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Forebrain (Prosencephalon)
Diagram depicting the main subdivisions of the embryonic vertebrate brain. These regions will later differentiate into forebrain, midbrain and hindbrain structures.
Identifiers
MeSHD016548
NeuroNames27
NeuroLex IDbirnlex_1509
TA98A14.1.03.006
TA25416
TEE5.14.1.0.2.0.10
FMA61992
Anatomical terms of neuroanatomy

In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions.

Vesicles of the forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary brain vesicles during the early development of the nervous system. At the five-vesicle stage, the forebrain separates into the diencephalon (thalamus, hypothalamus, subthalamus, and epithalamus) and the telencephalon which develops into the cerebrum. The cerebrum consists of the cerebral cortex, underlying white matter, and the basal ganglia.

In humans, by 5 weeks in utero it is visible as a single portion toward the front of the fetus. At 8 weeks in utero, the forebrain splits into the left and right cerebral hemispheres.

When the embryonic forebrain fails to divide the brain into two lobes, it results in a condition known as holoprosencephaly. The main structures of the forebrain include the cerebrum, thalamus and hypothalamus.

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References

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Forebrain

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The forebrain, or prosencephalon, is the anterior-most and largest division of the vertebrate brain, encompassing structures essential for higher cognitive processes, sensory integration, and autonomic regulation. It originates embryologically from the primary brain vesicle at the rostral end of the neural tube during the third week of gestation, differentiating into two secondary vesicles: the telencephalon and the diencephalon. The telencephalon primarily develops into the cerebrum, including the cerebral cortex divided into frontal, parietal, occipital, and temporal lobes, as well as subcortical components such as the basal ganglia, amygdala, and hippocampus. These structures facilitate voluntary motor control, language, memory formation, emotional processing, and spatial navigation. In contrast, the diencephalon forms the thalamus, hypothalamus, epithalamus, and subthalamus, serving as a relay for sensory and motor signals while regulating homeostasis, hormone release, sleep-wake cycles, and stress responses. The forebrain's intricate architecture, featuring gray matter for neuronal cell bodies and white matter for myelinated axons, along with cortical convolutions (gyri and sulci) that expand surface area, underscores its role in complex neural computation. Overall, the forebrain integrates sensory inputs with executive functions, enabling adaptive behavior and consciousness in humans and other vertebrates.

Anatomy

Major Divisions

The forebrain, also known as the prosencephalon, is the anterior-most region of the , developing from the rostral end of the and comprising the telencephalon and . It serves as the primary site for higher cognitive processing and sensory integration in humans. Spatially, the forebrain occupies a rostral position relative to the and , enveloping much of the central structures and extending forward to form the bulk of the . In adult humans, it accounts for approximately 80-90% of the total volume, with the telencephalon dominating this proportion due to the expansion of the cerebral hemispheres. The lies centrally, nestled beneath the telencephalon and surrounding the third ventricle. The key components of the forebrain include the telencephalon, which encompasses the cerebral hemispheres and major components of the (such as the and ), and the , consisting of the , , , and subthalamus. The cerebral hemispheres form the outer mantle, while the provide subcortical nuclei for ; in the , the acts as a relay hub, the regulates , the includes the , and the subthalamus contributes to circuits. Interconnections within the forebrain are facilitated by extensive tracts, such as the , which links the two cerebral hemispheres of the telencephalon to enable interhemispheric communication. Additional tracts, including projection fibers from the to the telencephalon, integrate signals across these divisions. Histologically, forebrain regions feature diverse types, including pyramidal neurons predominant in the with their characteristic triangular somata, apical dendrites, and long axons forming corticofugal pathways, and granular neurons found in structures like the with small, round somata and short dendrites. Glial cells, particularly and , provide essential support, with astrocytes maintaining the blood-brain barrier and regulating synaptic environments uniquely adapted to the forebrain's high metabolic demands.

Telencephalon

The telencephalon, the anterior portion of the forebrain, encompasses the cerebral hemispheres and serves as the primary site for higher cognitive functions, including , voluntary movement, and complex decision-making. It is structurally divided into the outer and deeper subcortical nuclei, with the cortex featuring a convoluted surface that maximizes neural packing. The comprises two main types: the , characterized by six distinct layers of neurons and that facilitate advanced processing, and the , which has fewer layers (typically three to five) and is involved in more primitive functions like olfaction and . Subcortical components of the telencephalon include the striatum and globus pallidus, which are key parts of the basal ganglia and the limbic system, which modulate motor control and emotional responses, respectively. The basal ganglia consist of the striatum (comprising the caudate nucleus and putamen), the globus pallidus, and the subthalamic nucleus, forming interconnected circuits that refine voluntary movements and habit formation. The limbic system incorporates the amygdala for emotional processing, the hippocampus for memory consolidation, and the cingulate gyrus for integrating cognitive and affective information, linking these structures to broader telencephalic networks. Cortical organization is further delineated by gyri (raised folds) and sulci (grooves), which partition the surface into functional lobes, while cytoarchitectonic maps like Brodmann areas provide finer parcellation based on cellular structure; for instance, areas 1–3 process primary somatosensory input, area 4 handles primary motor output, and area 17 receives visual signals from the retina. Hemispheric lateralization enhances efficiency, with the left hemisphere typically specializing in language production and analytical tasks, and the right in spatial navigation and holistic perception. The telencephalon's white matter underlies the cortex, consisting of myelinated axons that facilitate communication. Projection fibers, such as those in the , connect cortical regions to subcortical and spinal structures, transmitting motor and sensory signals. Association fibers link different cortical areas within the same hemisphere, supporting intra-hemispheric integration, while commissural fibers, including the , enable inter-hemispheric coordination by crossing the midline. In humans, the telencephalon accounts for about 80–85% of total mass, averaging 1,200–1,400 grams, with notable and sex differences: male telencephala are typically 8–15% larger in volume than female counterparts, even after adjusting for body size, though females often exhibit proportionally greater cortical folding. Blood supply to the telencephalon arises mainly from the , which perfuses medial frontal and parietal regions, and the , which vascularizes lateral temporal and frontal areas, both originating from the internal carotid arteries to ensure oxygenated delivery for high metabolic demands. Venous drainage bypasses traditional veins, instead channeling through superficial and deep cerebral veins into the dural sinuses, which converge to form the internal jugular veins for systemic return.

Diencephalon

The , a midline structure of the , serves as a critical and integration center, comprising four primary subdivisions: the , , , and subthalamus. Positioned between the telencephalon and , it surrounds the third ventricle and facilitates the processing of sensory, motor, and regulatory signals. The occupies the dorsal portion as the principal nucleus, while the forms the ventral regulatory center, with the and subthalamus providing specialized supportive functions. The , constituting approximately 80% of the , consists of paired ovoid masses of gray matter that act as a gateway for sensory and motor information to the . It contains numerous nuclei, including specific relay nuclei such as the , which relays visual inputs from the to the primary , and the , which conveys auditory signals from the to the . Additionally, intralaminar nuclei contribute to and by projecting diffusely to the cortex and . The hypothalamus, located ventrally, regulates homeostasis through its diverse nuclei and is divided into regions including the paraventricular and supraoptic nuclei. The paraventricular nucleus primarily synthesizes oxytocin, which promotes uterine contractions and milk ejection, while the supraoptic nucleus mainly produces vasopressin (antidiuretic hormone), which enhances water reabsorption in the kidneys; both hormones are transported via axons to the posterior pituitary for release. These magnocellular neurosecretory cells enable direct hormonal output in response to osmotic and stress signals. The , situated dorsally near the third ventricle, includes the and . The secretes to modulate circadian rhythms and reproductive functions, receiving sympathetic input via the . The , divided into medial and lateral components, integrates limbic signals; the lateral habenula influences reward processing by projecting to dopaminergic areas, while the medial habenula is involved in aversion via connections to the interpeduncular nucleus. The subthalamus, positioned ventral to the , primarily encompasses the subthalamic nucleus, which integrates with the circuitry. It receives glutamatergic inputs from the (hyperdirect pathway) and externus, and sends excitatory projections to the globus pallidus internus and pars reticulata, modulating and inhibiting unwanted movements. Key connectivities underscore the diencephalon's integrative role, with thalamocortical projections forming the primary pathway for relaying information to the cortex via radiations through the , including anterior fibers to the and posterior fibers to parietal-occipital areas. The links to the pituitary via the hypothalamic-pituitary axis, where the serves as a neurohemal interface for releasing factors to the and axonal tracts from paraventricular/suprachiasmatic nuclei to the . Protective barriers in the exhibit regional variations, particularly in the , where circumventricular organs such as the and lack a complete blood-brain barrier to allow direct sensing of circulating hormones and nutrients, facilitating rapid endocrine responses while maintaining barrier integrity elsewhere in the and subthalamus.

Development

Embryonic Formation

The embryonic formation of the forebrain begins during the third week of , when the emerges from the induced by signals from the underlying and prechordal . By the end of week 3, the rostral portion of the differentiates into the primary brain vesicles, with the prosencephalon representing the initial forebrain vesicle. This process is critically regulated by Sonic Hedgehog (SHH) signaling, secreted from the , which patterns the ventral forebrain and promotes midline development. By week 5, the prosencephalon subdivides into the telencephalon and , establishing the major divisions of the forebrain. This vesicle division is followed by the evagination of the cerebral hemispheres from the telencephalon around weeks 7-8, where the hemispheres expand rostrally and dorsally to initiate the formation of the . Key transcription factors guide this patterning: FOXG1 is essential for telencephalon specification and ventral identity, enabling cells to respond to morphogens like SHH and FGF8 to adopt subpallial fates. Similarly, OTX2 defines boundaries, particularly at interfaces such as between the and prethalamus, preventing caudal expansion and ensuring regional identity. Cellular processes during this period include , which peaks from weeks 6 to 20 as cortical neurons generated in the ventricular zone undergo radial migration along glial scaffolds to form the cortical plate. Gliogenesis subsequently follows, with progenitors differentiating into and primarily after the main wave of neuronal production, supporting the emerging neural architecture. A critical milestone is the risk of if the SHH pathway is disrupted, resulting in failed separation of the cerebral hemispheres and a spectrum of midline defects from mild facial anomalies to severe malformation.

Postnatal Maturation

Postnatal maturation of the forebrain involves extensive structural refinements that shape its functional architecture, extending from birth through and into early adulthood. During the first two years of life, rapid dendritic arborization occurs in cortical neurons, expanding the surface area for synaptic connections and supporting early learning processes. This phase coincides with a surge in , where synaptic density in the reaches peak levels around age 2-3 years. Subsequently, predominates, eliminating excess connections to optimize neural efficiency; in the cortex, this process intensifies between ages 3 and 10, reducing synaptic density by approximately 40-50% to refine circuits for specialized functions. Myelination of forebrain white matter progresses gradually, beginning posteriorly in sensorimotor regions and advancing anteriorly into association areas. This process enhances signal conduction speed and efficiency, with significant increases in the first of followed by continued development through . In humans, neocortical myelination remains protracted compared to other , with white matter maturation in prefrontal and temporal regions extending into the mid-20s, achieving peak myelin content around age 25-30. Environmental factors profoundly influence forebrain plasticity during sensitive developmental windows, particularly through modulation of molecular mechanisms like (BDNF) expression, which promotes synaptic strengthening and circuit refinement. For instance, the for native , encompassing phonological and grammatical learning, spans from birth to approximately age 7, after which plasticity declines but remains viable for certain aspects until . BDNF signaling facilitates this by regulating dendritic growth and synaptic stability in language-related areas such as Broca's and Wernicke's regions. Sexual dimorphisms emerge prominently during postnatal forebrain maturation, influenced by gonadal hormones. Females typically exhibit earlier onset and peak of myelination, reaching adult-like patterns by late , whereas males show a steeper trajectory in volume increase during this period. By , the male enlarges more substantially relative to females, correlating with testosterone levels and contributing to differences in emotional circuits. As forebrain maturation stabilizes in early adulthood, subtle signs of aging begin to appear, with cortical gray matter volume in prefrontal regions starting to decline around the mid-30s at a rate of about 0.2-0.5% per year. This early loss reflects initial synaptic and dendritic retraction, setting the stage for more pronounced changes later in life.

Functions

Cognitive and Executive Processes

The forebrain, particularly the telencephalon, orchestrates higher cognitive functions through intricate networks centered in the (PFC) and associative areas. The (DLPFC) plays a pivotal role in , including and , by integrating goal-directed and suppressing habitual responses to facilitate flexible to complex tasks. Lesion studies have demonstrated that damage to the DLPFC impairs value-based , as evidenced by altered and reward evaluation in patients. These processes rely on the DLPFC's ability to maintain cognitive control, coordinating and inhibitory mechanisms to prioritize relevant information over distractions. Working memory, essential for temporarily holding and manipulating information, is supported by persistent neural firing in the PFC during delay periods of tasks, such as delayed-response paradigms where subjects must remember spatial locations or stimuli. This sustained activity, first identified in seminal electrophysiological recordings from nonhuman primates, encodes item-specific representations that bridge sensory input and motor output, enabling tasks like problem-solving. Associative cortices further refine these functions: the parietal cortex directs spatial attention, modulating visuospatial orienting and feature integration to enhance perceptual salience in dynamic environments. Meanwhile, the temporal cortex, especially its anterior regions, integrates semantic memory by linking conceptual knowledge across modalities, as shown in functional imaging studies where it activates during tasks requiring word meaning retrieval and categorical associations. Large-scale network models highlight the forebrain's distributed architecture for . The (DMN), encompassing medial PFC and posterior cingulate regions, activates during and self-referential thinking, supporting and retrieval when external demands are low. In contrast, the , anchored in the anterior insula and , prioritizes emotionally or behaviorally relevant stimuli, dynamically switching between internal reflection (DMN) and goal-directed action (central executive network). systems modulate these processes; projections from the to the facilitate reward-based learning by signaling prediction errors, reinforcing adaptive behaviors through midbrain-forebrain loops. Synaptic plasticity underpins memory consolidation within forebrain circuits. (LTP) in hippocampal-entorhinal pathways strengthens connections following high-frequency stimulation, stabilizing episodic memories over extended periods, as demonstrated in rodent models where LTP persists for months post-induction. This mechanism, involving activation and trafficking, enables the to relay contextual information to the hippocampus, consolidating declarative knowledge essential for executive processes.

Sensory and Motor Integration

The forebrain's sensory-motor integration begins with thalamic relay nuclei, which serve as critical gateways for ascending sensory information to the cerebral cortex. The ventral posterolateral (VPL) nucleus of the thalamus receives input from the spinothalamic tract, conveying sensations of pain, temperature, and crude touch from the body, while the ventral posteromedial (VPM) nucleus handles similar inputs from the face. Similarly, the lateral geniculate nucleus (LGN) acts as the primary relay for visual information, receiving retinotopic projections from the optic tract and relaying them to the visual cortex while preserving spatial organization. These first-order thalamic nuclei filter and modulate sensory signals before transmission, ensuring efficient processing in higher cortical areas. In the , primary sensory areas initiate detailed processing of these relayed inputs. The (S1), located in the , maps somatosensory information topographically via the , enabling precise localization of touch and . The primary (V1), in the , processes basic features like edges and orientation from LGN inputs. Higher integration occurs in association areas, such as the middle temporal (MT) area, which specializes in by combining inputs from V1 and analyzing direction and speed of visual stimuli. These cortical stages transform raw sensory data into perceptually meaningful representations that inform motor planning. Motor output is organized hierarchically within forebrain structures, linking sensory integration to action. The plans and sequences movements based on sensory cues, generating motor commands for complex behaviors like reaching. These commands descend to the (M1) in the , which executes fine by activating specific muscle groups through the . loops, involving the , , and subthalamic nucleus, refine these outputs by inhibiting unwanted movements and facilitating smooth, goal-directed actions via parallel circuits that modulate thalamic projections back to the cortex. Cross-modal integration in the forebrain unifies inputs from different senses to enhance perceptual accuracy. The (STS), particularly its posterior region, fuses audiovisual information, such as matching with lip movements, through convergent projections from auditory and visual association areas. This multisensory convergence improves detection thresholds and response times in dynamic environments. Feedback loops via corticothalamic projections from cortical layer 6 neurons modulate thalamic activity, refining sensory-motor integration. These projections enhance attentional focus by amplifying relevant sensory signals in the thalamus, such as boosting visual contrast in the LGN during selective attention, while suppressing irrelevant inputs through inhibitory interneurons. This bidirectional communication creates dynamic gain control, adapting sensory relay to behavioral demands.

Homeostatic and Endocrine Regulation

The forebrain, particularly the within the , plays a central role in homeostatic and endocrine regulation by integrating neural and hormonal signals to maintain physiological balance, including , circadian timing, and stress responses. Key hypothalamic nuclei detect circulating factors and environmental cues, coordinating autonomic outputs and pituitary release to adjust bodily functions such as , body temperature, and . This regulation ensures adaptation to internal and external demands, preventing disruptions in and survival mechanisms. The arcuate nucleus of the is pivotal for appetite regulation, sensing adiposity signals like from peripheral fat stores to modulate feeding behavior and energy expenditure. binds to receptors on arcuate neurons, inhibiting orexigenic agouti-related peptide (AgRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons, which project to other hypothalamic regions to suppress during sufficient energy states. Disruptions in this signaling pathway, as seen in models, lead to hyperphagia and impaired satiety. Similarly, the serves as the master circadian pacemaker, receiving photic input via the to synchronize peripheral clocks and orchestrate daily rhythms in sleep-wake cycles, hormone secretion, and metabolism. Lesions here abolish rhythmic behaviors, underscoring its essential role in temporal . The hypothalamus interfaces directly with the pituitary gland to regulate endocrine functions, exerting control over both anterior and posterior lobes. For the anterior pituitary, hypothalamic releasing hormones such as corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) are transported via the hypophyseal portal system to stimulate adrenocorticotropic hormone (ACTH) and thyroid-stimulating hormone (TSH) secretion, respectively, influencing stress and metabolic responses. The posterior pituitary, by contrast, stores and releases antidiuretic hormone (ADH, or vasopressin) synthesized in hypothalamic magnocellular neurons, aiding osmoregulation and fluid balance. In stress responses, CRH neurons in the paraventricular nucleus activate the hypothalamic-pituitary-adrenal (HPA) axis, triggering glucocorticoid release from the adrenal cortex to mobilize energy during threats; chronic activation can dysregulate this axis, contributing to disorders like anxiety. Autonomic control is mediated by the , which promotes sympathetic activation to enhance arousal, cardiovascular output, and during wakefulness or energy demands, integrating with neurons to link feeding and activity. Connections from the to the facilitate pain modulation, where descending pathways inhibit nociceptive transmission during stress or defensive behaviors, involving release to prioritize survival. Temperature regulation centers on the , which contains thermosensitive neurons acting as effectors to elicit or via autonomic efferents; adjacent osmoreceptors in the median preoptic nucleus detect plasma osmolarity changes, coordinating with ADH release to maintain hydration and thermal stability.

Evolution and Comparative Anatomy

In Non-Mammalian Vertebrates

In basal vertebrates such as and amphibians, the forebrain exhibits a relatively simple organization without the laminated structures seen in mammals. The functions as a non-laminated sensory integration center, processing inputs from olfactory, visual, and somatosensory pathways, while the subpallium contains homologs of the , including striatal regions that modulate motor and reward-related behaviors through projection neurons. This nuclear organization reflects an evolutionary precursor to more complex pallial expansions, with the in ray-finned showing everted morphology that differs from the evaginated form in tetrapods. In reptiles, the forebrain maintains a predominantly nuclear architecture, with the dorsal ventricular ridge (DVR) serving as a functional equivalent to the mammalian cortex by receiving thalamic inputs for . The reptilian forebrain shows olfactory dominance, as evidenced by the large size of the olfactory bulbs and their extensive projections to the , which prioritize chemosensory integration over visual or somatosensory modalities in many species. The telencephalon constitutes a smaller proportion of the total volume in reptiles than in mammals, underscoring the constrained expansion of higher cognitive regions. Avian forebrains demonstrate specialized adaptations within this nuclear framework, particularly in pallial regions. The hyperpallium, including the Wulst, is a prominent dorsal structure dedicated to visual processing and spatial navigation, receiving direct retinal and thalamic inputs for and motion detection. In songbirds, the nidopallium houses circuits essential for vocal learning and production, with nuclei like the high vocal center integrating auditory feedback and through modulation. Across non-mammalian vertebrates, evolutionary constraints limit forebrain complexity, lacking the neocortical that enables layered processing in mammals and instead relying on clustered for parallel sensory-motor integration. This arrangement supports essential survival functions but restricts advanced associative observed in mammalian expansions.

Mammalian Adaptations

The mammalian forebrain underwent significant evolutionary modifications, most notably the emergence of the , a six-layered structure that distinguishes it from the simpler seen in reptilian dorsal (DVR). This reorganization is thought to have arisen through the transformation of the reptilian DVR into a laminated cortex. These changes likely occurred in the common ancestor of mammals, enabling greater processing capacity for sensory integration and behavior. A key metric of mammalian forebrain advancement is the (EQ), which measures brain size relative to body mass and correlates with cognitive capabilities. exhibit notably higher EQ values, with humans reaching approximately 7.5, compared to about 1 in cats, reflecting the disproportionate expansion of the forebrain in lineages adapted for advanced problem-solving and social interaction. In , the forebrain's expanded significantly, comprising up to 29% of the in humans versus about 11% in other mammals, driving advancements in such as and . This region hosts mirror neuron systems, first identified in monkeys, which activate during both action performance and observation, facilitating and social learning critical for . Across mammals, —the folding of the cortical surface—increases with and body size to accommodate more neurons within a compact , with the gyrification index rising allometrically. Dolphins, for instance, display indices rivaling those of humans (around 3.0-3.5 in odontocetes versus 2.6 in humans), allowing their large forebrains to support sophisticated echolocation and social behaviors despite aquatic constraints. Fossil evidence from endocasts reveals rapid forebrain growth in hominins, with achieving an average volume of about 1,000 cc by 1.8 million years ago, nearly double that of earlier australopiths and indicative of selective pressures for enhanced in early human ancestors.

Clinical Significance

Developmental Disorders

Developmental disorders of the forebrain encompass a range of congenital malformations arising from disruptions during embryonic and early fetal development, primarily affecting the prosencephalon and leading to incomplete division or abnormal neuronal organization. These conditions often result from genetic mutations, chromosomal anomalies, or environmental teratogens, manifesting as structural defects that impair cognitive, motor, and sensory functions. (HPE) represents the most severe and common forebrain malformation, characterized by failed cleavage of the prosencephalon into distinct hemispheres. HPE is classified into types based on severity, with alobar HPE featuring a single holosphere, fused thalami, and a monoventricle, while semilobar HPE shows partial separation of the hemispheres posteriorly but fused frontal lobes. Mutations in the (SHH) gene, which plays a critical role in midline patterning, account for approximately 37% of familial autosomal dominant HPE cases, though overall genetic contributions from SHH and related genes like ZIC2, SIX3, and TGIF1 explain about 25% of nonsyndromic instances. The incidence of HPE is estimated at 1 in 10,000 live births, though higher (up to 1 in 250) in early conceptuses due to significant prenatal lethality. A strong correlation exists between the degree of malformation and facial anomalies, such as or midline clefts in alobar forms, reflecting the shared developmental fields of the forebrain and face; milder involvement often pairs with subtler facial dysmorphisms like . Agenesis of the corpus callosum (ACC), another key forebrain disorder, involves the partial or complete absence of the midline commissure connecting the cerebral hemispheres, disrupting interhemispheric communication. ACC can occur in isolated forms, where it presents without other anomalies, or as part of syndromic conditions, such as , which combines ACC with chorioretinal lacunae and infantile spasms, almost exclusively in females and leading to profound . Diagnosis relies on (MRI), which reveals the absent callosum, associated Probst bundles (misdirected ), and potential . In isolated ACC, cognitive outcomes vary, with many individuals achieving normal intelligence quotients but exhibiting deficits in processing speed, executive function, , and novel problem-solving due to impaired hemispheric integration. Lissencephaly, or "smooth brain," arises from defective neuronal migration during the 12th to 24th gestational weeks, resulting in a lack of cortical gyri and sulci, thick cortex, and disorganized lamination. Mutations in the LIS1 gene (PAFAH1B1), encoding a essential for cytoskeletal dynamics, cause classical subtype I, often in Miller-Dieker syndrome due to contiguous gene deletions. This leads to a pachygyric surface with agyria or , severe developmental delays, and evolving to . affects more than 90% of individuals with lissencephaly, typically presenting as infantile spasms or refractory seizures in early infancy. Both genetic and environmental factors contribute to these forebrain disorders, with prenatal disruptions increasing risks of midline fusion failures like HPE. Maternal pregestational significantly elevates HPE risk (up to 200-fold in some studies), potentially through hyperglycemia-induced impairing SHH signaling. Periconceptional alcohol exposure also heightens odds (adjusted OR ≈ 2.0), likely via interference with pathways critical for ventral forebrain patterning. Prognosis varies by malformation severity; alobar HPE carries near-universal early mortality, with most infants not surviving beyond the first months due to hypothalamic-pituitary dysfunction and apnea. Semilobar HPE offers a more favorable outlook, with about 50% surviving past infancy, though survivors often face profound , seizures, and endocrine issues requiring lifelong management. Isolated ACC generally permits longer survival and better function than syndromic forms, while prognosis remains guarded, with median survival into adolescence but high rates of epilepsy-related complications.

Acquired Pathologies

Acquired pathologies of the forebrain arise from external injuries, progressive degeneration, vascular insults, or infectious processes, primarily affecting the , limbic structures, , , and , resulting in disrupted neural connectivity and function. These conditions lead to symptoms such as cognitive decline, sensory alterations, motor impairments, and behavioral changes, with pathophysiological mechanisms involving neuronal loss, , , and ischemia. Understanding these pathologies is crucial for delineating the forebrain's vulnerability to post-developmental insults. Traumatic brain injury (TBI) frequently targets the forebrain, particularly through contusions that cause direct cortical damage and secondary effects like and hemorrhage. often result from acceleration-deceleration forces in high-impact trauma, leading to personality changes such as increased , , and due to disruption of prefrontal executive networks. These alterations persist chronically in moderate to severe cases, impairing social functioning and . Complementing cortical damage, (DAI) in TBI shears tracts throughout the forebrain, including the and subcortical projections, due to rotational forces that exploit the viscoelastic properties of axons. This microstructural disruption propagates and demyelination, contributing to widespread cognitive and motor deficits by interrupting inter-regional communication. In neurodegenerative disorders, Alzheimer's disease (AD) prominently affects forebrain structures like the hippocampus and temporal lobes through accumulation of amyloid-beta plaques and neurofibrillary tangles. Amyloid plaques form extracellular deposits that trigger neuroinflammation and synaptic loss in the hippocampus, a key forebrain region for memory, leading to anterograde amnesia and spatial disorientation as early symptoms. Hippocampal atrophy, detectable via volumetric MRI, correlates with plaque burden and tau pathology spreading from the entorhinal cortex. Frontotemporal dementia (FTD), another tau-mediated pathology, targets the prefrontal cortex, causing neuronal loss and gliosis that manifest as behavioral disinhibition, apathy, and executive dysfunction. Tau inclusions in prefrontal neurons disrupt microtubule stability, accelerating degeneration in frontal lobes and anterior temporal regions, with atrophy patterns confirmed by neuroimaging. Parkinson's disease (PD) involves forebrain basal ganglia pathology, characterized by progressive dopamine loss in the substantia nigra projections to the striatum, compounded by alpha-synuclein Lewy body formation. This dopaminergic depletion impairs motor circuits, resulting in bradykinesia and rigidity, while Lewy bodies in basal ganglia neurons contribute to non-motor symptoms like cognitive fluctuations through widespread protein misfolding. Vascular pathologies in the forebrain include ischemic strokes in the (MCA) territory, which supplies the lateral , including sensory-motor areas. MCA occlusions lead to of the frontal, parietal, and temporal lobes, causing contralateral , sensory deficits, and due to ischemia-induced and penumbral . In the forebrain's subcortical components, thalamic lacunar infarcts from small vessel disease produce pure by damaging the ventral posterior nucleus, which relays somatosensory information to the cortex. These lacunes, often hypertensive in origin, result in hemisensory syndromes affecting touch and pain modalities without motor involvement, stemming from focal ischemia in thalamocortical pathways. Infectious processes can selectively invade forebrain regions, as seen in herpes simplex virus type 1 (HSV-1) encephalitis, which preferentially targets the including temporal lobes and cingulate . HSV-1 reactivation causes necrotizing with and hemorrhage, leading to acute symptoms like seizures, impairment, and psychiatric disturbances due to viral for limbic neurons. Sepsis-related hypothalamic involvement exacerbates forebrain dysfunction through systemic penetrating the blood-brain barrier, inducing cytokine-mediated neuronal and microglial activation in the . This hypothalamic pathology disrupts autonomic regulation and contributes to sepsis-associated , manifesting as and long-term cognitive deficits via amplified inflammatory signaling.

Diagnostic and Therapeutic Approaches

Diagnostic approaches to forebrain disorders rely on advanced techniques to assess structural and functional integrity. (fMRI), particularly resting-state fMRI, maps forebrain functional connectivity by identifying networks such as the , which spans cortical and subcortical regions, aiding in the diagnosis of conditions like where network disruptions are evident. Diffusion tensor imaging (DTI) evaluates integrity in the forebrain by quantifying in tracts like the , revealing demyelination or axonal damage in . (PET) using fluorodeoxyglucose (FDG) measures glucose in forebrain structures, with hypometabolism in the temporal and parietal lobes serving as a for early detection. Electrophysiological methods provide complementary insights into forebrain electrical activity. (EEG) detects abnormal rhythms and epileptiform discharges in the , essential for diagnosing focal seizures originating in forebrain regions like the frontal or temporal lobes. (MEG) offers superior spatial resolution for localizing sources in deeper forebrain structures, such as the , by measuring magnetic fields from neuronal currents, which is particularly useful in presurgical planning for . Therapeutic interventions target specific forebrain circuits to alleviate symptoms in various pathologies. (DBS) of the subthalamic nucleus, a key forebrain-adjacent structure, modulates basal ganglia-forebrain loops, significantly reducing motor symptoms in with long-term efficacy demonstrated in randomized trials. therapies, including infusions, aim to promote in forebrain areas affected by ischemic ; phase II and III trials as of 2025 have shown modest improvements in motor function and safety profiles in ischemic penumbra regions. Pharmacologically, cholinesterase inhibitors like donepezil enhance cholinergic signaling in the forebrain, slowing cognitive decline in Alzheimer's by increasing levels in the cortex and hippocampus. For , involving forebrain glutamate imbalances, low-dose anti-NMDA receptor modulators address hypofunction of NMDA receptors in cortical circuits, though primarily explored in adjunctive therapy settings. Emerging techniques hold promise for precise forebrain interventions. in animal models precisely activates or inhibits hypothalamic circuits within the forebrain, offering insights into disorders like and informing potential human translation via light-sensitive proteins. AI-assisted lesion mapping, leveraging on multimodal imaging data, has advanced post-2023 to predict functional outcomes from forebrain s with over 85% accuracy in cohorts, enhancing personalized rehabilitation planning. As of 2025, phase 3 trials like continue to evaluate allogeneic stem cells for acute ischemic , with promising safety and efficacy data. AI models have achieved up to 87% accuracy in predicting outcomes from lesions.

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK542179/
  2. https://openbooks.lib.msu.edu/neuroscience/chapter/internal-brain-anatomy/
  3. https://www.ncbi.nlm.nih.gov/books/NBK234157/
  4. https://www.ncbi.nlm.nih.gov/books/NBK551718/
  5. https://www.ncbi.nlm.nih.gov/books/NBK575742/
  6. https://radiopaedia.org/articles/cerebral-cortex?lang=us
  7. https://www.sciencedirect.com/science/article/pii/S089662731930635X
  8. https://www.ncbi.nlm.nih.gov/books/NBK537141/
  9. https://www.ncbi.nlm.nih.gov/books/NBK538491/
  10. https://www.ncbi.nlm.nih.gov/books/NBK537247/
  11. https://pmc.ncbi.nlm.nih.gov/articles/PMC4874870/
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC3652620/
  13. https://radiopaedia.org/articles/white-matter-tracts?lang=us
  14. https://www.imaios.com/en/e-anatomy/anatomical-structures/commissural-fibers-of-telencephalon-1553798764
  15. https://faculty.washington.edu/chudler/facts.html
  16. https://bionumbers.hms.harvard.edu/bionumber.aspx?id=106398&ver=3
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC6869393/
  18. https://www.ncbi.nlm.nih.gov/books/NBK11042/
  19. https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2020.611485/full
  20. https://www.ncbi.nlm.nih.gov/books/NBK542184/
  21. https://www.ncbi.nlm.nih.gov/books/NBK535380/
  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC10801627/
  23. https://www.frontiersin.org/journals/neuroanatomy/articles/10.3389/fnana.2020.00013/full
  24. https://www.ncbi.nlm.nih.gov/books/NBK546699/
  25. https://www.ncbi.nlm.nih.gov/books/NBK279126/
  26. https://www.ncbi.nlm.nih.gov/books/NBK557414/
  27. https://www.nature.com/articles/ng1196-357
  28. https://pmc.ncbi.nlm.nih.gov/articles/PMC8657641/
  29. https://embryology.med.unsw.edu.au/embryology/index.php/Neural_-_Prosencephalon_Development
  30. https://www.ncbi.nlm.nih.gov/books/NBK563181/
  31. https://link.springer.com/article/10.1007/BF00315698
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC2858907/
  33. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2012.00073/full
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC6672534/
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC8106805/
  36. https://link.springer.com/article/10.1007/s11065-010-9148-4
  37. https://www.pnas.org/doi/10.1073/pnas.1117943109
  38. https://www.nature.com/articles/s41598-020-79540-3
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC2947444/
  40. https://royalsocietypublishing.org/doi/10.1098/rspb.2021.1025
  41. https://pmc.ncbi.nlm.nih.gov/articles/PMC6673466/
  42. https://pmc.ncbi.nlm.nih.gov/articles/PMC2818549/
  43. https://www.jneurosci.org/content/32/20/6745
  44. https://www.brainfacts.org/thinking-sensing-and-behaving/aging/2019/how-the-brain-changes-with-age-083019
  45. https://pmc.ncbi.nlm.nih.gov/articles/PMC8627478/
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC8617292/
  47. https://www.pnas.org/doi/10.1073/pnas.1206608109
  48. https://www.sciencedirect.com/topics/neuroscience/dorsolateral-prefrontal-cortex
  49. https://pmc.ncbi.nlm.nih.gov/articles/PMC4163787/
  50. https://www.frontiersin.org/journals/systems-neuroscience/articles/10.3389/fnsys.2015.00181/full
  51. https://pmc.ncbi.nlm.nih.gov/articles/PMC2664449/
  52. https://pmc.ncbi.nlm.nih.gov/articles/PMC4884670/
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC3553600/
  54. https://www.jneurosci.org/content/39/50/9878
  55. https://pmc.ncbi.nlm.nih.gov/articles/PMC2134972/
  56. https://www.jneurosci.org/content/22/21/9626
  57. https://www.ncbi.nlm.nih.gov/books/NBK507824/
  58. https://www.sciencedirect.com/topics/neuroscience/ventral-posterolateral-nucleus
  59. https://www.ncbi.nlm.nih.gov/books/NBK541137/
  60. https://www.cell.com/current-biology/fulltext/S0960-9822%2801%2900379-7
  61. https://www.ncbi.nlm.nih.gov/books/NBK555915/
  62. https://nba.uth.tmc.edu/neuroscience/m/s2/chapter15.html
  63. https://www.eneuro.org/content/3/6/ENEURO.0163-16.2016
  64. https://nba.uth.tmc.edu/neuroscience/m/s3/chapter03.html
  65. https://nba.uth.tmc.edu/neuroscience/m/s3/chapter04.html
  66. https://www.jneurosci.org/content/37/33/7893
  67. https://pmc.ncbi.nlm.nih.gov/articles/PMC2536697/
  68. https://www.jneurosci.org/content/34/20/6813
  69. https://www.nature.com/articles/s41598-025-05592-y
  70. https://elifesciences.org/articles/70469
  71. https://www.frontiersin.org/journals/neural-circuits/articles/10.3389/fncir.2015.00080/full
  72. https://pmc.ncbi.nlm.nih.gov/articles/PMC5483000/
  73. https://pmc.ncbi.nlm.nih.gov/articles/PMC8905335/
  74. https://www.nature.com/articles/s41583-018-0026-z
  75. https://www.sciencedirect.com/science/article/pii/S0303720721000174
  76. https://pmc.ncbi.nlm.nih.gov/articles/PMC4867107/
  77. https://academic.oup.com/book/40402/chapter/347238124
  78. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1380171/full
  79. https://www.pnas.org/doi/10.1073/pnas.1616255114
  80. https://journals.physiology.org/doi/full/10.1152/ajpregu.00270.2013
  81. https://www.nature.com/articles/s42003-024-06315-1
  82. https://www.sciencedirect.com/science/article/abs/pii/S0301008298000082
  83. https://pubmed.ncbi.nlm.nih.gov/19729896/
  84. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2015.00402/full
  85. https://pmc.ncbi.nlm.nih.gov/articles/PMC3824149/
  86. https://www.pnas.org/doi/10.1073/pnas.2121624119
  87. https://anatomypubs.onlinelibrary.wiley.com/doi/full/10.1002/ar.a.20253
  88. https://pmc.ncbi.nlm.nih.gov/articles/PMC2481519/
  89. https://pmc.ncbi.nlm.nih.gov/articles/PMC4650131/
  90. https://www.sciencedirect.com/science/article/pii/S096098221201322X
  91. https://pmc.ncbi.nlm.nih.gov/articles/PMC7917222/
  92. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0058840
  93. https://www.sciencedirect.com/topics/neuroscience/encephalization-quotient
  94. https://firstvet.com/us/articles/10-facts-about-your-cats-brain
  95. https://www.science.org/doi/10.1126/science.abo7257
  96. https://pmc.ncbi.nlm.nih.gov/articles/PMC5810456/
  97. https://anatomypubs.onlinelibrary.wiley.com/doi/10.1002/ar.20530
  98. https://pmc.ncbi.nlm.nih.gov/articles/PMC11485192/
  99. https://www.researchgate.net/publication/350777083_The_primitive_brain_of_early_Homo
  100. https://www.science.org/doi/10.1126/science.aaz0032
  101. https://www.ncbi.nlm.nih.gov/books/NBK560861/
  102. https://www.ncbi.nlm.nih.gov/books/NBK1530/
  103. https://pubmed.ncbi.nlm.nih.gov/10556296/
  104. https://medlineplus.gov/genetics/condition/nonsyndromic-holoprosencephaly/
  105. https://www.health.mn.gov/diseases/cy/holoprosencephaly.html
  106. https://www.ncbi.nlm.nih.gov/books/NBK1381/
  107. https://pmc.ncbi.nlm.nih.gov/articles/PMC7565833/
  108. https://pmc.ncbi.nlm.nih.gov/articles/PMC7989584/
  109. https://www.ncbi.nlm.nih.gov/books/NBK560766/
  110. https://pubmed.ncbi.nlm.nih.gov/27998308/
  111. https://pubmed.ncbi.nlm.nih.gov/10710231/
  112. https://pmc.ncbi.nlm.nih.gov/articles/PMC5763157/
  113. https://jamanetwork.com/journals/jamaneurology/fullarticle/2813591
  114. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494898/
  115. https://www.nature.com/articles/s41598-025-04405-6
  116. https://svn.bmj.com/content/early/2024/12/24/svn-2024-003372
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