Brain Anatomy

The central nervous system consists of the brain and spinal cord. The peripheral nervous system consists of the extensions of neural structures beyond the central nervous system and includes somatic and autonomic divisions.

The brain is composed of three main structural divisions: the cerebrum, brainstem, and cerebellum (see the images below). At the base of the brain is the brainstem, which extends from the upper cervical spinal cord to the diencephalon of the cerebrum. The brainstem is divided into the medulla, pons, and midbrain. Posterior to the brainstem lies the cerebellum. The brain consists of gray matter (neuronal cell bodies) and white matter (myelinated axons). The gray matter processes information and the white matter transmits it. ^[1]

The cerebrum is the largest component of the brain. It is divided into right and left hemispheres. The corpus callosum is the collection of white matter fibers that joins these hemispheres.

Each of the cerebral hemispheres is further divided into four lobes: the frontal, parietal, temporal, and occipital lobes. The medial temporal lobe structures are considered by some to be part of the so-called limbic lobe. Some texts divide the brain into five lobes, insula being the fifth one. ^[2]

Frontal lobe - The frontal lobe is distinguished from the parietal lobe posteriorly by the central sulcus (see the image below). It is involved in high-order cognitive processes, control of voluntary movement, and perception of sensory stimuli. The precentral gyrus within the frontal lobe houses the primary motor cortex, essential for voluntary movement. The frontal lobe also plays a key role in speech (Broca's area). ^{[1, 3, 2]}

Parietal lobe - It is located posterior to the frontal lobe and is separated from the frontal lobe by the central sulcus and from the occipital lobe by the parieto-occipital sulcus on the medial surface. The parietal lobe processes sensory information such as touch, temperature, and pain. The postcentral gyrus here contains the primary somatosensory cortex. ^{[1, 3, 2]}

Temporal lobe - It is located inferior to the frontal and parietal lobes, separated by the lateral sulcus (or the Sylvian fissure). The temporal lobe is crucial for auditory processing and memory formation, particularly via the hippocampus. It has other important roles, including speech, hearing, and vision (temporooccipital junction). ^{[1, 3, 2]}

Occipital lobe - It is located in the posterior part of the cerebrum. The occipital lobe is primarily responsible for visual processing, including color perception, visuospatial processing, facial recognition, and memory formation. ^{[1, 3, 2]}

The cerebrum is further divided into the telencephalon and diencephalon.

The telencephalon consists of the cortex, subcortical fibers, and basal nuclei, which are involved in motor control. The cerebral cortex is the outer layer of grey matter, characterized by gyri and sulci, which increase its surface area. Telencephalon is well-developed in humans compared with other mammals, reflecting advanced cognitive abilities. ^{[1, 3, 2]}

The diencephalon mainly consists of the thalamus and hypothalamus, which are involved in sensory and autonomic functions. ^{[1, 3, 2]}

Human brains exhibit a disproportionately large cerebral cortex relative to their body size, a phenomenon quantified by the encephalization quotient, a characteristic not entirely unique among mammals. The cerebral cortex's expansion in humans has been linked to enhanced cognitive capabilities, with particular emphasis on areas associated with executive functions and complex social behaviors. This cortical growth has coevolved with changes in other brain regions, including the cerebellum, which has also expanded significantly in humans compared with other species. ^{[1, 3, 2]}

Cortex and subcortical fibers

The outermost layer of the cerebrum is the cortex, which has a slightly gray appearance — hence the term "gray matter." The cortex has a folded structure; each fold is termed as a gyrus, while each groove between the folds is termed as a sulcus. This cortical folding is now known to enhance cognitive functions and neural connectivity. ^{[1, 2, 4]} Cortical anatomy is discussed in greater detail below.

Below the cortex are axons, which are long fibers that emanate from and connect neurons. Axons are insulated by myelin, which increases the speed of conduction. Myelin is what gives the white appearance to these fibers of the brain — hence the term "white matter." White matter integrity plays a crucial role in various neurological conditions and cognitive processes. ^{[1, 2, 4]}

Overall, the interplay between the gray matter of the cortex and the white matter of subcortical fibers is critical for efficient communication within the brain, facilitating higher order functions such as learning, memory, and executive control. ^{[1, 2, 4]}

Limbic system

The limbic system is a grouping of cortical and subcortical structures involved in memory formation and emotional responses. The limbic system allows for complex interactions between the cortex, thalamus, hypothalamus, and brainstem. The limbic system is not defined by strict anatomic boundaries but incorporates several important structures. The limbic structures conventionally include the amygdala, hippocampus, fornix, mammillary bodies, cingulate gyrus, and parahippocampal gyrus.

The functional connections within the limbic system are best summarized by the Papez circuit. From the hippocampus, signals are relayed via the fornix to the mammillary bodies and via the mammillothalamic tract to the anterior nucleus of the thalamus. The thalamocingulate radiation then projects to the cingulate gyrus and back to the hippocampus to complete the circuit. The hippocampus serves as a primary output structure of the limbic system.

Unlike the six-layered neocortex, the hippocampus only has three layers and is termed as the archicortex. The hippocampus is crucial to memory formation — more specifically, a type of memory called declarative or explicit memory. Declarative memory is essentially the ability to recall life events of the past such as what meal was eaten for breakfast or where the car is parked.

However, over time, certain declarative memories from the distant past can be independently recalled without the hippocampal structures. The hippocampus likely allows long-term memory encoding in the cortex and allows short-term memory retrieval. In laboratory studies of animals and humans, the hippocampus has been shown to also have a cellular memory termed "long-term potentiation."

The limbic system is integral to the interplay between memory and emotion, influencing behaviors and responses essential for survival. External factors may affect the limbic system. For instance, the severe acute respiratory syndrome coronavirus 2 infection can lead to limbic system damage, affecting emotion recognition, memory, and olfactory abilities. Additionally, new criteria for age-related memory loss syndromes specifically affecting the limbic system have been identified, distinguishing them from conditions such as Alzheimer's disease. ^{[1, 5]}

The amygdala is a collection of nuclei that lies within the uncus. It receives multiple modes of sensory information as inputs. The outputs from the amygdala travel through the stria terminalis and the ventral amygdalofugal pathway. Output structures include the hypothalamus as well as the thalamus, hippocampus, brainstem, and cortex. The amygdala appears to be involved in mediating the emotional aspects of memory, especially the subjective aspects of fear responses.

Basal nuclei (ganglia)

The basal nuclei (formerly referred to as the basal ganglia) comprise the caudate nucleus, putamen, globus pallidus, subthalamic nucleus, and substantia nigra. Pairs of these structures bear different names. The putamen and globus pallidus combined form the lentiform nuclei. The putamen and caudate nucleus combined form the striatum. The striatum derives its name from the striped appearance given by the gray matter connections bridging across the internal capsule. The basal nuclei are closely integrated with the motor cortex, premotor cortex, and motor nuclei of the thalamus and play a crucial role in the modulation of movement.

The primary input to the basal nuclei is from the primary motor cortex and premotor cortex (Brodmann areas 4 and 6) and consists primarily of the pyramidal cells in cortical layer V. These excitatory projections lead primarily to the striatum. The striatum also receives input from the dopaminergic cells of the substantia nigra. In turn, the striatum sends inhibitory projections to the globus pallidus externa and interna. The globus pallidus externa sends inhibitory projections to the subthalamic nucleus, which sends excitatory projections to the globus pallidus interna. The globus pallidus interna in turn projects to the ventral anterior and ventral lateral nuclei of the thalamus.

The basal nuclei are now recognized as integral components of broader neural circuits that influence behavior beyond mere movement. For instance, new pathways such as the hyperdirect pathway have been identified, which connect cortical areas directly to the subthalamic structures, enhancing our understanding of how these regions interact during complex behaviors. ^{[1, 6, 7]}

The basal nuclei also contain diverse populations of neurons that utilize various neurotransmitters, including gamma-aminobutyric acid (GABA) and dopamine. The intricate balance between these neurotransmitters is crucial for maintaining normal function within these circuits. ^{[1, 6, 7]}

Certain movement disorders can be traced to pathologies in the basal nuclei, the most notable being Parkinson's disease, which is related to deficiencies of dopaminergic cells of the substantia nigra. Huntington disease is a heritable disorder that involves degeneration of the striatum and leads to progressive jerky, or choreiform, movement. Complex intrinsic connectivity within the basal nuclei that includes bridging collaterals between direct and indirect pathways, suggesting a more integrated functional network than previously understood. This has implications in understanding diseases such as Parkinson's disease, where these pathways may become dysfunctional. ^{[1, 6, 7]}

Basal nuclei are also involved in conditions such Tourette syndrome, obsessive-compulsive disorder, and other movement disorders, suggesting a broader functional significance beyond motor control alone. ^{[1, 6, 7]}

The complex roles of the basal nuclei are important in both motor control and higher order functions such as learning and emotional regulation, highlighting their significance in both health and disease. ^{[1, 6, 7]}

Thalamus

Positioned between the brainstem and the telencephalon, the diencephalon is composed of the thalamus, epithalamus, subthalamus, and hypothalamus. The thalamus serves as a relay station for ascending input to the cortex and receives information from each of the cardinal senses (except smell). It is hypothesized that the thalamus serves a gating function in filtering information. The thalamus consists of multiple nuclei that are briefly described here (see the image below).

The left and right sides of the thalamus are divided by the third ventricle. Each side is then divided by the internal medullary lamina into a series of anterior nuclei, ventrolateral nuclei, and medial nuclei. Smaller nuclei are found within these regions, numbering perhaps in excess of 100.

The role of the thalamus is also crucial as an integrative hub for functional brain networks. The thalamus is connected with the distributed cortical regions, integrating multimodal information across diverse cortical functional networks. This connectivity supports various cognitive functions, including attention, memory, and information processing. ^{[1, 8, 9]} The anterior thalamic nuclei are functionally associated with the limbic system and share reciprocal connections with the cingulate gyrus and the mammillary bodies. The medial nuclei project to the frontal association cortex and premotor cortex, with reciprocal connectivity. These nuclei are involved in higher cognitive functions and emotional regulation. ^{[1, 8, 9]}

The ventrolateral nuclei can be further divided into the ventral anterior (VA), ventral lateral (VL), ventral posterolateral (VPL), and ventral posteromedial (VPM) nuclei. The VA and VL nuclei share input from the globus pallidus and projections to the motor cortex. The VPL and VPM serve as sensory relays in the body and face, respectively. These nuclei also play a role in motor planning and execution. ^{[1, 8, 9]}

The lateral nuclei are divided into lateral dorsal and lateral posterior nuclei, with projections to the cingulate gyrus and parietal cortex, respectively. These nuclei are involved in spatial attention and sensory integration. ^{[1, 8, 9]}

Other thalamic structures not included in the anatomic divisions above include the medial and lateral geniculate bodies, which process auditory and visual information, respectively. The pulvinar connects reciprocally with the parietal and occipital association cortex. Intralaminar nuclei within the internal medullary lamina obtain input from the brainstem, cerebellum, and other thalamic nuclei and project to basal nuclei structures and other thalamic nuclei. Among the intralaminar nuclei, the centromedian nucleus is a part of the reticular activating system, which plays a role in maintaining cortical arousal.

Neuroimaging and electrophysiological techniques have enhanced our understanding of the thalamus's integrative role in sensory perception and cognitive processing and its potential involvement in neurologic disorders. Disruptions in the thalamic function may contribute to conditions such as schizophrenia, attention-deficit hyperactivity disorder, and Alzheimer's disease. ^{[1, 8, 9]}

Epithalamus

The epithalamus is made up of the habenula, habenular commissure, posterior commissure, and pineal gland. It forms the roof of the third ventricle. This region plays significant roles in various physiological processes, including the regulation of circadian rhythms, emotional responses, and neuroendocrine functions. ^{[1, 10]}

Habenula - The habenula is involved in modulating emotional and motivational states. Alterations in habenular function can impact anxiety and depression-related behaviors. For instance, specific genetic deletions affecting the habenula can lead to significant developmental changes and increased neuron subtypes within this area, highlighting its complexity and importance in brain function. The lateral habenula has been shown to produce spontaneous theta oscillatory activity, which is correlated with hippocampus-dependent spatial information processing and memory performance. ^{[1, 10]}

Habenular commissure - This structure connects the left and right habenulae, facilitating communication between the two sides of the brain. It has been shown to play a role in the integration of sensory information and emotional responses. ^{[1, 10]}

Posterior commissure - The posterior commissure is primarily involved in reflexive eye movements and pupillary light reflexes. It serves as a conduit for visual information processing and coordination between the two hemispheres. ^{[1, 10]}

Pineal gland - The pineal gland is a small endocrine gland responsible for producing melatonin, which regulates sleep-wake cycles. Age-related changes in the pineal gland's morphology and function, including an increase in calcification over time, may correlate with diminished secretory activity. Furthermore, its role extends beyond sleep regulation; it is implicated in various neurodevelopmental disorders where dysfunction can lead to significant psychological effects. Deletion of the genetic factors Foxg1, which plays a key role in the development of the epithalamus, can lead to abnormal habenular development and a reduced pineal gland size, indicating that specific genetic pathways are crucial for proper epithalamic formation. ^{[1, 10]}

Epithalamus's role is crucial in connecting the limbic system to other parts of the brain, particularly through the dorsal diencephalic conduction system. This system is crucial for transmitting information from the limbic forebrain to the limbic midbrain structures. ^{[1, 10]}

Dysfunction in the epithalamus can be associated with mood disorders such as major depression and schizophrenia as well as sleep disorders such as insomnia. Calcification of the epithalamus has also been linked to periventricular lesions near the limbic system. ^{[1, 10]}

Subthalamus

Located between the midbrain and the thalamus, the subthalamus contains the subthalamic nucleus, red nucleus, and substantia nigra. These structures are intricately connected with the basal ganglia and are crucial for the modulation of movement. ^{[1, 11]}

Subthalamic nucleus (STN) - This is a small, lens-shaped structure that plays a significant role in regulating the output of the basal ganglia. It receives inputs from the cerebral cortex, thalamus, globus pallidus externus, and brainstem and projects to the globus pallidus, substantia nigra, striatum, and brainstem. It is primarily composed of glutamatergic neurons, which are excitatory and essential for its function in movement control. STN also plays a role in emotional processing, suggesting its involvement in aversion and discomfort. ^{[1, 11]}

Red nucleus - This structure is involved in motor coordination. It receives inputs from the cerebellum and motor cortex and sends outputs to the spinal cord. The red nucleus is essential for the control of limb movements, particularly in the context of fine motor skills. ^{[1, 11]}

Substantia nigra - Divided into the pars compacta and pars reticulata, the substantia nigra is critical for movement regulation. The pars compacta contains dopaminergic neurons that project to the striatum, playing a key role in the modulation of motor activity and reward pathways. The pars reticulata acts as an output nucleus of the basal ganglia, influencing motor control. ^{[1, 11]}

Subthalamic structures are closely integrated with the basal nuclei and play a role in the modulation of movement. Dysfunction in this area can result in movement disorders such as Parkinson's disease, where deep brain stimulation of the STN has proven effective in alleviating symptoms and improving patients' quality of life. Research highlights the involvement of STN in motor control, cognitive functions, and emotional regulation, linking dysregulation to various neuropsychiatric disorders. Advanced neuroimaging has revealed its complex connections with other brain regions, furthering our understanding of its role in behavior and neurologic conditions. Additionally, STN shows neuroplasticity, adapting its functions in response to experiences, which may inform rehabilitation strategies for injuries or neurodegenerative diseases. ^{[1, 11]}

Hypothalamus

Thy hypothalamic nuclei lie in the walls of the third ventricle anteriorly. The hypothalamus is involved in mediating endocrine, autonomic, visceral, and homeostatic functions. It can roughly be divided into anterior, posterior, and middle groups of nuclei.

The anterior nuclei include the preoptic, supraoptic, and paraventricular nuclei. They are primarily involved in regulating body temperature, fluid balance, and release of hormones from the pituitary gland. ^{[1, 12, 13, 14, 15]}

The posterior nuclei include the supramammillary, mammillary, intercalate, and posterior nuclei. They play a key role in sympathetic responses and memory processing. ^{[1, 12, 13, 14, 15]}

The middle nuclei include the infundibular, tuberal, dorsomedial, ventromedial, and lateral nuclei. They are crucial for energy balance, including the regulation of hunger and satiety. ^{[1, 12, 13, 14, 15]}

Parasympathetic control can be attributed to the anterior and medial nuclear groups, whereas sympathetic control can be attributed to the posterior and lateral nuclear groups. Satiety can be localized to the stimulation of medial nuclei, and hunger can be localized to the stimulation of lateral nuclei. Other functions of the hypothalamus include regulation of body temperature, heart rate, blood pressure, and water balance.

The hypothalamus has close connections with the cingulate gyrus, frontal lobe, hippocampus, thalamus, brainstem, spinal cord, basal nuclei, and pituitary gland. This allows it to integrate sensory information and coordinate responses to maintain homeostasis. Advances in neuroimaging and electrophysiological techniques show that the hypothalamus is also involved in emotional regulation, social behavior, and circadian rhythms. ^{[1, 12, 13, 14, 15]}

The hypothalamus and pituitary gland work together to regulate various physiological processes. Recent studies have identified new neuropeptides, including kisspeptin and neurokinin B, that influence pituitary hormone secretion and have clarified the role of tanycytes in hormone transport. Disruptions in their signaling can lead to conditions such as hypopituitarism and Prader-Willi syndrome. ^{[1, 12, 13, 14, 15]}

The hypothalamus also shows significant structural and functional plasticity, with adult-born neurons integrating into its circuits, allowing for lifelong physiological and behavioral adaptations. ^{[1, 12, 13, 14, 15]}

Clinically, advancements in understanding the hypothalamus could lead to targeted therapies using optogenetic tools and deep brain stimulation for conditions such as obesity. Additionally, identifying genetic factors may enhance diagnostics and interventions for congenital hypothalamic disorders. ^{[1, 12, 13, 14, 15]}

The neocortex is the most phylogenetically developed structure of the human brain compared with the brains of other species. The complex pattern of folding allows an increased cortical surface to occupy a smaller cranial volume. The pattern of folding that forms the sulcal and gyral patterns remains highly preserved across individuals. This enables a nomenclature for the cortical anatomy.

The left and right cerebral hemispheres are separated by the longitudinal cerebral fissure. The principal connection between the two hemispheres is the corpus callosum. Each cortical hemisphere can be divided into four lobes: frontal, temporal, parietal, and occipital. The frontal lobe can be distinguished from the temporal lobe by the lateral sulcus (the Sylvian fissure). The frontal lobe can be distinguished from the parietal lobe by the central sulcus (the Rolandic fissure). The parieto-occipital sulcus, which is visible on the medial aspect of the hemisphere, divides the parietal and occipital lobes. Within the lateral sulcus is another cortical surface referred to as the insula.

The frontal lobe can then be further divided into the superior, middle, and inferior frontal gyri, which are divided by the superior and inferior frontal sulci, respectively. The inferior frontal gyrus forms the frontal operculum, which overlies the lateral sulcus. The frontal operculum can be divided into three triangular gyri: the pars orbitalis, pars triangularis, and pars opercularis, in order from anterior to posterior. The precentral gyrus is the gyrus immediately anterior to the central sulcus.

Similarly, the temporal lobe is divided into the superior, middle, and inferior temporal gyri, which are separated by the superior and inferior temporal sulci. On the inferior surface of the temporal lobe just lateral to the midbrain, the parahippocampal gyrus can be identified, with the collateral sulcus lying lateral. Between the parahippocampal gyrus and the inferior temporal gyrus lies the occipitotemporal gyrus, also known as the fusiform gyrus.

Within the parietal lobe, the superior temporal sulcus is capped by the angular gyrus. Just above this, the lateral sulcus is capped by the supramarginal gyrus. Just below the angular gyrus, the lateral occipital gyrus caps the inferior temporal sulcus.

Advanced neuroimaging has improved our understanding of the dynamic nature and functional connectivity of the neocortex, showing its involvement in complex cognitive functions. It reveals that the variations in cortical folding correlate with cognitive abilities and neurodevelopmental disorders, emphasizing the significance of individual differences in cortical morphology. Advances in neuroanatomical mapping and machine learning have allowed for more precise identification of functional regions, aiding in the study of health and disease. Additionally, genetic research has highlighted how neurogenesis, neural migration, and maturation during development affect the cortical structure, linking abnormalities to conditions such as microcephaly and macrocephaly. ^{[16, 17]}

Evolutionarily, the brainstem is the most ancient part of the brain. Structurally, it can be divided into the medulla oblongata, pons, and midbrain. These three structures are briefly described below. Cross-sectional anatomy of the brainstem is rather complex, given the multiple traversing pathways and cranial nerve nuclei (see the image below). ^{[18, 19, 20]}

Medulla oblongata

The medulla oblongata, or simply medulla, is continuous and superior to the cervical spinal cord. There are several external anatomical features of the medulla that can be visible grossly. Ventrally, the pyramids and pyramidal decussation is visualized just below the pons. These are the descending corticospinal tracts. Just lateral to the pyramids, the rootlets of the hypoglossal nerve can be seen as they exit the brainstem. Lateral to the rootlets of the hypoglossal nerve is the inferior olive. Dorsolateral to the inferior olive, the rootlets of the ninth and tenth cranial nerves (glossopharyngeal and vagus) exit.

Dorsally, two pairs of protrusions are visible, which are the gracile tubercles medially and the cuneate tubercles just lateral to those. These represent the nuclei where sensory information from the dorsal columns is relayed onto thalamic projection neurons. Just superior to these protrusions is the floor of the fourth ventricle, which bears several characteristic impressions. The vagal trigone is the dorsal nucleus of the vagus nerve (cranial nerve X) and lies inferiorly, just below the hypoglossal trigone.

The medulla oblongata also houses the nuclei of the four inferior most cranial nerves: the glossopharyngeal nerve (CN IX), vagus nerve (CN X), accessory nerve (CN XI), and hypoglossal nerve (CN XII). The medulla oblongata serves as a critical hub for autonomic control and sensory-motor integration. Its complex anatomy reflects its multifaceted roles in maintaining homeostasis and facilitating communication between various parts of the nervous system. ^{[1, 21]}

Pons

The pons is a critical structure in the brainstem, located above the medulla and below the midbrain. It plays a significant role in connecting various parts of the brain, notably acting as a bridge between the cerebellum and cerebrum. The blood supply to the pons primarily comes from branches of the basilar artery. ^{[1, 22]} Its ventral surface has a characteristic band of horizontal fibers. These fibers are the pontocerebellar fibers that are in turn projections from the corticopontine fibers. They cross to enter the contralateral middle cerebellar peduncle and thus enter the cerebellum.

On either side of the midline, there are bulges that are produced by the descending corticospinal tracts. At the pontomedullary junction, the sixth cranial nerve (abducens) can be seen exiting the brainstem. Laterally, but anterior to the middle cerebellar peduncle, the fifth cranial nerve (trigeminal) is seen exiting the brainstem. Below the middle cerebellar peduncle, the seventh and eighth cranial nerves (facial and vestibulocochlear) can be seen exiting. Dorsally, the pons forms the floor of the fourth ventricle.

The pons is divided into two main parts: the ventral (basilar) pons and the pontine tegmentum. The ventral pons contains the pontine nuclei and the transverse pontocerebellar fibers, while the pontine tegmentum houses the cranial nerve nuclei and various ascending and descending tracts. ^{[1, 22]}

The pons is a vital component of the brainstem anatomy, serving as a conduit for signals between various parts of the nervous system while housing critical nuclei that influence numerous physiological functions. ^{[1, 22]}

Midbrain

The midbrain, also termed as the mesencephalon, is the superior most aspect of the brainstem and plays a crucial role in various functions, particularly related to movement, vision, and hearing. Structurally, the midbrain consists of several key components. ^{[1, 23]}

Cerebral peduncles - These are bundles of nerve fibers that connect the forebrain to the hindbrain. They contain motor pathways that transmit signals from the cortex to the spinal cord, facilitating movement control. Between these peduncles, the third cranial nerve (oculomotor nerve) exits ventrally, contributing to eye movement control. ^{[1, 23]}

Tectum - The posterior region contains two pairs of protrusions known as the superior and inferior colliculi. The superior colliculi are involved in processing visual information and mediating eye movements, while the inferior colliculi manage auditory information and sound localization. ^{[1, 23]}

Cranial nerves - The third cranial nerve (oculomotor) exits from the ventral aspect, and the fourth cranial nerve (trochlear) exits dorsally — this unique dorsal exit is one of the distinguishing features of the trochlear nerve. The trochlear nerve then wraps around the brainstem to assist in eye movement. ^{[1, 23]}

The posterior aspect of the midbrain has two pairs of characteristic protrusions, the superior and inferior colliculi. The superior colliculi are involved in mediating the vestibulo-ocular reflex, whereas the inferior colliculi are involved in sound localization. The midbrain also houses several important nuclei and gray matter structures, including the substantia nigra, which produces dopamine that is crucial for motor function and is affected in Parkinson's disease. Additionally, it contains the red nucleus, which plays a role in motor coordination. Overall, the midbrain integrates sensory information and coordinates motor responses, playing a pivotal role in maintaining bodily functions and facilitating interaction with our environment. ^{[1, 23]}

Cranial nerves

There are 12 pairs of cranial nerves that function mainly to convey motor signals to and sensory information from the head and neck. The lower cranial nerves have somewhat more complex visceral functions that are not strictly limited to the head and neck. The cranial nerves are as follows:

• I - The olfactory nerve relays information from the nerves of the olfactory epithelium to the mesial temporal lobe and frontal lobe structures. It is involved in the sense of smell. Studies emphasize its role in not only detecting odors but also in influencing emotional responses and memory. ^{[1, 24, 25]}
• II - The optic nerve relays visual information from the retina; the right and left optic nerves then join at the optic chiasm, where they give rise to the optic tracts, which convey visual information to the thalamus and brainstem and ultimately the visual cortex; optic gliomas can arise from the optic nerve.
• III - The oculomotor nerve is principally involved in the control of eye movements through its innervation of the superior rectus, medial rectus, inferior rectus, and inferior oblique muscles. It facilitates pupil constriction, eyelid elevation, and autonomic functions, including reflexive responses to light. ^{[1, 24, 25]}
• IV - The trochlear nerve innervates the superior oblique muscle and is purely a motor nerve, enabling downward and lateral eye movement. It is unique as it is the only cranial nerve that exits from the dorsal aspect of the brainstem. ^{[1, 24, 25]}
• V - The trigeminal nerve is both a motor and sensory nerve and has three divisions, V₁ (the ophthalmic division), V₂ (the maxillary division), and V₃ (the mandibular division); it is involved in conveying sensory information from the face and also in controling the muscles of mastication; vascular compression of the branches of the trigeminal nerve near its entry into the brainstem has been associated with some types of facial pain, including trigeminal neuralgia.
• VI - The abducens nerve innervates the lateral rectus nerve, allowing lateral eye movements. Damage to this nerve can lead to binocular horizontal diplopia. ^{[1, 24, 25]}
• VII - The facial nerve is principally involved in innervation of the muscles of facial expression and also plays a role in tearing, salivation, and taste from the anterior two thirds of the tongue. ^{[1, 24, 25]} Bell's palsy is a relatively common facial nerve palsy.
• VIII - The vestibulocochlear nerve is a purely sensory nerve that conveys auditory information from the cochlea to the brainstem via the cochlear branch; the vestibular branch conveys proprioceptive information about the head position and movement from the inner ear to the brainstem; acoustic neuromas are typically benign tumors that can arise from the vestibular portion of this nerve.
• IX - The glossopharyngeal nerve is involved in taste and salivation, as well as sensation in the oropharynx; the afferent limb of the gag reflex is mediated by the glossopharyngeal nerve.
• X - The vagus nerve conveys visceral sensation to the brainstem and also controls some visceral functions such as heart rate and gastrointestinal motility. Vagus nerve stimulation has therapeutic roles in conditions such as epilepsy, migraine, and depression. ^{[1, 24, 25]}
• XI - The accessory nerve has contributions from a spinal component and innervates neck muscles involved in head turning.
• XII - The hypoglossal nerve is a motor nerve that innervates muscles of the tongue. It controls tongue movements essential for speech and swallowing. Disorders affecting this nerve can lead to symptoms such as dysarthria and dysphagia. ^{[1, 24, 25]}

The cerebellum occupies the posterior fossa, dorsal to the pons and medulla. It is involved primarily in modulating motor control to enable precisely coordinated body movements. Similar to the cerebrum, which has gyri and sulci, the cerebellum has finer folia and fissures that increase the surface area.

The cerebellum is divided into three main lobes — anterior, posterior, and flocculonodular — each of which contributes to various functional regions such as the vestibulocerebellum (involved in balance and eye movements), spinocerebellum (posture and coordination), and cerebrocerebellum (planning and voluntary movements). ^{[1, 26, 27]}

The cerebellum consists of two hemispheres, connected by a midline structure called the vermis. In contrast to the neocortex of the cerebrum, the cerebellar cortex has three layers: molecular, Purkinje, and granular. There are four deep cerebellar nuclei: the fastigial, globose, emboliform, and dentate nuclei, in sequence from medial to lateral. These deep nuclei interact with other brain regions to coordinate movement. ^{[1, 26, 27]} The afferent and efferent pathways to and from the cerebellum exist within the three cerebellar peduncles: superior, middle, and inferior. These pathways carry both afferent and efferent signals essential for motor coordination and sensory processing. ^{[1, 26, 27]}

In children, the cerebellum is a common location for tumors such as juvenile pilocytic astrocytomas and medulloblastomas. In adults, the posterior fossa is a very common location not only for metastatic tumors but also for tumors such as hemangioblastomas. Another pathology of the posterior fossa can occur when the cerebellar tonsils descend below the foramen magnum; this is termed a Chiari I malformation.

The cerebellum also plays an important role in cognitive and affective functions, and disruptions here can lead to cerebellar cognitive affective syndrome, which includes impairments in executive function, language, and emotional regulation. ^{[26, 27]}

There are therapeutic strategies aimed at enhancing "cerebellar reserve," which refers to the brain's ability to compensate for damage. This includes both cause-cure treatments for specific pathologies and neuromodulation therapies designed to restore function. ^{[1, 26, 27]}

The meninges consist of three tissue layers that cover the brain and spinal cord: the pia, arachnoid, and the dura mater (see the image below). The pia along with the arachnoid are referred to as the leptomeninges, whereas the dura is referred to as the pachymeninx.

The innermost of the three layers is the pia mater, which tightly covers the brain itself, conforming to its grooves and folds. This layer is rich in blood vessels that descend into the brain. providing it with essential nutrients and oxygen. It also plays a role in the blood-brain barrier, helping regulate the movement of substances into the brain from the bloodstream. Studies have shown that the pia mater actively participates in maintaining central nervous system (CNS) homeostasis. ^{[1, 28, 29, 30]}

Outside the pia mater, which tightly contours the brain, is the arachnoid mater. The arachnoid mater is a thin weblike layer. Between the pia mater and the arachnoid mater is a space called the subarachnoid space, which contains cerebrospinal fluid (CSF). This fluid acts as a cushion for the brain and spinal cord and facilitates nutrient transport. ^{[1, 28, 29, 30]} This space is where the major arteries supplying blood to the brain lie. If a blood vessel ruptures in this space, it can cause a subarachnoid hemorrhage. The arachnoid cap cells can give rise to meningiomas, a usually benign tumor.

The outermost meningeal layer is the dura mater, which lines the interior of the skull. The dura mater is composed of two individual layers, the meningeal dura and the periosteal dura. For the most part, these layers are fused; venous sinuses can be found in areas of separation. The tentorium cerebelli is a dura mater fold that separates the cerebellum from the cerebrum. The falx cerebri is a fold that separates the left and right cerebral hemispheres. The dura mater provides structural support and protection against mechanical injury. Studies have indicated that damage to this layer can affect glymphatic flow and compromise the blood-brain barrier. ^{[1, 28, 29, 30]}

Between the arachnoid mater and the dura mater is the subdural space. If bleeding occurs in the space underneath the dura mater, it is called a subdural hematoma. If bleeding occurs outside the dura but underneath the skull, this is called an epidural hematoma.

Research has introduced a potential fourth meningeal layer known as the subarachnoid lymphatic-like membrane. This newly identified membrane divides the subarachnoid space into distinct compartments, suggesting a more complex organization of CSF flow than previously recognized. This discovery may have significant implications for understanding CNS waste clearance and immune interactions during inflammation. ^{[1, 28, 29, 30]}

Studies show that meningeal cells exhibit diverse populations with specialized functions in CNS development and response to injury. These cells are crucial for maintaining homeostasis and could play roles in various pathologies such as multiple sclerosis, dementia, and traumatic brain injury. ^{[1, 28, 29, 30]}

The brain is bathed in CSF, which is continuously produced and absorbed. The ventricles are CSF-containing cavities within the brain. The ventricles contain structures called choroid plexuses that produce CSF. CSF is produced at a rate of about 450 mL/day, although at any given time about 150 mL can be found within the CSF spaces. Thus, the volume of CSF in most adults is turned over about three times per day.

The brain has four ventricles (see the image below). Within the cerebral hemispheres are the lateral ventricles, which are connected to each other and to the third ventricle through a pathway called the interventricular foramen (of Monro). The third ventricle lies in the midline, separating deeper brain structures such as the left and right thalami. The third ventricle communicates with the fourth ventricle through the cerebral aqueduct (of Sylvius), which is a long narrow tube.

From the fourth ventricle, CSF flows into the subarachnoid space around both the brain and the spinal cord. From the subarachnoid space, CSF is then absorbed into the venous system. Arachnoid granulations or villi are structures projecting into the superior sagittal sinus that release CSF back into the venous system.

Hydrocephalus is a condition wherein CSF production is disproportionate to absorption. This is most commonly caused by impaired absorption resulting from obstruction of the CSF circulatory pathways, in which case it is termed obstructive hydrocephalus. This also occurs when the absorption of CSF is impaired, in which case it is termed communicating hydrocephalus. Rarely is hydrocephalus caused by increased CSF production.

Arteries supply blood to the brain via two main pairs of vessels: the internal carotid artery and the vertebral artery on each side. The internal carotid artery on each side terminates into the anterior cerebral artery, middle cerebral artery, and posterior communicating artery. The vertebral arteries on each side join to form the basilar artery. The basilar artery then gives rise to the posterior cerebral arteries and superior cerebellar arteries.

The basilar artery, posterior cerebral arteries, posterior communicating arteries, and anterior cerebral arteries, along with the anterior communication artery, form an important collateral circulation at the base of the brain termed the cerebral arterial circle (of Willis). These vessels lie within the subarachnoid space and are a common location for cerebral aneurysms to form.

Venous return to the heart occurs through a combination of deep cerebral veins and superficial cortical veins. The veins then contribute to larger venous sinuses, which lie within the dura and ultimately drain through the internal jugular veins to the brachiocephalic veins and then into the superior vena cava.

The cellular structure of the brain is composed primarily of neurons and their support cells, which are broadly termed glial cells. The three principal types of glial cells are astrocytes, oligodendrocytes, and microglia. Neurons transmit signals, while glial cells support neuronal function, maintain the environment, and play a role in immune responses. Recent studies show a 1:1 ratio of glial cells to neurons in certain regions, challenging the old 10:1 assumption. ^{[1, 31]} These glial cells can give rise to glial tumors, such as astrocytomas, oligodendrogliomas, and glioblastomas, which are among the most common primary brain tumors. Glial cells, especially microglia, influence brain tumors and neurologic disorders by affecting synaptic function and inflammation. ^{[1, 31]}

When examined histologically, the neurons of the cortical gray matter demonstrate a laminar pattern. The neocortex contains six distinct layers, in contrast to the evolutionarily older paleocortex and archicortex, which typically contain three layers. The specific cytoarchitectural patterns of the cortex are not uniform throughout the cerebral cortex, and their variation was mapped by the German physician Korbinian Brodmann and presented in 1909. The so-called Brodmann areas represent cytoarchitectural differences across different brain regions, and the numbering scheme developed by Brodmann is still used to refer to distinct areas of the cortex. ^[32]

Layers of neocortex

See the list below:

• I - The molecular layer is the outermost layer of the cortex, which lies adjacent to the pial surface. It contains a sparse population of neurons and is primarily composed of horizontally oriented axons, dendrites, and glial cells. It also has a sparse population of GABAergic interneurons. Studies have identified four distinct subtypes of interneurons in layer I, each with unique molecular profiles, morphologies, and electrophysiological properties. It plays a role in modulating cortical activity through long-range projections and synaptic inputs from other layers and brain regions. It plays an essential part in integrating and coordinating input from other cortical regions. ^[33]
• II - The external granular layer is a dense layer of primarily inhibitory granule cells; this layer serves mainly to establish intracortical connections. This layer is involved in higher order cognitive processes, such as working memory and attention, due to its extensive communication with the prefrontal cortex. ^[33]
• III - The external pyramidal layer contains smaller neurons than its deeper counterpart; this layer provides projections to association fibers and commissural fibers. The role of this layer is in cortico-cortical connectivity, especially in higher cognitive functions such as language and abstract thinking. Changes in layer III thickness and neuron density have also been associated with neuropsychiatric conditions such as schizophrenia. Layer III is particularly well-developed in the prefrontal cortex, contributing to its role in complex cognitive processes. ^[33]
• IV - The internal granular layer is the principal input layer of the cortex, with input derived largely from the thalamus. It is enriched with stellate cells, a type of glutamatergic neuron specialized in receiving and distributing sensory information to other cortical layers. The thickness and cellular composition of layer IV varies across different cortical areas, reflecting their specific sensory processing functions. ^[33]
• V - The internal pyramidal layer is typically the largest layer within the cortex, containing large pyramidal cells; it is one of the principal output layers of the cortex, projecting to subcortical and spinal pathways; in the motor cortex, cells of this layer are termed Betz cells. Layer V plays a crucial role in motor control and is involved in generating voluntary movements. ^[33]
• VI - The fusiform layer contains cells that form association and projection fibers. These neurons establish reciprocal connections with the thalamus, providing feedback and modulating incoming sensory information. Layer VI is also involved in cortical development and plasticity. ^[33]

White matter

White matter tracts connect both nearby and distal brain structures and can be distinguished according to the types of connections they mediate.

Projection fibers connect structures over the longest distances such as the corticospinal projections from the motor cortex to the anterior horn cells of the spinal cord. Association fibers connect structures within the same hemisphere, such as the arcuate fasciculus, which connects the temporoparietal receptive speech areas with the frontal speech areas. Commissural fibers connect homologous structures in the left and right hemispheres, the most notable example being the corpus callosum.

Diffusion tensor imaging has emerged as a magnetic resonance imaging (MRI) tool that provides exceptionally detailed white matter tractography in both normal and pathologic anatomy..

Glial cells

Glial cells provide supportive and regulatory functions for neurons and in fact outnumber neurons. Four principal types of glial cells exist: microglia, astrocytes, oligodendrocytes, and ependymal cells. ^[34]

Microglia have a function in the brain similar to that of the immune system. Astrocytes play a role in creating the blood-brain barrier, which allows certain substances to selectively pass from the capillary system. They are also responsible for reactive scar formation in the brain. Oligodendrocytes form myelin, which serves to electrically insulate the axons of nerve cells, allowing increased rates of conduction. Ependymal cells line the ventricles of the brain and the central canal of the spinal cord. They are involved in the production and circulation of CSF. ^[34]

Abnormal proliferation of oligodendrocytes and astrocytes can lead to primary brain tumors called oligodendrogliomas and astrocytomas. Collectively, these belong to a family of tumors called gliomas, and the most aggressive type is termed a glioblastoma multiforme.

Our current understanding of functional localization in the cortex (see the image below) is derived from several sources, which include insights from patients with lesions involving specific areas of the cortex, awake mapping of the cortex during brain surgery, and functional imaging studies such as functional MRI and positron emission tomography in healthy volunteers.

Some of the earliest contributions to modern language mapping can be traced to the work of the neurologist Paul Broca, who studied language deficits in patients with stroke. Broca's area, as it is termed, is a region of the frontal operculum, which also overlaps with Brodmann area 44 and 45. Three overlapping names describe this region, which is responsible for speech production. Selective damage to this region leads to difficulty speaking but typically with preserved comprehension.

In contrast, Wernicke's area refers to the posterior aspect of the superior temporal gyrus, which overlaps with Brodmann area 22. This region is generally responsible for speech comprehension, and selective injury to it can lead to impaired understanding with preserved speech production.

Additionally, language function is hemispherically dominant. This means that Broca's and Wernicke's aphasia typically result from damage to the hemisphere that is dominant for language. In right-handed individuals, the left hemisphere is nearly always dominant for language. However, in left-handed individuals, the left hemisphere is dominant for speech in only 70%. Bilateral representation occurs in 15% of left-handed people, and right-hemisphere language representation occurs in 15% of left-handed people.

The primary motor and sensory cortex have been mapped extensively through intraoperative stimulation in awake patients. Early work performed by the neurosurgeon Wilder Penfield in Montreal led to the conceptualization of the homunculus, which is the somatotopic representation of the body in both the primary motor and primary sensory cortex (see the image below).

The primary motor cortex corresponds with the precentral gyrus, or Brodmann area 4. Intraoperative stimulation of the motor cortex in awake patients leads to contralateral muscle contraction in a single muscle or a discrete group of muscles. The premotor cortex, which corresponds to Brodmann area 6, is also occupied with movement but more complex movements are typically elicited by stimulation here.

The primary sensory cortex corresponds with the postcentral gyrus, or Brodmann areas 1-3. The homunculus obtained from awake mapping corresponds to that of the motor cortex. Stimulation in awake patients during surgery typically leads to the subjective sensation of tingling of the corresponding body part on the opposite side of the body. Caudally, the superior parietal lobule, Brodmann areas 5 and 7, represents the secondary sensory cortex, which is believed to subserve multimodal sensory information.

The primary visual cortex corresponds to Brodmann area 17 and occupies the occipital pole. It is also termed the striate cortex. The visual cortex is retinotopically organized. Surrounding the primary visual cortex is the visual association cortex, or Brodmann areas 18 and 19.

The primary auditory cortex lies on the superior bank of the superior temporal gyrus and corresponds to Brodmann area 41. Like the primary motor, primary sensory, and visual cortices, the primary auditory cortex is tonotopically organized. The auditory association cortex, or Brodmann area 42, surrounds the primary auditory cortex.