Humanity Lost: The Cost of Cortical Maldevelopment. Is There Light Ahead?

Introduction

This essay seeks to explore the link between poor cortical development and problems with behaviour, learning, memory and attention. Specifically, the potential role of cortical maldevelopment in the psychosocial and learning problems associated with spina bifida and hydrocephalus. The behavioural problems experienced by children with spina bifida and/or hydrocephalus remain largely unexplained and remain a cause for concern. We will discuss data from laboratories investigating the process of neurogenesis, corticogenesis and the effects of hydrocephalus on these processes. We will also look ahead to potential answers to the problems identified in affected patients.

Rourke ([74]) postulated that children with non-verbal cognitive deficits were at high risk for the development of behaviour problems because of difficulties interpreting non-verbal cues and gestures, and understanding causal linkages in interpersonal relationships. It was suggested by Fletcher et al ([14]) that behaviour problems could not be attributed solely to the effects of physical handicap, failure in school, and in the environment. He proposed that reduction in cognitive skills were related to disruption of cerebral white matter ([13]), which may have been based on the frequent observation of this structural loss. Such children are known to have sequencing and perceptual problems, difficulties with short-term memory and motor set, retrieval of information, abstract concepts, future memory and prospective action. These children are also often described as being poorly motivated with an unrealistic outlook on life. Some of these may well be related to disruption of myelin and the resultant disruption in circuitry, but the overall deficit is clearly more complicated. Many studies have shown that there is a significant relationship between the degree of myelination, cortical development, and psychomotor development ([26], [57], [58]).

It has been shown that foetal-onset hydrocephalus has a detrimental effect upon neuronal migration and maturation ([50], [75]) and that a number of important aspects of development may have a substantial impact on these higher functions. Firstly, normal cortical layering occurs sequentially during development ([43], [46], [47], [48], [56]) and problems in this developmental process may result in failure to produce a full complement of layers ([50]) potentially leading to acquired cortical dysplasia ([48]). Some cases of epilepsy, cerebral palsy, dyslexia, cognitive impairment, and/or poor school performance may well be due to developmental abnormalities or post-injury maldevelopment of the cortex leading to abnormal functionality ([48]), an idea supported by recent MR studies of affected children ([65], [82]). In detailed studies, Marin-Padilla found that damage to the developing cortex results in progressive alterations in the structural and functional differentiation of neurons, synaptic profiles, fibre distribution, glial elements, and vasculature in adjacent areas that survive. The intrinsic fibres and some neurons of layer I survive even in severe lesions and seem to be capable of continuing to orchestrate cortical development (see below) but this may not follow the normal pattern. These post-injury alterations are thought to be dynamic, ongoing processes that affect the structural and functional differentiation of the still developing cortex and may eventually influence the neurologic and cognitive maturation of affected children. Marin-Padilla ([48]) suggests that the progressive post-injury reorganization of the undamaged cortex and its consequences (acquired cortical dysplasia), rather than the original damage to the cortex, drives the pathogenesis of ensuing neurological problems.

Looking across animal species, one distinguishing microscopic feature is the increasing number of layers in the cerebral cortex culminating in the 7 layers of the human cortex. Since increasing cortical size and neuronal complement is linked with increasing higher brain functions, any loss of neuronal complement would be expected to result in loss of, or detrimental effects on these functions. One distinguishing feature of the human is the unique ability to override biological drives. Our thesis here is that control over biological drives leads to higher intellectual functions (or vice versa) but this requires significant brainpower. The cerebral cortex is also known as the neocortex, or new brain, to distinguish it from the archecortex, those primitive parts of the central nervous system shared with lower animals and forming the “biological brain”. For survival and physiological function only the archecortex is required. However, this is the case only if the neocortex fails to develop normally. The development of a neocortex results in a reliance on its function and severe consequences leading to death if it is subsequently damaged. Thus, we can survive without a cortex if we fail to develop it, but rely upon it if we have it. Consequences of maldevelopment of the cortex will be complex depending both on what fails to develop, what develops abnormally, and how these structures interfere with the normal function of other parts of the brain ([67]). There is some debate about the role of nature vs nurture in higher cortical functions and some evidence that these may well be semi hard-wired in a similar fashion to sensory functions, and are then modified through experience ([34]). Failure to fully develop cortical layers and connections would then lead to a reduction in higher functionality.

The corpus callosum has been implicated in the establishment of higher functions since it is essential for specialisation across the two hemispheres and in the wiring required to shunt functions into one or other hemisphere. It also maintains the dialogue across the functional specialisations of the two hemispheres ([20]). Agenesis or damage to the corpus callosum may prevent the full development of these functions, including language and speech, major problem-solving capacities, facial recognition and attentional monitoring, and may deprive the developing brain of the ability to take advantage of the increased processing power resulting from connecting the two hemispheres together. Some of these higher functions are discussed below.

Fuster ([17], [18]) describes the prefrontal cortex as being one of the last regions of the neocortex to develop both phylogenetically as well as ontogenetically and is one of the last regions to undergo myelination, which is not complete until late adolescence. This is consistent with the late maturation of the executive functions it supports. The highest and most characteristically human cognitive activity is the spoken language and failure to develop this area of the neocortex would have severe consequences for this most important higher function that identifies the human species.

The prefrontal cortex is also involved in a range of other complex functions reflected in the fact that it is highly interconnected with other parts of the CNS. Afferent fibres are received from the brainstem, hypothalamus, the limbic system (amygdala and hippocampus), the thalamus and other areas of the neocortex. Information travelling upwards from the hippocampus is needed for the formation of motor memory. Sensory information about movement is essential in order for movement to adapt to the environment. Sensory connections flow upwards in the occipital cortex linking successive higher areas of the perceptual hierarchies. Information from the occipital cortex is therefore involved with sensory-motor integration at the highest level. Upon receiving the afferent inputs, the frontal cortex sends reciprocal efferent information downward and successive neurones are recruited down the frontal hierarchy before a motor act is generated. Also in the downflow from prefrontal to primary motor cortex there are connective loops through the basal ganglia and lateral thalamus ([1], [17], [23], [27]). This is not a simple cycle as at each junction there are reciprocal fibres that run in the opposite direction suggesting continuous checking and modification.

Neuronal Group Selection Theory (NGST) proposed by Edelman ([11], [12]) describes one of the theoretical frameworks for the processes in the development of motor control to explain the variation of normal development. Hadders-Algra ([24]) discusses the various theories of development. It used to be thought that motor development was due to the cortex increasing its control over lower reflexes ([21], [22]) which lead to the theories of cephalo-caudal development. The NGST however suggests that the ensemble of cortical and subcortical systems is dynamically organised into variable networks and that development, experience and behaviour selects their structure and function. The units of selection are neuronal groups acting as functional units dealing with a specific motor behaviour or information from a specific sensory modality. Motor development would then undergo two phases of variation. Development starts with the primary phase where the neuronal groups have crudely specified connections determined by evolution and the genome. Motor activity at this level is not perfectly tuned to the environment. Development progresses with selection on the basis of the afferent information produced by behaviour and experience. This afferent information modifies the neuronal groups resulting in the secondary phase. The timing of the change is specifically related to function, e.g., the development of more precise arm reaching movements that begins to take place after six months of age and the development of heel strike during locomotion after the age of two years. Thus efficient and fine-tuned movement emerges for each specific function ([24], [68], [80]). This theory mirrors the proposition that structural development for higher functions occurs in the absence of experience, driven essentially by the human genome, but that experience activates the required circuitry for functionality ([34]). This is mirrored in descriptions of morphological changes in cortical structure. Initially, there is no difference in the cytoarchitecture of different parts of the cerebral cortex. As input fibres arrive from sensory systems, the cytoarchitecture changes in response to experience and the requirements of information processing ([5]).

Fuster ([17]) describes the frontal cortex as being responsible for memory and motor set. The same cells in the motor cortex encode both sensory and motor aspects of memory and mediate the transfer of information from a stimulus in one location to an immediate motor response in another location ([44]). This is the basis of perception to action that on a longer time scale occurs higher up in the motor hierarchy, i.e., the prefrontal cortex. It would seem that short-term memory together with motor set form a bridge from perception to action across time, closing at the highest level in the cycle of perception and action ([17]).

The prefrontal cortex maintains the motor memory and it is here, especially in the dorsolateral part, that the highest schemes and plans of behaviour take place ([18]). They require inputs from lower centres, in particular the limbic system, and are believed to be responsible for maintaining drive and motivation. An extensive synaptic network is modulated in order for temporal organisation to occur so that a plan may be enacted and the sequence of behaviour is directed towards the attainment of a goal. Temporal structures require mediation of cross-temporal contingencies, which means a capacity to carry out logical behaviour, thinking and speech. Cross Temporal Mediation according to Fuster ([18]) is underpinned by three basic cognitive functions of the prefrontal cortex:

Short-term motor memory or preparatory set for forthcoming action. “Set cells” present in the dorsolateral prefrontal cortex seem to predict future actions and prepare the lower motor system for impending action. Clinical manifestations of dorsolateral dysfunction are disorders of drive, attention and motivation. Such people have poor recent memory with a poor ability to plan ahead. Life seems to be lived “here and now” in a concrete state without the perspective of backwards and forwards. Short-term perceptual memory (working memory) for retention of sensory information on which action is to depend. “Memory cells” are intermixed with “set cells” in the dorsolateral prefrontal cortex. Instead of looking forward in time to impending motor action, they look backwards in time to sensory information. In the clinical situation the person cannot construct plans of future action and the ability to generate new behaviour or speech is affected. Memory is necessary for the construction of language. The qualitative development of language is the capacity for representation and the subsequent development of the symbolic capacity. In the first year of life, actions and feelings are related to internal conditions, perceivable objects, persons and events in the environment. In the second year of life the child begins to think about objects that are removed in time and space. In the third year the child will develop the ability to act on the representations they have in mind rather than acting on objects directly. There is therefore a process of concrete to abstract thought (4, 62). Language deficits of children with spina bifida and hydrocephalus have shown that despite concrete vocabularies (64, 76) they have difficulty in acquiring abstract language and have inappropriate use of abstract terms (6). Children with hydrocephalus were found to have deficits in the pragmatic use of language (8, 9). Compared to age-matched controls, the results showed that the children with HC were less cohesive and less coherent. They conveyed less of the content needed for the message, included more ambiguous material, included uninterpretable or implausible content, and were more verbose and less economic in quality. The results showed that these children were at risk for discourse and pragmatic impairment. The deficits described are therefore related to problems with “memory of the future” (planning) and the ability to represent schemes of action. There is also an inability to execute schemes of action reflecting the lack of drive and inability to make decisions. Executive dysfunction has been described and dissociation of executive function can potentially contribute to confabulation (7, 30, 35, 36). PET scan studies implicate the left dorsal prefrontal cortex in executive processes and the right prefrontal cortex in memory retrieval (15, 16). Functional magnetic resonance imaging (fMRI) also implicates the left prefrontal cortex in the presentation of facial expression (66). Inhibitory control is essential to suppress all information that might interfere with action and temporal structures in progress (18). Lesions of the orbitofrontal cortex present with distractibility and problems with control of impulsive and instinctive behaviour. It appears to be the role of the orbitofrontal cortex to safeguard behaviour from interference. Unsuppressed interference allows instinctual drives to lead behaviour astray that may manifest as quarrelsome behaviour, hypersexuality and hyperphagia. In the absence of moral judgement (a unique human ability) to restrain instincts, unruly behaviour may occur. Reduced prefrontal and increased subcortical brain functioning has been assessed using PET in predatory and affective murderers. Results showed that whilst predatory murderers had sufficiently good prefrontal functioning to regulate aggressive impulses, the affective murderers lacked such prefrontal control over emotion (70). Emotional bias and inhibitory control processes in mania and depression have been described by Murphy et al (60) leading to the argument that schizophrenia is a prefrontal disorder and that sociopathy is a sign of orbitofrontal syndrome (18).

These three prefrontal functions described by Fuster ([18]) work together to maintain goal-directed behaviour and with their connections they affect the spoken language and internal sequences of logical reasoning and behaviour.

What emerges from a study of recent developments in the understanding of the cortex is that there is interaction between the development of the cortex, the development of connections within and between nuclei and hemispheres, the experience of individuals including sensory, motor and learning experiences, and in the development of higher cortical functions that identify the individual as fully functioning, and possessed of the powerful intellect that singles them out as humans. Failure of normal development will inevitably lead to failure to develop full functionality in one or more higher cortical functions, even allowing for plasticity. As a further thought, we put forward the following additional thought. The peculiarity of human beings is the ability to override instinctive behaviours driven by the requirements of physiological and behavioural homeostasis. For example, we can override our need for food, water and sex due to our ability to control our biological brain. This is peculiarly human and we know of no animal that can accomplish this without some form of conditioning and training, a requirement of lack of control. Thus, we can say that animal intelligence solves the problem of how to satisfy biological need while human intelligence allows us to transcend biological need and reach social, creative and intellectual heights. The development of the neocortex is central to this evolution and our thesis is ultimately a simple one. If we fail to develop a fully functional cortex, we may have many recognisable human qualities, but may lack those qualities of control that make us functional humans in the context of social order and acceptable norms of behaviour. Moreover, we may lose higher functions serving language, intelligence and complex behaviours.

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