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The Frontal Lobe is one of four lobes of the cerebral cortex and occupies a third of each cerebral hemisphere. As its name implies, it sits anteriorly, in the frontal aspect of the brain. The features that define the distinct appearance of the frontal cortex, and the entire cortical surface in general, are delineated by the grooves or sulci, and crests or gyri. The frontal lobe is evolutionarily newer than the other lobes and in comparison takes longer to develop. It is involved with goal-directed behavior, action and higher cognitive functions that are part of what makes us human. The Frontal lobe is responsible for planning and executing voluntary movements, making decisions, recognizing the consequences of actions, learning and memory, regulating emotions, and language comprehension and speaking. This region of the brain is critical for these functions as well as personality development and social behavior, thus damage compromises a person's ability to function in ways that can be immediate and fairly dramatic. Historically, research on the brain has been intricately associated with frontal lobe function, and the initial observations suggested that these regions played a central role in motor and what we know now to be other frontal lobe disorders.
Structural And Functional Anatomy
The Frontal lobe is functionally divided into regions that process different information related to, and including locomotion (Figure 1). The prefrontal cortex (PFC) sits in front of and occupies a large portion of the frontal lobe. The PFC is involved with higher-order executive functions. The significance of the PFC in emotional control, planning, and perception is apparent from observations of these deficits in patients with damage to the area. The PFC maintains reciprocal connections with other cortical regions and receives and integrates information from various sensory modalities. This internal perceptual representation in conjunction with past experiences, memory, and other cognitive processes enable an immediate and scaled response to the demands of the situation. Dysfunction of the PFC has been implicated in neuropsychiatric disorders, as it has elaborate connections with subcortical structures that regulate the release of principal neurotransmitters, such as dopamine, serotonin, and norepinephrine. The dorsolateral PFC is more involved with the cognitive aspects related to strategic planning and executive decisions for the response. Whereas, the orbito-ventromedial PFC, due to its connections with the hypothalamus, amygdala, and limbic and sensory systems, is vital for the social and emotional aspects of a response, including regulation of behavior, and autonomic functions. In this way the orbito-ventromedial PFC drives appropriate behavior through its connections to the dorsomedial PFC that then sends projections to the primary motor cortex via the premotor areas.
Thus, the information typically is processed first in the higher-order areas of the PFC and then flows to the primary motor cortex, M1 (Brodmann's Area 4). The primary motor cortex is located in precentral gyrus, anterior to the central sulcus, and is organized to correspond to movements in contralateral parts of the body. Wilder Penfield depicted the motor strip graphically as a 'homunculus' or little man, a somatotopic cortical representation of movements of different parts of the body. These early renderings allotted disproportionally greater area to smaller anatomical structures, such as hands, and lips. These iconic studies were based on movements elicited by electrical stimulations of discrete areas of the cortical surface performed on locally anesthetized patients suffering from epilepsy. Now these observations are being reexamined using advanced techniques and have shown to have inconsistencies. The researchers in a recent study, stimulated the precentral cortex and mapped the resulting movements of specific body parts to specific points on the cortical surface. The study revealed a medial-to-lateral organization with reference to the central sulcus, i.e., the shoulders represented more medially followed by the elbows, wrist, and hand more laterally. Similarly the face, lips, tongue, and larynx representations exhibited the medial-to-lateral somatotopy. There was considerable overlap between the areas with no distinct boundary to demarcate the different body parts, this stands in contrast to the earlier, understandably cruder studies. Both hemisphere's had similar representations, and faithfully maintained the medial-to-lateral 'relative somatotopy'. The other areas vital for motor function are the supplementary motor area that plays a role in initiation and sequence of internally-guided movements, and the premotor cortex that is important for visually, externally-guided movements.
The motor cortex exerts voluntary control over various muscle groups through the efferent projections originating from the pyramidal cells of layer 5 (see below). This constitutes the pyramidal tract and contains the corticospinal and coorticobulbar tracts. The corticospinal tract proceeds through the internal capsule, midbrain to the medulla, where majority of the fibers cross over the midline forming the pyramidal decussation, and from there they descend laterally to the lower motor neurons of the ventral horn of the spinal cord that control gross and fine movements of the limbs. The anterior division of the tract is composed of non-crossed fibers that continue down to the spinal cord and control trunk movements. The corticobulbar tract efferents form connections with the lower motor neurons of cranial nerves for movements involving the face, head, and neck
Another significant region in the posterior frontal lobe of the dominant hemisphere, is Broca's area that is crucial for speech production and comprehension. It is located in the pars opercularis and pars triangularis - Brodmann's area 44 and 45 - respectively. This area is named for Pierre Paul Broca, who in the mid 1800's discovered that lesions in this area left patients unable to produce speech, without impacting language comprehension. This failure of speech, referred to as expressive aphasia, manifests as difficulties in finding words, written or spoken, even though the patients know what they want to communicate. Broca's area is connected with other speech-related cortical structures that together are responsible for comprehensive linguistic functioning.
The human neocortex has expanded to a larger surface area, volume, and neuronal density compared to non-human primates, and other mammals. Comparatively, this is true for the neocortex, but not so much for other brain regions. The frontal lobe, like other regions of the cerebral cortex, is organized into six layers, that differ in size, shape, and number (Figure 2). Work on excitatory pyramidal cells in the mid-to late 1800's by Meynert and Brodmann established that the neocortex was partitioned into six layers. These layers extend from Layer 1 at the pial surface to Layer 6 at the border with the white matter. Each layer is characterized by neurons and their processes that are structurally distinct and are specialized to serve different functions. The cytoarchitectonic character of the different cortical lamina, and the density of neurons is highly correlated to the functional connections it forms with other similar or different regions of brain. The neurons have different inputs and outputs and are spatially distributed in these identifiable lamina. The motor cortex is referred to as agranular, as it lacks a distinct Layer 4 granular layer, and individual layers are further subdivided based on cell size and density.
Layer I (L1), the molecular layer, is primarily occupied by the tufts of the apical dendrites of deeper layer pyramidal cells, and also contains inhibitory interneurons, glial, and vascular endothelial cells. This layer is essential for integrating incoming bottom-up sensory, environmental signals from long-range corticocortical and subcortical afferents with top-down internal signals. Afferent axons provide input to the dendritic tufts of pyramidal neurons. This integration is critical for context-driven sensory processing permitting appropriate, finely-tuned responses to constantly changing environmental demands. The layer is sub-divided into L1A and L1B, that differ in cell density. Layer's 2 and 3, the supragranular layers, have to an extent, driven the enlargement of the neocortex. Layer 2, the external granular layer, contains small pyramidal and spherically shaped neurons. Layer 3, the external pyramidal cell layer, named for the shape of the neurons that increase in size, with smaller cells in L3A and larger cells in L3B and L3C deeper in the layer. The Layer 2 and 3 neurons, project to cortical regions in the vicinity and other cortical and subcortical regions. These two layers similarly receive corticocortical and other inputs, and in turn form connections with inner layer 5 pyramidal neurons - the main output neurons of the cortex - facilitating local, intralaminar information processing. Layer 4, the internal granular cell layer, broadly receives sensory input from the thalamus, and is highly represented in the sensory areas. There is some inconsistency as to the size or even the presence of L4 in the frontal lobe which concerns itself with processing motor input. L4 in the motor cortex is composed of a smaller to larger pyramidal cells stretching from L3 to L5A. Layer 5, the internal pyramidal cell layer, is the principal output layer in the cortex, with corticocortical and subcortical projections. The giant pyramidal neurons, the Betz cells of L5B distinguish this lamina, and represent the projections to the spinal cord motor neurons. The apical dendrites of L5 neurons ascend to the pia. Layer 6, the fusiform layer is located adjacent to the underlying white matter and contains fusiform and polymorphic neurons with different morphologies. It is sub-divided into L6A and L6B. Axon processes from different pathways traverse this layer.
The pyramidal neurons are excitatory and accumulate glutamate, and their activity is modulated and moderated by inhibitory interneurons. These interneurons are phenotypically different and contain different calcium-binding proteins. Parvalbumin and somatostatin represent the dominant interneuronal cell types and are present in all cortical layer. These interneurons form connections with basal and apical dendrites of the pyramidal cells within the same layer, and play a role in influencing pyramidal cell function. Interneurons are integral for proper functioning, and have been implicated in neurodegenerative, psychiatric disorders, and epilepsy.
This widely held, decades long perspective of 'point neurons' being sufficient to describe cortical activity is being revised. Cortical neurons are not limited to a single layer, and they elaborate dendrites in other lamina. As a consequence of this multilayer arrangement, neurons receive a wide variety of synaptic inputs along their length. The processing at the subcellular sites impacts the output of the neurons, and takes into account feed-forward and feedback activity of neural processes - axons, and apical, basal dendrites - across different layers.
The Neuronal Circuitry of the Frontal lobe
The frontal lobe has been extensively studied, and from early on it was proposed that it formed circuits with subcortical areas of the brain. These connection's serve to provide the frontal lobe with information from diverse sources and enables the it to fashion a response to incoming stimuli. The physical, behavioral, personality, and cognitive impairments observed in neurodegenerative diseases can be traced back to defects in these circuits. There are 5 frontal-subcortical circuits, two motor, and three nonmotor. The dorsal areas are more concerned with motivation and making sense of the external world and experiences, whereas the ventral division focuses on our emotions and internal states. The frontal lobe integrates the information from these two streams (Figure 3). The two pathways that form the circuits maintain their distinct and parallel paths as they map somatotopically onto, and functionally organize the dorsal and ventral striatum. The circuit continues from the striatum -caudate nucleus, putamen, or ventral striatum - to the globus pallidus or substantia nigra, these areas in turn project to specific areas of the thalamus, which in turn loops back to the original cortical area, completing the circuit.
The two motor circuits involve the skeletomotor and oculomotor areas of the cortex, mainly the supplementary motor cortex and frontal eye fields, respectively. The three circuits that influence behavior are: dorsolateral prefrontal cortex that organizes information relevant for executive function. Deficits in this circuit affect reasoning and impact memory. Considering that the circuit routes through the basal ganglia, it can be linked to 'subcortical dementia' seen in patients with Huntington's and Parkinson's disease. This circuit is crucial for cognitive functioning, and is compromised in disorders such as schizophrenia, obsessive-compulsive, depression, attention deficit and hyperactivity. The anterior cingulate circuit is intimately associated with a person's motivational state and a dysfunctioning circuit leads to apathy, loss of spontaneity and speech. The apathy observed in Alzheimer's disease involves damage to this circuit. The orbitofrontal circuit is connected to visceral and emotional states of a person, being more intertwined with limbic areas. The circuit orchestrates appropriate behavior, and a malfunctioning circuit disengages this control and leads to socially unacceptable behavior.
Current and Future Directions
The advances in technology have opened up novel ways of investigating the cytoarchitectonics of the brain and the connectivity between different cortical and sub-cortical regions. Deployment of innovative techniques in histology, optical imaging, computation, and visualization have fostered broader scientific collaborations. The increased spatial and temporal resolution of these imaging technologies is yielding credible insights into the study of brain structure and function, utilizing non-invasive methods to conduct in-vivo histology. The combination of ultra-high field (UHF) MRI at 7 Tesla with other non-invasive imaging techniques continue to add to our understanding of healthy and pathological states. UHF-MRI images at sub-millimeter resolution and provides details of cortical layer function, and its use in conjunction with quantitative MRI informs the structure of the layers (Figure 4). Functional MRI (fMRI), using blood oxygen level dependent (BOLD) principles, and various other volumetric approaches measure cerebral blood flow and activity. Magnetoencephalography (MEG) and electroencephalography (EEG) techniques have been deployed to provide electrophysiological correlates of function that can be related to specific cortical layers. Neurological disorders, such as schizophrenia and Parkinson's disease involve neurochemical changes. Magnetic resonance spectroscopy (MRS), allows detection of specific transmitters, reflecting the composition of neurons that underpin excitatory or inhibitory neurotransmission, including the loss of specific neurons that accumulate different neurotransmitters underlying disease.
There is great enthusiasm for combining all these approaches, and especially for the field of connectomics that uses big data in order to map and create neural networks. These models being employed in the planning of intervention for pathological conditions and could have a bearing on surgical outcomes.
Non-invasive longitudinal studies using these imaging modalities are being undertaken to assess the risk, prognosis and the utility of therapeutic interventions in normal and diseased cohorts. These efforts will continue to inform personalized healthcare in psychiatry and medicine well into the future.
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