Peters, A. (2009). Front. Neuroanat. 3:11. doi: 10.3389/neuro.05.011.2009.
Comment on point 16:
Is it possible that thin myelinated axons are more vulnerable with age and, therefore, thicker axons may seem to be more common or are there quantitative studies regarding this subject?
I wonder if there is any “intercommunication” or shared signal among the different axons that are myelinated by any given oligodendrocyte? Or, similarly, between those oligodendrocytes that myelinate a given segment of axon (point 2)?
Peters notes several conditions that could be assumed to result in circuitry-significant changes in conduction velocity. In this regard, see Kimura and Itami.
There is a loss of white matter (WM) from the cerebral hemispheres with age. Peters presents some of the observed ultrastructural morphological changes that may occur in WM during aging, including myelin balloons, redundant myelin, split sheaths and sheaths with dense cytoplasm. He discusses evidence that redundant myelin may be due to uncontrolled production of myelin with age, while thicker myelin sheaths may be evidence for the continued formation of myelin with aging. Some questions that arise are whether the myelin changes observed in aging are different in WM versus the grey matter, and if age-related changes in the grey matter can be area or layer specific. In addition, how are normal aging alterations in myelin different from those observed in disease, for example in schizophrenia (Uranova et al., 2001). Is there a commonality between normal aging and alterations seen in disease, which could lead to comparable alterations of neuronal communications and result in specific cognitive and behavioral changes?A Commentary On Oligodendrocyte development and the onset of myelination in the human fetal brain by Jakovcevski, I., Filipovic, R., Mo, Z., Rakic, S., and Zecevic, N. (2009). Front. Neuroanat. 3:5. doi: 10.3389/neuro.05.005.2009.
Comment on point 23.3:
It is not clear for me what is the relationship between the prolonged time of myelination and the presence of more specialized neocortical regions in humans compare to rodents, and to the fact that some regions of rodent brains are in human relatively underdeveloped.
The theme of heterogeneity and cellular diversity re-appears, in the context of multiple generative sources of oligodendrocytes (point 7). As the authors comment, the implications of this fact are poorly understood, but could include important issues of species specialization (point 22).
In this paper, correlation between oligodendrocyte development and other neurogeneic events is best documented for the subplate zone (remark 4). Dense accumulation of oligodendrocyte precursors in the zone of waiting thalamic afferents is important for later myelination of thalamo-cortical axons. Laminar specificity of glia distribution seams to be related to other neurogenetic events. Accordingly, oligodendrogliogenesis in the human brain is prolonged compared to rodent brain (remark 22).A Commentary On Growth of the human corpus callosum: modular and laminar morphogenetic zones by Jovanov-Milosevic, N., Culjat, M., and Kostovic, I. (2009). Front. Neuroanat. 3:6. doi: 10.3389/neuro.05.006.2009.
I was wandering if there are gender differences in the growth of the human corpus callosum.
I recently learned that agenesis of the corpus callosum is accompanied by vertical fingerlike structures (Probst's bundles) in the interhemispheric walls. Can the authors (or Others) comment on a possible relation to the developmentally important septa?
Comment on point 2:
I would say that callosal connections between the association areas, in particular, often involve layer 5 as well as 3, in macaque. This raises another possibly useful species difference, as I believe callosal connections in rodents originate more equally from layers 3 and 5?A Commentary On Could sex differences in white matter be explained by g ratio? by Paus, T., and Toro, R. (2009). Front. Neuroanat. 3:14. doi: 10.3389/neuro.05.014.2009.
Comment on point 3:
The authors claim that the total volume of white matter is determined by the number of axons, their calibre and the thickness of myelin sheath. However numerous neurons are present in the white matter. Do the authors think that the presence of these neurons has little impact on the volume of white matter?
Paus and Toro observed differential increases in WM volume in boys compared to girls during adolescence (i.e., after 12years of age). They propose that there is a disproportionate growth of axons compared to the growth of myelin sheaths during male adolescence (Perrin et al., 2008). It remains to be determined whether, or how, sex hormones play a role in this development.
Inherent to the issues of axon and myelin growth, is the issue of identifying a possible coupling between myelination and axon diameter. For example, several thin axons are unmyelinated, whereas large diameter axons are heavily myelinated. As such, what determines axon diameter, and what are the signals required for the axon to get myelinated? Paus and Toro discuss the link between axon diameter and neurofilament, the main axonal cytoskeletal protein. It turns out that neurofilament phosphorylation, which determines neurofilament spacing, may in fact be regulated by MAG (myelin associated glycoprotein) expressed in oligodendrocytes (Yin et al., 1998). These authors have shown that MAG modulates caliber, neurofilament spacing, and neurofilament phosphorylation of myelinated axons, and that absence of MAG results in axonal atrophy and Wallerian degeneration of myelinated fibers. Thus, MAG may provide one of the mechanisms that are responsible for the coupling between myelination and axonal caliber. Interestingly, it has been found by Hof and coworkers that MAG deficient mice do not exhibit any changes in FA of the cingulum bundle as measured by DTI, nor do they exhibit any changes in fiber length densities of the cingulum bundle as assessed by stereologic analysis (Segal, 2008). This may point to the fact that not all pathways are equally affected in the MAG knockout mouse. It is equally possible that sex hormones exert a direct or indirect effect on myelination or axon growth through mechanisms unknown as yet, which represent interesting targets for investigations considering the gender-dependent differences in white matter that occur during adolescence.A Commentary On Myelination and isochronicity in neural networks by Kimura, F., and Itami, C. (2009). Front. Neuroanat. 3:12. doi: 10.3389/neuro.05.012.2009.
Comment on points 7 and 10:
If each pathway has its own conduction time and isochronous activation of thalamocortical and cortico-cortical connections are thought to be crucial in the binding mechanisms of sensory perception, how can both arguments could be related to explain the global binding?
Concerning the statement of differential myelination along the axon (point 2), light microscopic analyses of individual axons have remarked what appears to be changes in axon caliber (Innocenti et al., 1994; Rockland and Drash, 1996). Since it has been difficult to investigate identified axons along their full length, data on this point are largely lacking. However, the changes and specializations along the trajectory of a single axon are likely to be a source of interesting and potentially important future research.A Commentary On Linking white and grey matter in schizophrenia: Oligodendrocyte and neuron pathology in the prefrontal cortex by Höistad, M., Segal, D., Takahashi, N., Sakurai, T., Buxbaum, J. D., and Hof P. R. (2009). Front. Neuroanat. 3:9. doi: 10.3389/neuro.05.009.2009.
The authors state that schizophrenia has been proposed to arise partly from altered brain connectivity. Could the authors, or whoever is interested, comment from his/her own experience on what particular connections are affected? How specific are these changes? Are GABAergic neurons affected or is it thought that mostly pyramidal neurons are vulnerable?
Response to DeFelipe's comment:
To the extent that long-distance connections are involved, this will be hard to determine in humans (as long as DiI or comparable post-mortem tracer remains refractory.) Also, it is hard to know what level to search: presynaptic arbors or synapses? Postsynaptic targets? Receptors, so this will involve a concerted ongoing effort. One related recent report is Rinaldi et al. (2008).
Comment on point 20.1:
It is not clear to me why only layers II and III pyramidal neurons in the ACC may be the targets of axonal pathways affected in schizophrenia. Are not affected pyramidal neurons in other cortical areas and layers?
There is a plethora of unsuspected pathologic alterations in schizophrenia. Many studies have demonstrated changes in pyramidal neuron populations in various cortical regions (hippocampus, cingulate, dorsolateral prefrontal, primary auditory cortices to name a few). Similarly GABAergic neurons have been shown to be affected, and to present abnormal distribution in frontal and temporal regions alike. Further hinting to a developmental problem is the fact that neurons do not migrate to their appropriate location, or tend to agglomerate in the white matter under the cortex. As such it is not only the ACC that is affected. It may be that some domains of cortex are more vulnerable to an underlying developmental pathology that is revealed postpuberty and may affect different regions in different patients. Assessing the true variability in distribution of changes and their severity among patients with schizophrenia is a daunting task to undertake, but is the necessary neuropathologic index ultimately required to understand the disease process fully, in the context of genetic influences, inferences from animal models and in vitro models, and in vivo functional imaging. This issue speaks to the need of rigorous, extensive, quantitative analyses of postmortem human materials to enhance our understanding of the disease.A Commentary On Regulation of myelin genes implicated in psychiatric disorders by functional activity in axons by Lee, P. R., and Fields, R. (2009). Front. Neuroanat. 3:4. doi: 10.3389/neuro.05.004.2009.
This article presents the myelin environment as an attractive paradigm for investigating coupling of neuronal activity and intracellular signaling, in this case by oligodendrocytes. Another application, emphasized by this and several of the other articles as well, is in the psychiatric domain. Because of its distinctiveness and quasi-isolation, white matter may offer some advantages over the more usual gray matter assays in investigating effects, possibly leading to new modes of treatment.
Lee and Fields review data indicating that myelination can be altered by activity in axons. Their paper illustrates the global interplay and communication that exists between axons, oligodendrocytes, and astrocytes. Three important aspects are discussed: how activity in axons is sensed by oligodendrocytes and astrocytes, the regulation of myelin and myelin-associated genes, and the relevance for psychiatric disorders.
The activity in axons needs to be sensed by the surrounding oligodendrocytes and astrocytes. For example, this can be done through axon-derived diffusible signals including ATP, adenosine, K+, glutamate, and GABA (Lee and Fields, 2009 Figure 1). [The issue of “diffusing signals” adheres to the concept of volume transmission, originally presented by Fuxe and Agnati (see Agnati et al., 2000; Fuxe et al., 2007) and discussed by Fields (2004)]. It has been shown that oligodendrocytes and astrocytes have receptors and ion channels that enable them to sense the activity in their surrounding. For example, oligodendrocytes have receptors for glutamate, serotonin, and dopamine, as well as purinergic receptors (Fields and Burnstock, 2006). Astrocytes have also been shown to have transmitter receptors (see, e.g., Magistretti et al., 1983; Hosli and Hosli, 1993; Porter and McCarthy, 1997). In addition, synaptic contacts between immature oligodendrocytes and axons have been found, as reviewed by Lee and Fields (Kukley et al., 2007; Karadottir et al., 2008). Astrocytes may also influence oligodendrocyte development by secretion of trophic factors and cytokines. For instance, extracellular factors generated by neuronal activity can regulate GFAP expression in astrocytes. It is possible that GFAP in astrocytes indirectly affects oligodendrocytes and myelination, axons, and neuron-glia interactions. In axons, cell adhesion molecules such as NCAM may influence axon-glia interactions. For example, myelin deposition is targeted to the correct axon site in response to a cell surface receptor expression induced by activity in the axon.
The regulation of myelin or myelin-associated genes can be made either in oligodendrocytes themselves, or via astrocytes and axons. For example, in oligodendrocytes, an important RNA-binding protein, QKI, has been shown to be downregulated in schizophrenia (Katsel et al., 2005; Aberg et al., 2006), which may have downstream consequences on oligodendrocyte development and myelination. It has also been found that the level of QKI mRNA can in fact be influenced by medication used to treat schizophrenia (Aberg et al., 2006). As several antipsychotic medications have their effects through dopamine (as well as serotonin) receptors, Lee and Fields discuss the evidence that dopamine can influence oligodendrocyte development. Although the authors state that “it is unclear exactly how dopamine function is disrupted by oligodendrocyte dysfunction”, it should be kept in mind that the axons of the mesolimbic and mesocortical monoamine neurons, which have been classically implicated in the pathophysiology of schizophrenia, are mainly unmyelinated (as observed by Fuxe, 1965a,b; Descarries and Mechawar, 2000). Hence, any potential effects that oligodendrocyte and myelin dysfunction would have on monoamine axons are likely indirect, or rather affect other axons in the circuitry of psychiatric disorders.
Hoistad and Hof raise an interesting question of what is the pathophysiology of schizophrenia. The literature suggests that the underlying cause of this disorder may be less certain and more complex than the comment suggests. In addition to dopamine, serotonin, and norepinephrine, other neurotransmitter systems, including glutamate, D-serine, and GABA are involved. Anatomical evidence also implicates involvement beyond the mesolimbic and mesocortical pathways. White matter differences have been detected in patients with schizophrenia in widespread brain regions, including prefrontal, hippocampal, temporal, uncinate fasciculus, fornix, cingulate fasciculus, anterior cingulum, superior cerebellar peduncle, and caudate (Fields, 2008, supplemental table). Most would agree that schizophrenia is a complex disorder and it is likely a group of disorders rather than a single disease.