- Email: [email protected]
Aristotle Got it right again!
Medical Hypotheses 83 (2014) 509–515
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Correspondence
Aristotle Got it right again! We would like to draw attention to the interesting implications of the existence of common cerebral networks demonstrated in several recent meta-analysis studies on time perception [1–3] to current knowledge of higher cognition processes. In particular we wish to highlight the results of a juxtaposition of two meta-analyses: a multimodal SDM study to identify brain regions involved in neuroimaging studies of response to increasing levels of cognitive difficulty; and an ALE meta-analysis on neuroimaging of time perception [2]. The former meta-analysis comprised 54 fMRI studies undertaken whilst subjects did tasks requiring executive functions. For the latter meta-analysis, there were 35 fMRI studies that looked at different aspects of temporal estimation, such as, interval estimation and discrimination of duration. We then used anatomic cerebral coordinates to carry out an overlapping analysis of statistically significant activation patterns from both meta-analyses. Note that what both groups of studies had in common was that they compared cerebral activation between two levels of difficulty of their respective experimental tasks. The methods and procedures involved are not new, they have been used in hundreds of neuroimaging studies over the last decade with a view to obtaining a functional neuroanatomical map and elucidating the connection between experimental tasks and superior functions. However, the same studies also reflect how the brain responds to an increase in cognitive load, an increase in the difficulty of what is demanded or an increase in the effort required. The fact that all the studies involve this kind of cognitive change is, we believe, critical to the interpretation of our results. Our main finding was that there is a group of brain regions engaged both by time perception tasks and by tasks involving an increase in cognitive load for non-time related executive functions.
There was a high degree of bilateral overlapping of cortical and subcortical regions, but also there were well-defined regions that did not overlap. That is, the overlapping regions participate in both temporal perception tasks and executive function tasks, whilst the non-overlapping regions were only activated by one of the task types. The bilateral cortical regions that overlapped were specifically the prefrontal and cingulate areas as well as the parietal and temporal (insula) regions (Fig. 1). The results and their interpretation have, we believe, two important implications. First, there are cerebral networks – that we might call Temporal Networks or Cognitive Change Networks; and second, that these networks sustain and are common to all mental processes and operations that demand increases (and possibly also decreases) in cognitive load. Another recent meta-analytic study [4] found evidence to support a hypothesized superordinate cognitive control network in the brain subserving diverse executive functions domains. This network involved dorsolateral prefrontal, anterior cingulate, and parietal cortices. On the basis of our study we would concur that these cerebral networks exist but also suggest that the networks respond to changes in the demands made of them. With regard to the regions involved, the meta-analyses coincide, but we found the temporal insula, medial frontal (supplementary motor areas) and basal ganglia were also implied in our Temporal/Cognitive Change Network. These findings shed light on the mechanisms underlying cognition of higher processes. Carrying out any cognitive task, for example, during everyday activity, involves continuous modulation of the level of effort needed to deal with the ever-changing difficulty. In addition to task-specific networks, such changes in cognitive load also require participation of the common cerebral networks whose existence is suggested by these recent studies. The common networks that support modulation of effort during tasks involving executive functions also support time perception tasks. This finding somewhat belatedly provides backing to
Fig. 1. Overlap and lack of overlap between brain regions engaged during time perception tasks and during tasks requiring cognitive effort. (Talairach axial slices in neurological convention (i.e. right is right, left is left) showing regions with statistically significant activation only during time perception tasks (meta-analysis, red), regions with statistically significant activation only during tasks requiring cognitive effort (meta-analysis, blue), and regions with statistically significant activation both during time perception tasks and during tasks requiring cognitive effort (green). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) (Radúa et al. [2]. With permission from Elsevier).
510
Correspondence / Medical Hypotheses 83 (2014) 509–515
Aristotle’s philosophical concepts [5] that time perception is related to the perception of change and that time is ubiquitous; just as time is omnipresent in the processes of nature, so are the higher human cognitive functions.
[3] Niendam TA, Laird AR, Ray KL, Dean YM, Glahn DC, Carter CS. Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions. Cogn Affect Behav Neurosci 2012;12:241–68. [4] Wiener M, Turkeltaub P, Coslett HB. The image of time: a voxel-wise meta-analysis. NeuroImage 2010;49(2):1728–40. [5] Physics, in Aristotle, The Complete Works of Aristotle, Princeton University Press, 1984.
Conflict of interest Felipe Ortuño Irene Alústiza Department of Psychiatry and Medical Psychology, Clínica Universidad de Navarra, University of Navarre, Navarre, Spain E-mail address: [email protected](F. Ortuño)
We declare that we have no conflict of interest. References [1] Ortuño F, Guillén-Grima F, López-García P, Gómez J, Pla J. Functional neural networks of time perception: challenge and opportunity for schizophrenia research. Schizophr Res 2011;125(2–3):129–35. [2] Radúa J, Ojeda N, Gómez J, Guillén-Grima F, Ortuño F. Meta-analysis of functional neuroimaging studies indicates that an increase of cognitive difficulty during executive tasks engages brain regions associated with time perception. Neuropsychologia 2014;58:14–22.
http://dx.doi.org/10.1016/j.mehy.2014.07.014
Designer’s microglia with novel delivery system in neurodegenerative diseases q Abdul Mannan Baig ⇑ Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
a r t i c l e
i n f o
Article history: Received 18 April 2014 Accepted 5 August 2014
a b s t r a c t Neurodegenerative diseases are a group of central nervous system diseases that have a high rate of morbidity and mortality. More disabling than lethal, the pathogenesis of many of these diseases, like Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and Multiple sclerosis, (MS) remains to be established. Even after passage of several decades subsequent to their first recognition, these diseases have proven to be notoriously refractory towards drug treatment. Stem cell therapy itself has faced problems like ethical issues with such transplants, difficult and risky implantation routes and immune rejections of the implanted stem cells. Somatic cell nuclear transfer (SCNT) offers a hope to the aforesaid diseases if the cells selected for nuclear donation itself has inherent regenerative and scavenging properties. Here we propose olfactory ensheathing cells (OEC’s) as the donor somatic cell that conceivably would attempt regeneration in above mentioned diseases by differentiating into glia, which would have healthy mitochondria and without any fear of immune rejection. Also proposed is a method of delivering these cells after SCNT to the brain by a novel ‘‘transcribrial route’’ through a device that can deliver cells to the brain across the cribriform plate of ethmoid bone. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction There is currently no treatment for the loss of neuronal function after damage to the nervous system, multiple attempts at nerve re-growth across the peripheral nervous system (PNS) and the central nervous system (CNS) transition have not been successful [1]. Injuries and neurodegenerative (ND) diseases of (CNS) are unique in that they almost always get repaired by gliosis leading to loss of neurological function and resultant neurological deficits in the affected individual. In humans, neurogenesis largely ceases during adulthood, but in two areas of the brain, the hippocampus and olfactory bulb, there is strong evidence of regeneration of substantial numbers of new neurons [2]. Majority of ND diseases are characterized by activation of microglia, and mitochondrial q
This research is partly funded by Aga Khan University.
⇑ Address: Department of Biological and Biomedical Sciences, Aga Khan University, Stadium Road, Karachi, Pakistan. Tel.: +92 (0)21 3486 4435; fax: +92 (0)21 3493 4294. E-mail address: [email protected]
dysfunction in microglial cells is thought to contribute to the detrimental effects of neuroinflammation seen in ND diseases [3] Olfactory ensheathing cells (OECs) physiologically perform regenerative, scavenging and innate immune functions at the olfactory region and have been investigated in-depth in relation to spinal cord injuries, amyotrophic lateral sclerosis and other neurodegenerative diseases where research suggests that these cells possess a unique ability to remyelinate injured neurons [4]. The neurodegenerative diseases are slowly progressive and in contrast to the traumatic neuronal loss they can be targeted for decelerating their progression, prevention of onset and possible treatment by perhaps by modifying microglial cells cloned by somatic nucleus transfer (NT) from an (OEC’s) to an oocyte. After being reported that transplantation of fetal OECs into the frontal lobes can slow the rate of clinical progression in ALS patients, the subsequent neuropathologic analysis did not support a therapeutic efficacy for ALS patients even after OEC transplantation via the ventricles, although transplantation of OECs engi-
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Correspondence
Aristotle Got it right again! We would like to draw attention to the interesting implications of the existence of common cerebral networks demonstrated in several recent meta-analysis studies on time perception [1–3] to current knowledge of higher cognition processes. In particular we wish to highlight the results of a juxtaposition of two meta-analyses: a multimodal SDM study to identify brain regions involved in neuroimaging studies of response to increasing levels of cognitive difficulty; and an ALE meta-analysis on neuroimaging of time perception [2]. The former meta-analysis comprised 54 fMRI studies undertaken whilst subjects did tasks requiring executive functions. For the latter meta-analysis, there were 35 fMRI studies that looked at different aspects of temporal estimation, such as, interval estimation and discrimination of duration. We then used anatomic cerebral coordinates to carry out an overlapping analysis of statistically significant activation patterns from both meta-analyses. Note that what both groups of studies had in common was that they compared cerebral activation between two levels of difficulty of their respective experimental tasks. The methods and procedures involved are not new, they have been used in hundreds of neuroimaging studies over the last decade with a view to obtaining a functional neuroanatomical map and elucidating the connection between experimental tasks and superior functions. However, the same studies also reflect how the brain responds to an increase in cognitive load, an increase in the difficulty of what is demanded or an increase in the effort required. The fact that all the studies involve this kind of cognitive change is, we believe, critical to the interpretation of our results. Our main finding was that there is a group of brain regions engaged both by time perception tasks and by tasks involving an increase in cognitive load for non-time related executive functions.
There was a high degree of bilateral overlapping of cortical and subcortical regions, but also there were well-defined regions that did not overlap. That is, the overlapping regions participate in both temporal perception tasks and executive function tasks, whilst the non-overlapping regions were only activated by one of the task types. The bilateral cortical regions that overlapped were specifically the prefrontal and cingulate areas as well as the parietal and temporal (insula) regions (Fig. 1). The results and their interpretation have, we believe, two important implications. First, there are cerebral networks – that we might call Temporal Networks or Cognitive Change Networks; and second, that these networks sustain and are common to all mental processes and operations that demand increases (and possibly also decreases) in cognitive load. Another recent meta-analytic study [4] found evidence to support a hypothesized superordinate cognitive control network in the brain subserving diverse executive functions domains. This network involved dorsolateral prefrontal, anterior cingulate, and parietal cortices. On the basis of our study we would concur that these cerebral networks exist but also suggest that the networks respond to changes in the demands made of them. With regard to the regions involved, the meta-analyses coincide, but we found the temporal insula, medial frontal (supplementary motor areas) and basal ganglia were also implied in our Temporal/Cognitive Change Network. These findings shed light on the mechanisms underlying cognition of higher processes. Carrying out any cognitive task, for example, during everyday activity, involves continuous modulation of the level of effort needed to deal with the ever-changing difficulty. In addition to task-specific networks, such changes in cognitive load also require participation of the common cerebral networks whose existence is suggested by these recent studies. The common networks that support modulation of effort during tasks involving executive functions also support time perception tasks. This finding somewhat belatedly provides backing to
Fig. 1. Overlap and lack of overlap between brain regions engaged during time perception tasks and during tasks requiring cognitive effort. (Talairach axial slices in neurological convention (i.e. right is right, left is left) showing regions with statistically significant activation only during time perception tasks (meta-analysis, red), regions with statistically significant activation only during tasks requiring cognitive effort (meta-analysis, blue), and regions with statistically significant activation both during time perception tasks and during tasks requiring cognitive effort (green). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) (Radúa et al. [2]. With permission from Elsevier).
510
Correspondence / Medical Hypotheses 83 (2014) 509–515
Aristotle’s philosophical concepts [5] that time perception is related to the perception of change and that time is ubiquitous; just as time is omnipresent in the processes of nature, so are the higher human cognitive functions.
[3] Niendam TA, Laird AR, Ray KL, Dean YM, Glahn DC, Carter CS. Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions. Cogn Affect Behav Neurosci 2012;12:241–68. [4] Wiener M, Turkeltaub P, Coslett HB. The image of time: a voxel-wise meta-analysis. NeuroImage 2010;49(2):1728–40. [5] Physics, in Aristotle, The Complete Works of Aristotle, Princeton University Press, 1984.
Conflict of interest Felipe Ortuño Irene Alústiza Department of Psychiatry and Medical Psychology, Clínica Universidad de Navarra, University of Navarre, Navarre, Spain E-mail address: [email protected](F. Ortuño)
We declare that we have no conflict of interest. References [1] Ortuño F, Guillén-Grima F, López-García P, Gómez J, Pla J. Functional neural networks of time perception: challenge and opportunity for schizophrenia research. Schizophr Res 2011;125(2–3):129–35. [2] Radúa J, Ojeda N, Gómez J, Guillén-Grima F, Ortuño F. Meta-analysis of functional neuroimaging studies indicates that an increase of cognitive difficulty during executive tasks engages brain regions associated with time perception. Neuropsychologia 2014;58:14–22.
http://dx.doi.org/10.1016/j.mehy.2014.07.014
Designer’s microglia with novel delivery system in neurodegenerative diseases q Abdul Mannan Baig ⇑ Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
a r t i c l e
i n f o
Article history: Received 18 April 2014 Accepted 5 August 2014
a b s t r a c t Neurodegenerative diseases are a group of central nervous system diseases that have a high rate of morbidity and mortality. More disabling than lethal, the pathogenesis of many of these diseases, like Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and Multiple sclerosis, (MS) remains to be established. Even after passage of several decades subsequent to their first recognition, these diseases have proven to be notoriously refractory towards drug treatment. Stem cell therapy itself has faced problems like ethical issues with such transplants, difficult and risky implantation routes and immune rejections of the implanted stem cells. Somatic cell nuclear transfer (SCNT) offers a hope to the aforesaid diseases if the cells selected for nuclear donation itself has inherent regenerative and scavenging properties. Here we propose olfactory ensheathing cells (OEC’s) as the donor somatic cell that conceivably would attempt regeneration in above mentioned diseases by differentiating into glia, which would have healthy mitochondria and without any fear of immune rejection. Also proposed is a method of delivering these cells after SCNT to the brain by a novel ‘‘transcribrial route’’ through a device that can deliver cells to the brain across the cribriform plate of ethmoid bone. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction There is currently no treatment for the loss of neuronal function after damage to the nervous system, multiple attempts at nerve re-growth across the peripheral nervous system (PNS) and the central nervous system (CNS) transition have not been successful [1]. Injuries and neurodegenerative (ND) diseases of (CNS) are unique in that they almost always get repaired by gliosis leading to loss of neurological function and resultant neurological deficits in the affected individual. In humans, neurogenesis largely ceases during adulthood, but in two areas of the brain, the hippocampus and olfactory bulb, there is strong evidence of regeneration of substantial numbers of new neurons [2]. Majority of ND diseases are characterized by activation of microglia, and mitochondrial q
This research is partly funded by Aga Khan University.
⇑ Address: Department of Biological and Biomedical Sciences, Aga Khan University, Stadium Road, Karachi, Pakistan. Tel.: +92 (0)21 3486 4435; fax: +92 (0)21 3493 4294. E-mail address: [email protected]
dysfunction in microglial cells is thought to contribute to the detrimental effects of neuroinflammation seen in ND diseases [3] Olfactory ensheathing cells (OECs) physiologically perform regenerative, scavenging and innate immune functions at the olfactory region and have been investigated in-depth in relation to spinal cord injuries, amyotrophic lateral sclerosis and other neurodegenerative diseases where research suggests that these cells possess a unique ability to remyelinate injured neurons [4]. The neurodegenerative diseases are slowly progressive and in contrast to the traumatic neuronal loss they can be targeted for decelerating their progression, prevention of onset and possible treatment by perhaps by modifying microglial cells cloned by somatic nucleus transfer (NT) from an (OEC’s) to an oocyte. After being reported that transplantation of fetal OECs into the frontal lobes can slow the rate of clinical progression in ALS patients, the subsequent neuropathologic analysis did not support a therapeutic efficacy for ALS patients even after OEC transplantation via the ventricles, although transplantation of OECs engi-