The Cerebral Cortex in Neurodegenerative and Neuropsychiatric Disorders: Experimental Approaches to Clinical Issues

The Cerebral Cortex in Neurodegenerative and Neuropsychiatric Disorders

Experimental Approaches to Clinical Issues

Editors

David F. Cechetto

Nina Weishaupt

University of Western Ontario, London, ON, Canada

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Foreword

Introduction

Part I. Introductory Chapters

Chapter 1. Anatomy of the Cerebral Cortex

Introduction

Cortical Areas

Cortical Layers

Cortical Verticality (Columns)

Cell Types

Connections

Concluding Remarks

Chapter 2. Cortical Plasticity in Response to Injury and Disease

Plasticity: A Major Player in Recovery From Central Nervous System Injury and Disease

Systems Level Plasticity

Plasticity at the Microanatomical Level

How Can We Promote and Modify Plasticity?

Beware the Dark Side of Plasticity

Challenges and Hopes for the Investigation of Central Nervous System Plasticity

Chapter 3. Imaging Approaches to Cerebral Cortex Pathology

Introduction

Magnetic Resonance Imaging

Positron Emission Tomography

Future Direction and Expert Opinion

Part II. The Cerebral Cortex in Neurodegenerative Disorders

Chapter 4. Alzheimer’s Disease

Clinical Manifestations

Cerebral Cortex Pattern of Alzheimer’s Disease Progression

Imaging Alzheimer’s Disease Pathology

Alzheimer’s Disease Therapeutics

Future Directions

Chapter 5. Vascular Dementia

Introduction: The Challenge of Vascular Dementia

Risk Factors for Vascular Cognitive Impairment

Cortical Vascular Lesions Often Associated with Dementia

Vascular Alterations Leading to Cerebral Damage

Cerebral Lesions Resulting From Vascular Mechanisms

Vascular Contributions to Cognitive Impairment and Dementia

Potential Mechanisms of Interaction Between Vascular Conditions and Dementia

Experimental Models of Vascular Dementia

Prevention and Treatment

Chapter 6. Frontotemporal Dementia

Introduction

Clinical Manifestations

Imaging Studies of Frontotemporal Dementia

Frontotemporal Dementia Genetics

Experimental Models

Therapeutic Approaches

Future Directions

Chapter 7. Parkinson’s Disease and the Cerebral Cortex

Introduction

Pathophysiology of Parkinson’s Disease

Animal Models of Parkinson’s Disease

Tremors and the Cerebral Cortex

Akinesia and Bradykinesia and the Cerebral Cortex

Cognitive Impairment and the Cerebral Cortex

Neurotransmitters and Gene Expression in the Cortex

Conclusion

Chapter 8. Huntington Disease

Introduction

Clinical Features and Symptoms of Huntington Disease

Cerebral Cortex in Huntington Disease: Postmortem Studies

Cerebral Cortex in Huntington Disease: Brain Imaging Findings

Cerebral Cortex and Symptom Heterogeneity From Human Studies

Dysfunctional Corticostriatal Network in Huntington Disease Animal Models

Huntington Disease Pathogenesis: Mechanisms and Pathways in Relation to Cortex

Therapeutic Aspects and Future Directions

Conclusion

Chapter 9. Cortical Manifestations in Amyotrophic Lateral Sclerosis

Background

Neuropsychological Manifestations of Frontotemporal Dysfunction in Amyotrophic Lateral Sclerosis

Molecular, Clinical, and Neuropathological Correlates of Frontotemporal Dysfunction in Amyotrophic Lateral Sclerosis

Neuroimaging Correlates of Impaired Neural Network Function as the Basis of Frontotemporal Dysfunction in Amyotrophic Lateral Sclerosis

Models of Neuropsychological Dysfunction in Amyotrophic Lateral Sclerosis

Therapeutic Strategies

Conclusions and Future Directions

Chapter 10. Cortical Involvement in Multiple Sclerosis

Introduction

Relevance of Cortical Pathology to Multiple Sclerosis

Cortical Studies in Human Multiple Sclerosis

In Vivo Models of Multiple Sclerosis Cortical Pathology

In Vitro Studies Relevant to Cortical Pathology

Cortical Pathology and Therapeutics

Future Perspectives

Part III. The Cerebral Cortex in Neuropsychiatric Disorders

Chapter 11. Prefrontal Cortical Abnormalities in Cognitive Deficits of Schizophrenia

Introduction

Cognitive Deficits Represent Core Symptoms of Schizophrenia

The Prefrontal Cortex: A Nodal Point Mediating Cognitive Deficits

Abnormalities Involve Both Pyramidal and Nonpyramidal Neurons

Pyramidal Neuronal Abnormalities May Lower Their Excitability

γ-Aminobutyric Acid Neuronal Changes Reduce Inhibitory Tone in the PFC

Preclinical Animal Models of Schizophrenia With Prefrontal Cortex Abnormalities

Conclusions

Chapter 12. Role of the Prefrontal Cortex in Addictive Disorders

Introduction

Clinical Evidence for Prefrontal Cortical Pathology in Addiction

Effects of Acute Drug Exposure and Drug-Related Cue Exposure on Human Prefrontal Cortex Activity Patterns

Human Prefrontal Cortex Regulation of Inhibitory Control Mechanisms: Relevance to Addiction

The Prefrontal Cortex in Addiction-Related Neural Circuits

Modulation of Prefrontal Cortical Neurotransmitter Release by Drugs of Abuse: Evidence From Animal Models

Role of the Prefrontal Cortex in Addiction-Related Behavioral Phenomena: Evidence From Animal Behavioral Pharmacology Research

Neurochemical Control of Drug-Related Reward Processing in the Prefrontal Cortex: Role of Dopamine–Glutamate Interactions in Animal Models

Cannabinoid Modulation of Drug-Related Reward Processing in the Animal Prefrontal Cortex–Mesolimbic Circuitry

Summary

List of Acronyms and Abbreviations

Index

Copyright

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List of Contributors

A.E. Arrant,     University of Alabama at Birmingham, Birmingham, AL, United States

P. Bannerman,     Shriners Hospital for Children, Sacramento, CA, United States

R. Bartha,     University of Western Ontario, London, ON, Canada

D.F. Cechetto,     University of Western Ontario, London, ON, Canada

R.L.M. Faull,     University of Auckland, Auckland, New Zealand

M. Jog,     University of Western Ontario, London, ON, Canada

E.H. Kim,     University of Auckland, Auckland, New Zealand

S.R. Laviolette,     University of Western Ontario, London, ON, Canada

T.-Y. Lee

University of Western Ontario, London, ON, Canada

St. Joseph’s Health Centre, London, ON, Canada

N. Mehrabi,     University of Auckland, Auckland, New Zealand

A.J. Moszczynski,     Western University, London, ON, Canada

D.G. Munoz,     University of Toronto, Toronto, ON, Canada

S.H. Pasternak,     Western University, London, ON, Canada

N. Rajakumar,     University of Western Ontario, London, ON, Canada

J. Renard,     University of Western Ontario, London, ON, Canada

E.D. Roberson,     University of Alabama at Birmingham, Birmingham, AL, United States

K.S. Rockland,     Boston University School of Medicine, Boston, MA, United States

L. Rosen,     University of Western Ontario, London, ON, Canada

W.J. Rushlow,     University of Western Ontario, London, ON, Canada

M.J. Strong,     Western University, London, ON, Canada

J.H.K. Tam,     Western University, London, ON, Canada

L.J. Tippett,     University of Auckland, Auckland, New Zealand

H.J. Waldvogel,     University of Auckland, Auckland, New Zealand

N. Weishaupt,     University of Western Ontario, London, ON, Canada

Foreword

Knowledge accrues in pieces, but it is understood in patterns. As subspecialties grow, so do the gaps between them. The greatest gap of all occurs between experimental research and clinical application, within and among fields. This book goes a long way in bridging these gaps. It begins with an introductory chapter on the cerebral cortex, stressing the similarities and differences among species, particularly between humans and rodents, the favorite experimental species. Next comes a chapter on cortical plasticity and response to injury, setting out the dynamics of injury and repair that underpin most brain conditions. The chapter on imaging outlines how it is increasingly possible to study pathological and repair mechanisms in vivo both in humans and in animals. This is followed by a section on seven common neurodegenerative disorders, ending with a section on neuropsychiatric disorders, the other set of manifestations of a disordered brain.

A remarkable feature of this book lies in the joint coauthorship of basic scientists and clinicians accustomed to working with each other. This provides a coherent and unique understanding of how integrated, experimental, and clinical work can move forward together.

This volume should have a broad appeal to clinicians trying to understand experimental methodologies, techniques, and approaches; to basic scientists in seeing the clinical relevance of their work; and to all those interested in the brain who want to know how a myriad of little pieces coalesce to make up increasingly understandable patterns.

Vladimir Hachinski, CM MD DSc FRCPC FRSC Dr Hon causa (X4),     Distinguished University Professor, University of Western Ontario, London, Ontario, Canada

Introduction

The cerebral cortex has approximately 10  billion neurons that provide an inordinate amount of high-level processing. It is the neurons in the cerebral cortex in humans that is responsible for the cognitive processing or the conscious mind. The final site of termination for sensory signals is the cerebral cortex, leading to an awareness of the external and internal milieu. Complex processing using several different cortical networks leads to the generation of simple movements or even very complex executive functions, such as decision making and setting goals.

The cerebral cortex plays an important part in some of the most prevalent neurological diseases and neuropsychiatric disorders in our society. For some conditions, involvement of the cerebral cortex has only recently been emerging. Experimental research into the role of the cortex in disease has contributed greatly to our current knowledge, and further advances are needed. This book focuses on how preclinical investigations are addressing the clinical issues surrounding the involvement of the cerebral cortex in selected conditions of the nervous system. Each chapter has been written by an expert in his/her field in an effort to provide a comprehensive review of the clinical manifestations of cortical involvement, and a resource on leading animal models and experimental techniques currently available to tackle cortical issues in disease. Thus this book provides a link between cortical clinical problems and investigational approaches that we hope will help foster future research with high translational value.

Textbook resources on the cerebral cortex are abundant. The intent of this volume is to contribute cutting-edge insights into how the cerebral cortex functions in disease states, and how it is affected by individual neurological and neuropsychiatric disorders. What makes this book unique is the link it provides between clinical issues and preclinical research related to the cerebral cortex. The focus on animal models and experimental techniques is aimed at providing a practical resource on modeling clinical issues to be useful for researchers from students to principal investigators. A resource of this kind, covering major neurological and neuropsychiatric diseases and the role of the cerebral cortex, has not been previously available.

In this book, we have provided three general topics of particular importance to understanding and undertaking experimental investigations of diseases of the cerebral cortex. The remaining chapters are devoted to particular neurological or neuropsychiatric conditions and the role of the cerebral cortex. These chapters have some common themes related to pathology, as well as to the associated imaging technologies and the type of models used to investigate each condition.

The first chapter provides an excellent overview of the anatomy of the cerebral cortex. In particular, this chapter eloquently describes the similarities in the cerebral cortex between species, as well as the areas in which species have developed specialized components for specific behaviors. It is clear that there are many organizational similarities in the cerebral cortex of humans and animal models, even rodents. This chapter specifically states, the primary cortical areas are recognizable across species, as are the basic cortical layers and cell types, and the main neurochemical transmitter and neuromodulatory systems. However, the description of the differences emphasizes one of the major limitations in using animal models to examine important neurological and neuropsychiatric conditions. Unlike many subcortical sites, in animal models there is some degree of diversion from the patterns and cytoarchitecture seen in the human that may complicate the interpretation of results.

Chapter 2 deals with one of the unique features of the cerebral cortex that has major implications for the cerebral cortex in response to disease. This chapter emphasizes the importance of plasticity in CNS injury and disease, particularly in the cerebral cortex, in spite of the inability of cortical neurons to undergo adult neurogenesis. Of particular importance for some neurodegenerative and neuropsychiatric diseases is the impact of experience in plasticity in the cerebral cortex, especially as it relates to sensory input, using key examples from visual and auditory deprivation. Thus experience may begin to restore the loss of function caused by altered connections or chemistry of the cerebral cortex. On the other hand, after brain trauma or cerebral infarcts caused by stroke, part of the brain recovery process for function may be relocated in adjacent cortical areas, compensating for the loss of tissue. There are several means by which innate cortical plasticity may be manipulated to play a therapeutic role in neurodegenerative and neuropsychiatric diseases, many of which are described in other chapters. Some of the possible means may include maximizing cognitive reserve and cognitive training, transcranial magnetic stimulation to induce plasticity, and use of growth factors such as insulinlike growth factor (IGF), ciliary neurotrophic factor (CNTF), glial cell–derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) that are proving to be important in cortical plasticity.

As many of the chapters on specific cortical conditions indicate, neuroimaging experts continue to develop essential tools for early identification, experimental investigations, and assistance in therapeutic approaches. Chapter 3 does an excellent job of summarizing all of the recent imaging approaches available for neurodegenerative diseases and provides an excellent overview directly related to some of the discussion found in individual chapters on specific conditions of neurodegenerative diseases. The information provided listing the latest approaches, methods, and agents that are available for imaging the cerebral cortex can be very helpful to scientists intending to undertake new investigations. Furthermore, of particular interest is the discussion on the increased role that imaging is playing in the management of patients with neurodegenerative disease. For example, in Alzheimer disease (AD), neuroimaging can be used as a biomarker in the presymptomatic phase, to identify the etiology, establish pathophysiological changes, and predict progression.

This discussion on the role of imaging for cerebral cortex conditions is supported by many of the chapters on specific neurological and neuropsychiatric conditions affecting the cerebral cortex, indicating that imaging is becoming increasingly important. Many of these chapters indicate that new approaches are being used to monitor the progress of the disease or even may be critical biomarkers in early, treatable stages of cortical diseases.

For example, in Chapter 3 on brain imaging, the resting brain networks are described and it is stated that the default mode network (DMN) is the most relevant in AD because it is involved in episodic memory formation and attention. The DMN is composed of cortical regions such as the cingulate, precuneus, inferior parietal cortex, medial prefrontal cortices, and the hippocampus. Chapter 4 indicates how the DMN regions are involved in AD using the Pittsburgh-B (PiB) compound and positron emission tomography (PET) for imaging amyloid. PET has also been effective in neuropsychiatric conditions. Chapter 12 indicates that PET has demonstrated addiction-related effects in multiple cortical regions.

Functional magnetic resonance imaging (fMRI) is becoming particularly useful in several conditions because it is capable of demonstrating changes in the neural networks associated with cortical activity. Chapters 4 and 6 describe how fMRI is used to demonstrate a lower connectivity in the DMN in AD and frontotemporal dementia (FTD). Chapter 9 describes how a number of fMRI studies have been effective in showing that amyotrophic lateral sclerosis (ALS) produces changes in neural networks. In particular, this chapter describes how resting state fMRI has shown the impact of ALS on three different neural networks, including the salience network, the DMN, and the central executive network. Chapters 11 and 12 also indicate how the neural networks are affected in neuropsychiatric conditions using fMRI. Schizophrenic patients are unable to deactivate the DMN network during cognitive tasks, and regions such as the anterior cingulate cortex, orbitofrontal cortex, and dorsolateral prefrontal cortex have altered functional activity as a result of addiction.

In addition, Chapter 4 on AD suggests how fMRI techniques might be a very useful approach as an early biomarker of cortical changes. The role of fMRI as a biomarker is particularly emphasized in Chapter 6 on FTD, in which reduced connectivity of the DMN is seen 10–15  years before the neurological symptoms. This potential biomarker role is also described in Huntington disease, Chapter 8, in which impairments in the functional connections between the anterior cingulate and lateral prefrontal cortices are observed before the onset of symptoms. Furthermore, fMRI has demonstrated possible plasticity in Huntington disease because it has shown compensatory brain responses and reorganization of circuits.

In addition to imaging, there are some common themes that appear in the chapters on specific neurodegenerative and neuropsychiatric conditions. For example, several chapters refer to the role that tau and amyloid play in the pathology of the disease. The role of tau and amyloid is relatively well known in dementia, as described in Chapters 4, 5, and 6. For example, Chapter 4 describes how neurofibrillary tangles (NFTs) and insoluble aggregates of amyloid present different patterns of progression of AD pathology in the cerebral cortex, even though both of these were previously thought to be integral pathological components of the disease. Chapter 4 indicates that this discrepancy in disease progression may be resolved by an examination of the pattern of soluble oligomeric forms of amyloid. However, Chapter 9 has a very interesting discussion on the controversy surrounding alterations in tau metabolism in the frontotemporal dysfunction associated with ALS.

Another defining condition that appears to be important in many of the cerebral cortex disorders is neuroinflammation. This is emphasized in Chapters 4, 5, and 6 on AD, vascular dementia, and FTD. In Chapter 10 on multiple sclerosis (MS) the deleterious effects of inflammatory cytokines are described with effects that can include direct damage by the disruption of synaptic transmission leading to excitotoxicity and even demyelination or inhibition of remyelination. In Chapter 6 there is a discussion on antiinflammatory therapies for FTD. In Chapter 9 it is also indicated that immunoreactive glia are a significant feature of ALS. The discussion surrounding the role of neuroinflammation in multiple conditions suggests that the cerebral cortex may be particularly vulnerable to degeneration resulting from neuroinflammation. It also suggests that an antiinflammatory regimen developed for one condition may in fact be relevant for other degenerative conditions of the cerebral cortex. Of particular interest in this regard is the new methodologies provided by neuroimaging. As described in Chapter 3, it is now possible to use PET with benzodiazepine receptor ligands to visualize activated microglia in the cerebral cortex. This is permitting clinical investigations to be run in parallel with experimental studies to confirm some basic mechanisms related to neuroinflammatory changes in neurodegenerative diseases. Thus although the cerebral cortex is a very complex and differentiated structure anatomically and damage to specific cortical structures results in very different clinical expression of neurodegenerative disease, some common pathological mechanisms remain, including tau, amyloid, and neuroinflammation, that may be exploited for the purpose of understanding the diseases and designing therapeutic strategies.

Because of the large area of the cerebral cortex and the diverse regions all with different functions, it is difficult to create animal models that are based on making lesions, occluding blood vessels, stimulation of cortical sites, or other surgical techniques. As can be seen from multiple chapters, many experimental models for AD, FTD, ALS, and MS have focused on genetic changes associated with the condition. Often, because of the molecular heterogeneity of the cerebral cortex, transgenic or gene knockout models permit relatively specific molecular cortical disruptions that closely align with the neurodegenerative or neuropsychiatric condition. The exception to this approach, almost by definition, is that of the role of the prefrontal cortex in addictive disorders. In this case, as described in Chapter 12, animal models are based on the administration of drugs to induce animal concomitants of clinical addictive syndromes.

The last 2 chapters focus on conditions that can be considered neuropsychiatric. Chapter 12 on addiction examines in detail the role of the prefrontal cortex, similar to the focus of Chapter 11 on schizophrenia. Given that the overwhelming bulk of our understanding of how the prefrontal cortex controls reward and addiction-related behaviors comes from rodent-based basic neuroscience research approaches, a critical question concerns whether the rodent prefrontal cortex can actually serve as an effective analog for the complexity of the primate prefrontal cortex, an issue that was addressed to some extent in Chapter 1 in the examination of comparative cortical anatomy. It seems that both of these chapters indicate that current experimental models are very useful in our understanding of cortical mechanisms in neuropsychiatric conditions, as was also seen in the use of rodent models in neurodegenerative diseases.

Thus this volume provides the necessary information to understand the role of the cerebral cortex in a number of neurodegenerative and neuropsychiatric diseases, as well as a reference to important information on cortical anatomy, plasticity, and neuroimaging for context to these conditions. It is hoped that these chapters form the basis to assist those working in clinical settings, and early or advanced experimental investigators. In particular, the common themes, as well as the peculiar differences seen in the various diseases, suggest excellent opportunities for novel experimental and therapeutic approaches.

David F. Cechetto

Nina Weishaupt

Part I

Introductory Chapters

Outline

Chapter 1. Anatomy of the Cerebral Cortex

Chapter 2. Cortical Plasticity in Response to Injury and Disease

Chapter 3. Imaging Approaches to Cerebral Cortex Pathology

Chapter 1

Anatomy of the Cerebral Cortex

K.S. Rockland     Boston University School of Medicine, Boston, MA, United States

Abstract

The neocortex in rodents and primates exhibits several common properties; namely, areas, layers, columns, cell types, and connections. These properties are briefly reviewed here, with the goal of providing orientation and general background for the following chapters on experimental approaches to neurodegenerative and neuropsychiatric disorders. Special attention is given to primate and rodent homologies but also to species specializations. Because cortical anatomy, despite over 100  years of research, remains poorly understood, this chapter also aims to convey some appreciation of open questions and controversies.

Keywords

Areas; Columns; Connections; Homologies; Interneurons; Layers; Minicolumns; Neurochemistry; Pyramidal neurons

Introduction

The distinctive core features of neocortical anatomy were already recognized by the early architectonic investigators; namely, layers, verticality, and regional differences in cellular and myelin distribution, defined as discrete areas. In the 100  years or so since the first maps of the Vogts and Brodmann, cortical research has forged ahead, especially in terms of cell types, intraareal and interareal connectivity, and, most recently, gene expression. Needless to say, given the complexity of brain structure and function, the overall cortical organization is at best only partially understood, and almost every feature (layers, cell types, verticality or columns, and areas) remains under active investigation and debate. As just one example, a popular proposal of cortical uniformity (Rockel, Hiorns, & Powell, 1980) has been replaced, after the introduction of different counting techniques, by new data more supportive of systematic, cross-cortex and cross-species variation (Charvet, Cahalane, & Finlay, 2015; DeFelipe, Alonso-Nanclares, & Arellano, 2002).

The present chapter, while keeping in mind the open questions on cortical anatomy, aims to provide general orientation and background. Given the prominence of animal models in experimental approaches to disease, special attention is given to differences between human and rodent cortical anatomy. Finer species specializations are not considered, although these are increasingly attracting attention (in rodents, eg, Beaudin, Singh, Agster, & Burwell, 2013; Krubitzer, Campi, & Cooke, 2011). Some of the obvious specializations are briefly discussed in this introductory section, followed by more extensive discussion of areas, layers, verticality, cell types, and connections. A substantial body of longer reviews and chapters is available for further detail (eg, Douglas, Markram, & Martin, 2004; Kirkcaldie, 2012; Zilles, 2004, Chapter 27; Zilles & Wree, 1995).

An obvious distinction of the cerebral cortex in humans is the expansion, considered as a hallmark of human evolution. The human cortex is thicker, has more cells than the smaller brains of rats and mice, and has more areas. It has more white matter, in contrast with rodents, where connections often travel through the deeper cortical layers and not through the relatively shallow white matter. The human brain is gyrencephalic (ie, highly folded), albeit not uniquely so, because this property is shared with other species such as cats, dogs, nonhuman primates, and the large-brained elephant and cetaceans.

Gyrencephaly, whether in human or other large brains, has important consequences for differential architectonics and connectivity (Mota & Herculano-Houzel, 2012; Sun & Hevner, 2014). The laminar thickness and spatial arrangement are altered at the gyral crown, sulcal walls, and sulcal depths. The sulcal depths are preferentially associated with the short-distance U-fiber connections. Several causal mechanisms have been proposed for cortical folding (Zilles, Palomero-Gallagher, & Amunts, 2013), including an important role for the proliferative cycle in early development. Current ideas raise the possibility that gyrencephaly should be accepted as the ancestral mammalian trait (Lewitus, Kelava, Kalinka, Tomancak, & Huttner, 2014).

Hemispheric laterality, both functional and anatomical, is a pronounced feature of the human neocortex, although laterality effects have been reported in other species; for example, in aquatic mammals, unihemispheric sleep and hemispheric independence of eye movements (Mortensen et al., 2014). Hippocampal asymmetry in a long-term memory task has been reported in mice (Shipton et al., 2014).

With few exceptions, the same neuron types are found in primates and rodents, although there are differences in degree of dendritic branching and density of dendritic spines (Ballesteros-Yanez, Benavides-Piccione, Elston, Yuste, & DeFelipe, 2006; Benavides-Piccione, Ballesteros-Yanez, DeFelipe, & Yuste, 2002; Elston, Benavides-Piccione, Elston, Manger, & DeFelipe, 2011). Area distribution is variable, especially of interneurons (DeFelipe, Gonzalez-Albo, Del Rio, & Elston, 1999, DeFelipe, Ballesteros-Yanez, Inda, & Munoz (2006); Roux & Buzsaki, 2015). Narrow spindle cells (ie, Von Economo cells) are not found in rodents but do occur in other species besides humans (Butti, Santos, Uppal, & Hof, 2013; Evrard, Forro, & Logothetis, 2012; Seeley et al., 2012). Similarly, giant cells in the motor or visual cortex do not occur in rodents but do occur in other species besides humans. Astrocytes are disproportionately larger in humans than in mice, and their processes are more complex (Oberheim, Wang, Goldman, & Nedergaard, 2006).

An important difference between primates and rodents relates to the thalamus and, by extension, to the organization of thalamocortical connections. With the exception of the visual thalamus, there are significantly fewer inhibitory neurons in the rodent thalamus (Jones, 2010), and the reticular nucleus of the thalamus, composed of inhibitory neurons, is enlarged. The extent and density of axons immunoreactive (denoted by the suffix-ir) for the dopamine transporter (DAT) is remarkably greater in the macaque dorsal thalamus (and, by extension, presumably in humans), with the mediodorsal association nucleus and the ventral motor nuclei having the densest immunolabeling (Fig. 1.1). Ultrastructural analysis of the macaque mediodorsal nucleus reveals that thalamic interneurons (which are absent in the rodent) are a main postsynaptic target of DAT-ir axons (Garcia-Cabezas, Martinez-Sanchez, Sanchez-Gonzalez, Garzon, & Cavada, 2009).

Figure 1.1  Distribution of dopamine transporter immunoreceptive (DAT-ir) axons (red) in parasagittal sections of the rat (A–D) and macaque monkey thalamus (E, F). Note differential distribution and greater density in the macaque thalamus. Reproduced with permission from Oxford University Press, Garcia-Cabezas et al., (2009). Dopamine innervation in the thalamus: monkey vs rat. Cerebral cortex 19 (2), 424–434.

Almost as notable as species differences are the many conserved features of cortical organization between primates and rodents. The primary cortical areas are recognizable across species, as are the basic cortical layers and cell types, and the main neurochemical transmitter and neuromodulatory systems. Despite the previously mentioned differences in thalamic organization, both primates and rodents have a conspicuous parallel system of driving corticothalamic projections from layer 5 and modulatory corticothalamic projections from layer 6 (Rouiller & Welker, 2000).

Cortical Areas

In the general mammalian plan, the cerebral cortex is parcellated into discrete motor, primary sensory, and association areas (Zilles, 2004, Chapter 27). The number of cortical areas, exclusive of the primary sensory and motor areas, is species-dependent. Individual areas are specified by the interplay of intrinsic genetic mechanisms and extrinsic information conveyed by thalamocortical input (O’Leary, Chou, & Sahara, 2007). The primary areas are topographically organized (in terms of peripheral visual, auditory, and somatosensory fields) and are interconnected with primary thalamic nuclei. The degree of specialization of the primary areas is also species-dependent and correlated with dominant sensory modality and behaviors. In the highly visual primates, the primary visual cortex, although comparatively thin, has distinctive sublaminar structure as well as modular organization for ocular dominance and orientation selectivity. For rodents, the somatosensory barrel cortex is a highly specialized representation of the snout vibrissae.

Historically, areas were delineated on the basis of differences in cell and myelin density. More recently, gene expression profiles to some extent have confirmed area parcellations (Fig. 1.2), although only a very few area-specific genes have so far been reported (Bernard et al., 2012; Watakabe et al., 2007; Yamamori, 2011; Yamamori & Rockland, 2006). More common is the occurrence of gradient-wise gene expression across primary and association cortices. The distribution of various receptors (receptor fingerprints) is another marker for area boundaries (Zilles, Palomero-Gallagher, & Schleicher, 2004). Some areas have sharp boundaries (especially specialized primary sensory and limbic areas), but the majority seem to have less sharp borders (Rosa & Tweedale, 2005).

How are areas organized as networks? A popular view has emphasized a hierarchical organization, where primary sensory areas are at the lowest level, with progressive serial projections emanating through the association areas (Graziano & Aflalo, 2007; Markov & Kennedy, 2013). There have, however, been extensive discussions about reverse hierarchies, where connections proceed into the sensory areas (Hochstein & Ahissar, 2002); alternative hierarchies derived from properties such as reaction times (Petroni, Panzeri, Hilgetag, Kotter, & Young, 2001); and supraareal clusters based on functional imaging (Buckner & Yeo, 2014).

The great cortical sensory systems are largely, but not exclusively, modality specific. The primary sensory areas in rodents are mutually interconnected by a network of border-crossing, long-range connections (eg, Mongolian gerbil, Henschke, Noesselt, Scheich, & Budinger, 2014; rat, Stehberg, Dang, & Frostig, 2014). In rats, direct connections have been reported from the retrosplenial cortex, a higher order limbic association cortex, to the primary visual cortex (Vogt & Miller, 1983). Cross-sensory connections have been reported in primates (Borra & Rockland, 2011; Falchier, Clavagnier, Barone, & Kennedy, 2002; Rockland & Ojima, 2003), but appear to be sparser than in rodents. In monkeys, projections from parahippocampal areas to the primary visual cortex have been repeatedly verified (Doty, 1983; Kennedy & Bullier, 1985; Rockland & Van Hoesen, 1994).

The association areas receive converging cortical inputs from other association areas and sensory cortices, and from nonprimary thalamic nuclei, and are substantially expanded in human and nonhuman primate brains. Their organization is much less understood than is the case for primary and early association areas. Below is a walk-through of four classical cortical domains. This is very brief, and also noncomprehensive, leaving out the auditory cortex, insula, motor cortex, and other major areas. For the insula cortex, an important association area excluded because of space considerations, see Butti & Hof (2010) and Craig (2010). Primary areas are less directly implicated in neurodegenerative and neuropsychiatric disorders and have accordingly not been included, as well as for the sake of conciseness (see General Reviews, such as Zilles, 2004, Chapter 27).

Figure 1.2  Expression of occ1 (predominantly in area V1) and RBP (predominantly in association cortex) in the macaque neocortex, sagittal sections. Bottom : Higher magnification to show laminar distribution in selected areas. Reproduced from Elsevier, Yamamori & Rockland, (2006). Neocortical areas, layers, connections, and gene expression. Neuroscience Research 55, 11–27.

Frontal Cortex

In primates, three broad subdivisions of the frontal cortex are dorsolateral, medial, and orbital (Fig. 1.3). Each of these have further subdivisions, definable by cellular, myelin, or receptor architectonics and by differential connectivity with other cortical areas, mediodorsal and midline thalamic nuclei, striatum, amygdala, hypothalamus, and periaqueductal gray (Ongur & Price, 2000). In humans, monkeys, and, to some extent, rodents, separable networks have been associated with visceromotor or sensory functions (respectively, medial frontal or lateral orbital regions).

Several