- Email: [email protected]
At the forefront of clinical neuroscience
c o r t e x 4 8 ( 2 0 1 2 ) 1 e6
Available online at www.sciencedirect.com
Journal homepage: www.elsevier.com/locate/cortex
Special issue: Editorial
At the forefront of clinical neuroscience Marco Catani a,* and Donald T. Stuss b a b
Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, UK Ontario Brain Institute, Rotman Research Institute of Baycrest Centre, University of Toronto, Canada
Research on the functions of the frontal lobes has had a phenomenal growth in the last two decades, spurred in particular by the advent of functional magnetic resonance imaging (fMRI). The development of this method of analysis has proven invaluable. There is, however, a tendency to equate activation with a core function, and this is not necessarily true. In this special issue of Cortex, we emphasize the importance of the anatomy of the frontal lobes as a means of anchoring functional and clinical studies. A second objective is to underscore the historical salience of animal and human lesion research, in conjunction with older and newer structural imaging methods, as a framework on which to develop theoretical models. Three of the manuscripts provide unique historical insights that reveal the initial stages of research into the functions of the frontal lobes. Pendleton and colleagues’ review of Harvey Cushing’s research on frontal lobes presents in greater detail how Cushing prefaced Penfield’s groundwork research on brain localization using the technique of direct brain stimulation (Pendleton et al., 2012, this issue). Cushing’s position was in favour of Sherrington’s localization of the motor cortex in the precentral gyrus (Leyton and Sherrington, 1917) as opposed to Horsley’s idea of a motor cortex extending across both pre- and post-central gyri (Beevor and Horsley, 1890). Cushing’s description of the “distinct march of motor movements of fingers, wrist, elbow, shoulder” of Jacksonian reminiscence and his comparison of the effects of excision in humans to those in non-human primates, “just as in the anthropoid apes”, testify to the integrative spirit of that time when pioneers of the study of the frontal lobes were able to infer localization of brain function from both human clinical observations and animal experiments (Horsley, 1909). At the time of Cushing’s trial of the brain stimulation method, the localization of motor functions was a new and exciting field of investigation (Fig. 1). Initiated by the
anatomical work of Turner (1866) on the central sulcus and the experimental studies of Fritsch and Hitzig (1870) on the excitability of the motor cortex, this integrative approach culminated with Penfield’s description of the motor and sensory homunculus (Fig. 2). Cushing also had performed stimulation of subcortical white matter, again an innovative and prescient approach to a method that would gain wider use (Duffau, 2012, this issue). Among the anatomists that dedicated particular attention to the connections of the frontal lobe was a contemporary of Cushing, the German born Christfried Jakob (1866e1956). Jakob is largely unknown in the English speaking literature on the functions of the frontal lobes, as evidenced by the fact that he has largely not been cited in major historical reviews of frontal lobe functions. The translation of some of his work by Theodoridou and Triarhou (2012, this issue) is therefore a very welcome introduction of Jakob’s hodological approach. One of Jakob’s merits was to draw attention to the U-shaped fibres of the frontal lobe and its connections with subcortical nuclei of the thalamus and medial temporal lobe. In his drawings, he depicted all the major components of the limbic circuitry many years prior to Papez (1937) (Fig. 3). Jakob’s network approach to the frontal lobe had direct clinical relevance and provided an anatomical substrate for the concept of diaschisis. The term diaschisis, elaborated by Monakow (1914) to highlight the possible recovery of dysfunctional distant regions connected to the lesioned areas, was introduced into psychology by Alexander Luria in the second half of the 20th century. One of Luria’s first papers on “pseudo-frontal” symptoms secondary to a cerebellar tumour originally written in Russian had been translated into Italian, published in Cortex in 1964. This paper had not been further translated, and was not available to a broader audience. This new translation by Budisavljevic and Ramnani (2012, this issue)
* Corresponding author. Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, UK. E-mail address: [email protected] (M. Catani). 0010-9452/$ e see front matter ª 2011 Elsevier Srl. All rights reserved. doi:10.1016/j.cortex.2011.11.001
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Fig. 1 e The functional anatomy of regions in the proximity of the central sulcus. (A) Turner (1866) identified the Rolandic sulcus (R) as the landmark delimiting the posterior border of the frontal lobe. (B) Fritsch and Hitzig (1870) demonstrated the excitability of the motor cortex in the proximity of the central sulcus (indicated with D, #). (C) Beevor and Horsley (1890) continued the work of Fritsch and Hitzig and showed that the excitability of the motor cortex extends over both pre- and post-central regions. (D) Campbell (1905) used cytoarchitectonic neurohistology in post-mortem brains of amputees to identify the precentral cortex as the motor control area. (E) Leyton and Sherrington (1917) established precisely the true extent of the motor area and provided the first detailed ‘motor map’ of the primate motor cortex. In particular, they coupled cortical stimulation with surgical extirpation to show that the same cortical area giving rise to movement of a particular body part when stimulated, produces motor weakness and loss of the use of that same body part when extirpated.
adds this historical reference. As the authors comment, the paper reveals how prescient and observant Luria was, and indeed how he pursued critical hypothesis testing in explaining brain-behaviour relations. This case report also reminds the reader to examine the aetiology of the pathology and the extent of the lesion. For example, more limited focal lesions may provide even more precise bases for interpretation and comparison (Alexander et al., in press). Although Luria’s paper highlights the importance of a detailed understanding of circuitry that allow intercommunication between distant regions, his case reports constantly lacked detailed anatomical description of the lesion and its extension into underlying white matter connections. This problem was common to many studies of that time where the fine grained architecture of the mind outlined by neuropsychologists had not been paralleled by a comparable anatomical fractionation of the brain from anatomical examination. The lack of methods available to study the human brain in detail stimulated the extensive application of axonal tracing
studies in animals and the translation tout court of these results to humans. The orderly compartmentalization of the projections of different cortical areas within the corpus callosum summarized by Berlucchi (2012, this issue), for example, is mainly based on axonal tracing and degeneration studies performed in animals. Berlucchi also acknowledges that the study of anatomo-functional topography of the human corpus callosum has been “revolutionized” by the use of diffusion imaging tractography, particularly in conjunction with structural imaging (Catani and ffytche, 2010; Thiebaut de Schotten et al., 2011). By comparing human and monkey connectional anatomy, for example, we can unveil the architectural backbone of human cognition and the evolutionary changes that underlie our unique cognitive capacities (Fig. 4). Thiebaut de Schotten et al. (2012, this issue) provide in this special issue an example of the application of this approach applied to the comparative anatomy of frontal lobes connections underlying language, memory, and limbic functions. However, diffusion imaging is not without limitations and greater efforts will be
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Fig. 2 e (A) Penfield and Boldrev (1937) extended the work of Leyton and Sherrington (1917) in monkeys to humans and proposed the motor homunculus as a pictorial representation of the topographical distribution of the motoneurons controlling movements of different body parts. (B) Tractography reconstruction of U-shaped fibres of the central sulcus (Catani et al., 2012) showing a pattern of fibre distribution that corresponds to the topographical organization of the motor homunculus.
Fig. 3 e Jakob’s early work provided a prescient anatomical framework for what later become an intense area of investigation into the anatomical substrate of memory, emotions, and behavioural disorders associated with frontal lobe damage. Jakob very clearly drew out the U-shaped fibres of the frontal lobes (A), pathways that are now emphasized in contemporary anatomical imaging studies (B) (Catani et al., 2012). Jakob also identified in 1906 all the tracts of the limbic circuit (C), leading one to speculate on any possible relationship between him and Papez circuit (1937) (D).
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Fig. 4 e Comparative anatomy of the corpus callosum. Correspondence between the (A) post-mortem segmentation of the mid-sagittal area of the corpus callosum in the monkey (Macaca mulatta) based on axonal tracing methods (Schmahmann and Pandya, 2006) and (B) in the human brain based on spherical deconvolution tractography (Catani and Thiebaut de Schotten, 2012, this issue).
necessary to validate its results as forcefully stated by Petrides et al. (2012, this issue): “. although the stems of the major pathways can be visualized with diffusion tensor imaging (DTI) in the human brain, detailed information about the precise cortical origins of axons and their precise cortical terminations must be derived from anterograde and retrograde tracer studies in the macaque monkey.” The basic anatomical work on the frontal lobe architectonics (Petrides et al., 2012, this issue) and connectivity (Yeterian et al., 2012, this issue) has been completed in the macaque monkey. Yeterian et al. (2012, this issue) focus on the issue of why knowledge of pathways is key, particularly in understanding how neural circuits are related to behaviour. One important contribution of this article is the emphasis on frontal intra-lobar connections, which could explain in part the uniqueness of the human frontal lobe functions. Catani et al. (2012) also address this aspect providing a new framework for the local frontal circuitry using tractography in the human brain. These are important advances, but tractography remains an anatomical tool and does not provide information on the functional correlates of each tract. The papers by Krause et al. (2012, this issue) and Duffau (2012, this issue) suggest a purpose for, and at least partial validation of, tractography as a method of examining in vivo human anatomical connections. Krause et al. (2012, this issue) illustrate the importance of the clinical case study in understanding brain-behaviour relations. Two important lessons can be extracted from this paper. First, if one understands anatomical circuits and networks, case studies can be invaluable in investigating the
role of local nodes in the network. Second, there is the recognition that single case studies provide faster insights into brain-behaviour functions, but at the same time, with intra-individual variability, there is a need to follow-up with larger group lesion and functional imaging studies. In interpreting these data, one should consider distance effects such as frontal hypoperfusion after sub-cortical lesions, suggesting a diaschisis mechanism. Duffau’s paper is a modern exemplar of the value and practical application of stimulation techniques pioneered by Cushing and Penfield to localize functions. But Duffau has a different motive and interpretation e to move beyond cortical localization to understand the role of systems and white matter pathways. This lesson cannot be underestimated. Understanding the functions of different regions serves as the building blocks for understanding systems and more complex brain organization. In such a view, that is understanding both the fractionation and the existence of systems, one indeed can question the existence of a “frontal syndrome”. Duffau emphasizes the importance of links between disciplines and approaches. Part 2 of the Special issue contains a series of papers that exemplify the use of neuroimaging methods applied to different neurological and psychiatric disorders to test the advantages of a network approach to frontal lobe symptoms. One can ask questions about how a circuit works, and differentiate, for example, qualitative (different processes) from quantitative (same basic process, but more or less salient) processes. Directionality of the network related to function could be examined. Another important and clinically relevant research theme would focus on how networks change with recovery (Berthier et al., 2012; Bizzi et al., 2012). For example, if one node in a circuit is damaged, one could examine if the connected region
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is still functional. Alternatively, damage in one part of a network might “release” the functions of a connected area, causing markedly aberrant behaviour. If such behaviour is transient, neural network analysis might explain why. Studying groups of patients with different frontal lobe disorders demonstrates the value of complementary neuroimaging approaches. The article by Towgood et al. (in press) presents an interesting observation based on voxel-based analysis of T1 and DTI data. Even in HIV asymptomatic patients, imaging appears to be sensitive to changes in medial and superior frontal gyri, suggesting a sensitivity of the approach in the early disease stage. Tsermentseli et al. (2012) summarize decades of neuroimaging studies in motor neuron disease and put forward a strong case for considering premotor and prefrontal dysfunction in a disorder whose pathology is classically considered to be limited to the motor regions. Zappala` et al. (2012) discuss the value of DTI to map changes in the microstructure of frontal white matter pathology in traumatic brain injury (TBI). Although pathology in this region is almost universal after TBI, the relation to specific networks is sometimes missed. DTI then becomes an important biomarker. Interestingly, the classification of TBI outcomes in distinct syndromes related to different areas of maximum pathology maps onto those regions of frontal lobe functions that have been described in groups of patients with focal lesions (Stuss and Alexander, 2007; Stuss, 2011). The content in the manuscript by Arevalo et al., (in press) address the relation between lesions in sensorimotor regions and the processing of linguistic stimuli related to motorrelated concepts. In addition to the content, the paper exemplifies the importance of group lesion studies, and demonstrates how to do such studies well. These authors isolated the functions of specific regions by testing performance of patients with and without pathology in defined areas. This type of anatomical approach with patients can be a very valuable method for functional localization and identifying which regions are necessary. As such, this evidence can provide the validation for the interpretation of imaging studies (see also Stuss et al., 2005; Stuss and Alexander, 2007; Vallesi et al. 2009a,b). However, there are limitations in both
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the method and interpretation of these lesion studies: e.g., adequate representation of all relevant regions; the number of patients involved and statistical power; the potential overinterpretation of localization without adequate consideration of local impact on underlying white matter pathology and more distant networks (Catani and Thiebaut de Schotten, 2012, this issue; Poppenk et al., 2010). Contemporary neuroimaging approaches can be applied to gain potential insights into the neural dysfunction of those neurodevelopmental disorders where a clear pathology is often not visible on conventional MRI. Three manuscripts reporting neuroimaging findings in psychiatric disorders demonstrate how knowledge of brain-behaviour relations can lead to improved understanding of the disorder. Cubillo et al. (in press) used fMRI to demonstrate that childhood and adult ADHD could be explained by the impairment of different overlapping cortico-subcortical networks, all involving the frontal lobes. Langen et al. (in press) used DTI tractography and voxel-based analysis to examine the fronto-striatal white matter tracts in individuals with autism, and relating this to specific phenomena of repetitive behaviour and inhibitory control deficits. Sundram et al. (in press) applied voxel-based analysis to antisocial behaviour and their results suggest frontolimbic disconnectivity in adult psychopaths, particularly in the right hemisphere. The manuscript by O’Muircheartaigh and Richardson (in press) highlights the necessity of a hodological approach to epileptic disorders of the frontal lobe. Here, understanding the anatomical networks could help predict spreading of the epileptic discharge, thereby facilitating the diagnosis and planning of neurosurgical approaches. We are well aware that there are many areas that the special issue has not covered in relation to the clinical neuroanatomy of the frontal lobes. Our hope is to stimulate new ideas and novel approaches to frontal lobe dysfunction and highlight advantages and limitations of current methods of investigation. The delineation of the anatomical connections of the human brain remains the greatest challenge ahead (Fig. 5). We look forward to progresses in this area and hope that some of the ideas presented in this special issue will be put to test.
Fig. 5 e Comparison between (A) frontal lobe connections in the monkey (Bailey and von Bonin, 1951) and (B) recent attempts to produce similar maps in the human brain with spherical deconvolution tractography (Catani et al., 2012).
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references
Alexander MP, Gillingham S, Schweizer TA and Stuss DT. Cognitive impairments due to focal cerebellar injuries in adults. Cortex, in press. Arevalo AL, Balco JV, and Dronkers NF. What do brain lesions tell us about theories of embodied semantics and the human mirror neuron system? Cortex, doi:10.1016/j.cortex.2010.06.001. Bailey P and von Bonin G. The Isocortex of Man. Urbana: University of Illinois Press, 1951. Beevor C and Horsley V. An experimental investigation into the arrangement of the excitable fibres of the internal capsule of the bonnet monkey (Macacus sinicus). Philosophical Transactions of the Royal Society of London, Series B, 181: 49e88, 1890. Berlucchi G. Frontal callosal disconnection syndromes. Cortex, 48(1): 35e44, 2012. Berthier ML, Lambon Ralph MA, Pujol J, and Green C. Arcuate fasciculus variability and repetition: The left sometimes can be right. Cortex, doi:10.1016/j.cortex.2011.06.014. Bizzi A, Nava S, Ferre` F, Castelli G, Aquino D, Ciaraffa F, et al. Gliomas infiltrating the ventrolateral frontal region: Clinical anatomo-functional language assessment with neuropsychology, diffusion MR tractography and functional MR imaging. Cortex, doi:10.1016/j.cortex.2011.11.015. Budisavljevic S and Ramnani N. Cognitive deficits from a cerebellar tumour: A historical case report from Luria’s laboratory. Cortex, 48(1): 26e34, 2012. Campbell AW. Histological Studies on the Localisation of Cerebral Function. Cambridge: Cambridge University Press, 1905. Catani M and ffytche DH. On ‘the study of the nervous system and behaviour’. Cortex, 46(1): 106e109, 2010. Catani M, Dell’Acqua F, Vergani F, Malik F, Hodge H, Roy P, et al. Short frontal lobe connections of the human brain. Cortex, doi:10.1016/j.cortex.2011.12.001. Catani M and Thiebaut de Schotten M. Atlas of human brain connections. Oxford: Oxford University Press, 2012. Cubillo A, Halari R, Smith A, Taylor E, and Rubia K. A review of fronto-striatal and fronto-cortical brain abnormalities in children and adults with Attention Deficit Hyperactivity Disorder (ADHD) and new evidence for dysfunction in adults with ADHD during motivation and attention. Cortex, doi:10.1016/j.cortex.2011.04.007. Duffau H. The “frontal syndrome” revisited: Lessons from electrostimulation mapping studies. Cortex, 48(1): 118e129, 2012. ¨ ber die elektrische Erregbarkeit des Fritsch G and Hitzig E. U Grosshirns. Archiv fu¨r Anatomie, Physiologie und wissenschaftliche Medizin, 37: 300e332, 1870. Horsley V. The functions of the so-called motor area of the brain: Linacre lecture. British Medical Journal, 2(2533): 125e132, 1909. Krause M, Mahant N, Kotschet K, Fung VS, Vagg D, Wong CH, et al. Dysexecutive behaviour following deep brain lesions e A different type of disconnection syndrome. Cortex, 48(1): 96e117, 2012. Langen M, Leemans A, Johnston P, Ecker C, Daly E, Murphy CM, et al. Fronto-striatal circuitry and inhibitory control in autism: Findings from diffusion tensor imaging tractography. Cortex, doi:10.1016/j.cortex.2011.05.018. Leyton SSF and Sherrington CS. Observations on the excitable cortex of the chimpanzee, orang-utan and gorilla. Quarterly Journal of Experimental Physiology, 11: 135e222, 1917. Monakow C. von. Die Lokalisation im Grosshirn und der Abbau der Funktion durch kortikale Herde. Wiesbaden: JF Bergmann, 1914. O’Muircheartaigh J and Richardson MP. Epilepsy and the frontal lobes. Cortex, doi:10.1016/j.cortex.2011.11.012.
Papez JW. A proposed mechanism of emotion. Archives of Neurology & Psychiatry, 38(4): 725e743, 1937. Pendleton C, Zaidi HA, Chaichana KL, Raza SM, Carson BS, CohenGadol AA, et al. Harvey Cushing’s contributions to motor mapping: 1902e1912. Cortex, 48(1): 7e14, 2012. Penfield W and Boldrev E. Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain, 60(4): 389e443, 1937. Petrides M, Tomaiuolo F, Yeterian EH, and Pandya DN. The prefrontal cortex: Comparative architectonic organization in the human and the macaque monkey brains. Cortex, 48(1): 45e56, 2012. Poppenk J, Moscovitch M, Mcintosh AR, Ozcelik E, and Craik FIM. Encoding the future: Successful processing of intentions engages predictive brain networks. NeuroImage, 49(1): 905e913, 2010. Schmahmann JD and Pandya DN. Fibre Pathways of the Brain. Oxford: Oxford University Press, 2006. Sundram F, Deeley Q, Sarkar S, Daly E, Latham R, Craig M, et al. White matter microstructural abnormalities in the frontal lobe of adults with antisocial personality. Cortex, doi:10.1016/j. cortex.2011.06.005. Stuss DT. Functions of the frontal lobes: Relation to executive functions. Journal of the International Neuropsychological Society, 17(5): 759e765, 2011. Stuss DT and Alexander MP. Is there a dysexecutive syndrome? Philosophical Transactions of the Royal Society of London, Series B, 362(1481): 901e915, 2007. Stuss DT, Alexander MP, Shallice T, Picton TW, Binns MA, MacDonald R, et al. Multiple frontal systems controlling response speed. Neuropsychologia, 43(3): 396e417, 2005. Theodoridou Z and Triarhou LC. Challenging the supremacy of the frontal lobe: Early views (1906e1909) of Christfried Jakob on the human cerebral cortex. Cortex, 48(1): 15e25, 2012. Thiebaut de Schotten M, ffytche DH, Bizzi A, Dell’Acqua F, Allin M, Walshe M, et al. Atlasing location, asymmetry and inter-subject variability of white matter tracts in the human brain with MR diffusion tractography. NeuroImage, 54(1): 49e59, 2011. Thiebaut de Schotten M, Dell’Acqua F, Valabregue R, and Catani M. Monkey to human comparative anatomy of the frontal lobe association tracts. Cortex, 48(1): 81e95, 2012. Towgood KJ, Pitkanen M, Kulasegaram R, Fradera A, Kumar A, Soni S, et al. Mapping the brain in younger and older asymptomatic HIV-1 men: Frontal volume changes in the absence of other cortical or diffusion tensor abnormalities. Cortex, doi:10.1016/j.cortex.2011.03.006. Tsermentseli S, Leigh N, and Goldstein LH. The anatomy of cognitive impairment in amyotrophic lateral sclerosis: More than frontal lobe dysfunction. Cortex, doi:10.1016/j.cortex. 2011.02.004. Turner W. The Convolutions of the Human Cerebrum Topographically Considered. Edinburgh: Maclachlan and Stewart, 1866. Vallesi A, McIntosh AR, Alexander MP, and Stuss DT. fMRI evidence of a functional network setting the criteria for withholding a response. NeuroImage, 45(2): 537e548, 2009a. Vallesi A, McIntosh AR, Shallice T, and Stuss DT. When time shapes behavior: fMRI evidence of brain correlates of temporal monitoring. Journal of Cognitive Neuroscience, 21(6): 1116e1126, 2009b. Yeterian EH, Pandya DN, Tomaiuolo F, and Petrides M. The cortical connectivity of the prefrontal cortex in the monkey brain. Cortex, 48(1): 57e80, 2012. Zappala` G, Thiebaut de Schotten M, and Eslinger PJ. Traumatic brain injury and the frontal lobes: what can we gain with diffusion tensor imaging. Cortex, doi:10.1016/j.cortex.2011.06.020.
Available online at www.sciencedirect.com
Journal homepage: www.elsevier.com/locate/cortex
Special issue: Editorial
At the forefront of clinical neuroscience Marco Catani a,* and Donald T. Stuss b a b
Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, UK Ontario Brain Institute, Rotman Research Institute of Baycrest Centre, University of Toronto, Canada
Research on the functions of the frontal lobes has had a phenomenal growth in the last two decades, spurred in particular by the advent of functional magnetic resonance imaging (fMRI). The development of this method of analysis has proven invaluable. There is, however, a tendency to equate activation with a core function, and this is not necessarily true. In this special issue of Cortex, we emphasize the importance of the anatomy of the frontal lobes as a means of anchoring functional and clinical studies. A second objective is to underscore the historical salience of animal and human lesion research, in conjunction with older and newer structural imaging methods, as a framework on which to develop theoretical models. Three of the manuscripts provide unique historical insights that reveal the initial stages of research into the functions of the frontal lobes. Pendleton and colleagues’ review of Harvey Cushing’s research on frontal lobes presents in greater detail how Cushing prefaced Penfield’s groundwork research on brain localization using the technique of direct brain stimulation (Pendleton et al., 2012, this issue). Cushing’s position was in favour of Sherrington’s localization of the motor cortex in the precentral gyrus (Leyton and Sherrington, 1917) as opposed to Horsley’s idea of a motor cortex extending across both pre- and post-central gyri (Beevor and Horsley, 1890). Cushing’s description of the “distinct march of motor movements of fingers, wrist, elbow, shoulder” of Jacksonian reminiscence and his comparison of the effects of excision in humans to those in non-human primates, “just as in the anthropoid apes”, testify to the integrative spirit of that time when pioneers of the study of the frontal lobes were able to infer localization of brain function from both human clinical observations and animal experiments (Horsley, 1909). At the time of Cushing’s trial of the brain stimulation method, the localization of motor functions was a new and exciting field of investigation (Fig. 1). Initiated by the
anatomical work of Turner (1866) on the central sulcus and the experimental studies of Fritsch and Hitzig (1870) on the excitability of the motor cortex, this integrative approach culminated with Penfield’s description of the motor and sensory homunculus (Fig. 2). Cushing also had performed stimulation of subcortical white matter, again an innovative and prescient approach to a method that would gain wider use (Duffau, 2012, this issue). Among the anatomists that dedicated particular attention to the connections of the frontal lobe was a contemporary of Cushing, the German born Christfried Jakob (1866e1956). Jakob is largely unknown in the English speaking literature on the functions of the frontal lobes, as evidenced by the fact that he has largely not been cited in major historical reviews of frontal lobe functions. The translation of some of his work by Theodoridou and Triarhou (2012, this issue) is therefore a very welcome introduction of Jakob’s hodological approach. One of Jakob’s merits was to draw attention to the U-shaped fibres of the frontal lobe and its connections with subcortical nuclei of the thalamus and medial temporal lobe. In his drawings, he depicted all the major components of the limbic circuitry many years prior to Papez (1937) (Fig. 3). Jakob’s network approach to the frontal lobe had direct clinical relevance and provided an anatomical substrate for the concept of diaschisis. The term diaschisis, elaborated by Monakow (1914) to highlight the possible recovery of dysfunctional distant regions connected to the lesioned areas, was introduced into psychology by Alexander Luria in the second half of the 20th century. One of Luria’s first papers on “pseudo-frontal” symptoms secondary to a cerebellar tumour originally written in Russian had been translated into Italian, published in Cortex in 1964. This paper had not been further translated, and was not available to a broader audience. This new translation by Budisavljevic and Ramnani (2012, this issue)
* Corresponding author. Natbrainlab, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, King’s College London, UK. E-mail address: [email protected] (M. Catani). 0010-9452/$ e see front matter ª 2011 Elsevier Srl. All rights reserved. doi:10.1016/j.cortex.2011.11.001
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Fig. 1 e The functional anatomy of regions in the proximity of the central sulcus. (A) Turner (1866) identified the Rolandic sulcus (R) as the landmark delimiting the posterior border of the frontal lobe. (B) Fritsch and Hitzig (1870) demonstrated the excitability of the motor cortex in the proximity of the central sulcus (indicated with D, #). (C) Beevor and Horsley (1890) continued the work of Fritsch and Hitzig and showed that the excitability of the motor cortex extends over both pre- and post-central regions. (D) Campbell (1905) used cytoarchitectonic neurohistology in post-mortem brains of amputees to identify the precentral cortex as the motor control area. (E) Leyton and Sherrington (1917) established precisely the true extent of the motor area and provided the first detailed ‘motor map’ of the primate motor cortex. In particular, they coupled cortical stimulation with surgical extirpation to show that the same cortical area giving rise to movement of a particular body part when stimulated, produces motor weakness and loss of the use of that same body part when extirpated.
adds this historical reference. As the authors comment, the paper reveals how prescient and observant Luria was, and indeed how he pursued critical hypothesis testing in explaining brain-behaviour relations. This case report also reminds the reader to examine the aetiology of the pathology and the extent of the lesion. For example, more limited focal lesions may provide even more precise bases for interpretation and comparison (Alexander et al., in press). Although Luria’s paper highlights the importance of a detailed understanding of circuitry that allow intercommunication between distant regions, his case reports constantly lacked detailed anatomical description of the lesion and its extension into underlying white matter connections. This problem was common to many studies of that time where the fine grained architecture of the mind outlined by neuropsychologists had not been paralleled by a comparable anatomical fractionation of the brain from anatomical examination. The lack of methods available to study the human brain in detail stimulated the extensive application of axonal tracing
studies in animals and the translation tout court of these results to humans. The orderly compartmentalization of the projections of different cortical areas within the corpus callosum summarized by Berlucchi (2012, this issue), for example, is mainly based on axonal tracing and degeneration studies performed in animals. Berlucchi also acknowledges that the study of anatomo-functional topography of the human corpus callosum has been “revolutionized” by the use of diffusion imaging tractography, particularly in conjunction with structural imaging (Catani and ffytche, 2010; Thiebaut de Schotten et al., 2011). By comparing human and monkey connectional anatomy, for example, we can unveil the architectural backbone of human cognition and the evolutionary changes that underlie our unique cognitive capacities (Fig. 4). Thiebaut de Schotten et al. (2012, this issue) provide in this special issue an example of the application of this approach applied to the comparative anatomy of frontal lobes connections underlying language, memory, and limbic functions. However, diffusion imaging is not without limitations and greater efforts will be
c o r t e x 4 8 ( 2 0 1 2 ) 1 e6
3
Fig. 2 e (A) Penfield and Boldrev (1937) extended the work of Leyton and Sherrington (1917) in monkeys to humans and proposed the motor homunculus as a pictorial representation of the topographical distribution of the motoneurons controlling movements of different body parts. (B) Tractography reconstruction of U-shaped fibres of the central sulcus (Catani et al., 2012) showing a pattern of fibre distribution that corresponds to the topographical organization of the motor homunculus.
Fig. 3 e Jakob’s early work provided a prescient anatomical framework for what later become an intense area of investigation into the anatomical substrate of memory, emotions, and behavioural disorders associated with frontal lobe damage. Jakob very clearly drew out the U-shaped fibres of the frontal lobes (A), pathways that are now emphasized in contemporary anatomical imaging studies (B) (Catani et al., 2012). Jakob also identified in 1906 all the tracts of the limbic circuit (C), leading one to speculate on any possible relationship between him and Papez circuit (1937) (D).
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Fig. 4 e Comparative anatomy of the corpus callosum. Correspondence between the (A) post-mortem segmentation of the mid-sagittal area of the corpus callosum in the monkey (Macaca mulatta) based on axonal tracing methods (Schmahmann and Pandya, 2006) and (B) in the human brain based on spherical deconvolution tractography (Catani and Thiebaut de Schotten, 2012, this issue).
necessary to validate its results as forcefully stated by Petrides et al. (2012, this issue): “. although the stems of the major pathways can be visualized with diffusion tensor imaging (DTI) in the human brain, detailed information about the precise cortical origins of axons and their precise cortical terminations must be derived from anterograde and retrograde tracer studies in the macaque monkey.” The basic anatomical work on the frontal lobe architectonics (Petrides et al., 2012, this issue) and connectivity (Yeterian et al., 2012, this issue) has been completed in the macaque monkey. Yeterian et al. (2012, this issue) focus on the issue of why knowledge of pathways is key, particularly in understanding how neural circuits are related to behaviour. One important contribution of this article is the emphasis on frontal intra-lobar connections, which could explain in part the uniqueness of the human frontal lobe functions. Catani et al. (2012) also address this aspect providing a new framework for the local frontal circuitry using tractography in the human brain. These are important advances, but tractography remains an anatomical tool and does not provide information on the functional correlates of each tract. The papers by Krause et al. (2012, this issue) and Duffau (2012, this issue) suggest a purpose for, and at least partial validation of, tractography as a method of examining in vivo human anatomical connections. Krause et al. (2012, this issue) illustrate the importance of the clinical case study in understanding brain-behaviour relations. Two important lessons can be extracted from this paper. First, if one understands anatomical circuits and networks, case studies can be invaluable in investigating the
role of local nodes in the network. Second, there is the recognition that single case studies provide faster insights into brain-behaviour functions, but at the same time, with intra-individual variability, there is a need to follow-up with larger group lesion and functional imaging studies. In interpreting these data, one should consider distance effects such as frontal hypoperfusion after sub-cortical lesions, suggesting a diaschisis mechanism. Duffau’s paper is a modern exemplar of the value and practical application of stimulation techniques pioneered by Cushing and Penfield to localize functions. But Duffau has a different motive and interpretation e to move beyond cortical localization to understand the role of systems and white matter pathways. This lesson cannot be underestimated. Understanding the functions of different regions serves as the building blocks for understanding systems and more complex brain organization. In such a view, that is understanding both the fractionation and the existence of systems, one indeed can question the existence of a “frontal syndrome”. Duffau emphasizes the importance of links between disciplines and approaches. Part 2 of the Special issue contains a series of papers that exemplify the use of neuroimaging methods applied to different neurological and psychiatric disorders to test the advantages of a network approach to frontal lobe symptoms. One can ask questions about how a circuit works, and differentiate, for example, qualitative (different processes) from quantitative (same basic process, but more or less salient) processes. Directionality of the network related to function could be examined. Another important and clinically relevant research theme would focus on how networks change with recovery (Berthier et al., 2012; Bizzi et al., 2012). For example, if one node in a circuit is damaged, one could examine if the connected region
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is still functional. Alternatively, damage in one part of a network might “release” the functions of a connected area, causing markedly aberrant behaviour. If such behaviour is transient, neural network analysis might explain why. Studying groups of patients with different frontal lobe disorders demonstrates the value of complementary neuroimaging approaches. The article by Towgood et al. (in press) presents an interesting observation based on voxel-based analysis of T1 and DTI data. Even in HIV asymptomatic patients, imaging appears to be sensitive to changes in medial and superior frontal gyri, suggesting a sensitivity of the approach in the early disease stage. Tsermentseli et al. (2012) summarize decades of neuroimaging studies in motor neuron disease and put forward a strong case for considering premotor and prefrontal dysfunction in a disorder whose pathology is classically considered to be limited to the motor regions. Zappala` et al. (2012) discuss the value of DTI to map changes in the microstructure of frontal white matter pathology in traumatic brain injury (TBI). Although pathology in this region is almost universal after TBI, the relation to specific networks is sometimes missed. DTI then becomes an important biomarker. Interestingly, the classification of TBI outcomes in distinct syndromes related to different areas of maximum pathology maps onto those regions of frontal lobe functions that have been described in groups of patients with focal lesions (Stuss and Alexander, 2007; Stuss, 2011). The content in the manuscript by Arevalo et al., (in press) address the relation between lesions in sensorimotor regions and the processing of linguistic stimuli related to motorrelated concepts. In addition to the content, the paper exemplifies the importance of group lesion studies, and demonstrates how to do such studies well. These authors isolated the functions of specific regions by testing performance of patients with and without pathology in defined areas. This type of anatomical approach with patients can be a very valuable method for functional localization and identifying which regions are necessary. As such, this evidence can provide the validation for the interpretation of imaging studies (see also Stuss et al., 2005; Stuss and Alexander, 2007; Vallesi et al. 2009a,b). However, there are limitations in both
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the method and interpretation of these lesion studies: e.g., adequate representation of all relevant regions; the number of patients involved and statistical power; the potential overinterpretation of localization without adequate consideration of local impact on underlying white matter pathology and more distant networks (Catani and Thiebaut de Schotten, 2012, this issue; Poppenk et al., 2010). Contemporary neuroimaging approaches can be applied to gain potential insights into the neural dysfunction of those neurodevelopmental disorders where a clear pathology is often not visible on conventional MRI. Three manuscripts reporting neuroimaging findings in psychiatric disorders demonstrate how knowledge of brain-behaviour relations can lead to improved understanding of the disorder. Cubillo et al. (in press) used fMRI to demonstrate that childhood and adult ADHD could be explained by the impairment of different overlapping cortico-subcortical networks, all involving the frontal lobes. Langen et al. (in press) used DTI tractography and voxel-based analysis to examine the fronto-striatal white matter tracts in individuals with autism, and relating this to specific phenomena of repetitive behaviour and inhibitory control deficits. Sundram et al. (in press) applied voxel-based analysis to antisocial behaviour and their results suggest frontolimbic disconnectivity in adult psychopaths, particularly in the right hemisphere. The manuscript by O’Muircheartaigh and Richardson (in press) highlights the necessity of a hodological approach to epileptic disorders of the frontal lobe. Here, understanding the anatomical networks could help predict spreading of the epileptic discharge, thereby facilitating the diagnosis and planning of neurosurgical approaches. We are well aware that there are many areas that the special issue has not covered in relation to the clinical neuroanatomy of the frontal lobes. Our hope is to stimulate new ideas and novel approaches to frontal lobe dysfunction and highlight advantages and limitations of current methods of investigation. The delineation of the anatomical connections of the human brain remains the greatest challenge ahead (Fig. 5). We look forward to progresses in this area and hope that some of the ideas presented in this special issue will be put to test.
Fig. 5 e Comparison between (A) frontal lobe connections in the monkey (Bailey and von Bonin, 1951) and (B) recent attempts to produce similar maps in the human brain with spherical deconvolution tractography (Catani et al., 2012).
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