From Localization to Connectomics: A Contemporary View of Human Brain Structure and Dynamic Network Function

The human brain represents one of the most complex systems in nature, comprising approximately 86 billion neurons and an even greater number of glial cells interconnected through trillions of synapses. Historically, neuroscience has been dominated by localizationist theories, which propose discrete brain regions as the anatomical substrates for specific cognitive functions. This perspective, rooted in 19th-century phrenology and reinforced by lesion studies, suggested a one-to-one correspondence between brain areas and mental faculties. While this framework provided valuable initial insights into brain organization, accumulating evidence from modern neuroimaging and computational neuroscience has necessitated a fundamental reconceptualization of how the brain operates. The advent of non-invasive neuroimaging technologies, particularly functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), has enabled researchers to visualize both the functional dynamics and structural connectivity of the living human brain with unprecedented resolution. These advances have catalyzed a shift toward network neuroscience, which emphasizes the brain's organization into distributed, functionally integrated systems. The Human Connectome Project and related initiatives have systematically mapped the brain's structural and functional connections, revealing a complex architecture that defies simple localizationist interpretations. Contemporary neuroscience now recognizes that cognitive processes and behaviors emerge from the coordinated activity of multiple brain regions operating within large-scale networks, rather than from isolated neural territories. This review examines the anatomical foundations of brain organization while foregrounding the network-level principles that govern brain function, incorporating recent discoveries regarding glial cell activity, neuroplasticity, and the molecular mechanisms underlying neural communication.

1. Major Anatomical Divisions and Their Network Participation
   1. The Cerebrum and Cortical Architecture

The cerebrum constitutes the largest division of the human brain, characterized by its extensively folded cerebral cortex that maximizes surface area while maintaining a compact volume. The cortical surface is organized into gyri (ridges) and sulci (grooves), creating a distinctive topography that varies systematically across individuals while maintaining consistent functional zones. The cerebral cortex is divided into two hemispheres connected by the corpus callosum, a massive white matter tract containing approximately 200 million axonal fibers that facilitate interhemispheric communication and functional integration. The frontal lobe encompasses regions critical for executive functions, including the prefrontal cortex, which orchestrates complex cognitive operations such as planning, decision-making, working memory, and cognitive control. The primary motor cortex, located in the precentral gyrus, contains the motor homunculus and initiates voluntary movements through its projections to the spinal cord. Broca's area, typically localized to the left inferior frontal gyrus, plays an essential role in language production and grammatical processing. Contemporary research has revealed that frontal regions participate in multiple large-scale networks, including the executive control network and the salience network, which coordinate attention allocation and task switching. (Gratton et al., 2024; Menon & D'Esposito, 2023) The parietal lobe processes somatosensory information through the primary somatosensory cortex in the postcentral gyrus, which maintains a topographic representation of the body surface. Beyond basic sensory processing, parietal regions support spatial awareness, attention, and sensorimotor integration. The superior parietal lobule contributes to visuospatial processing and reaching movements, while the inferior parietal lobule participates in multisensory integration and aspects of language processing. Parietal cortex forms crucial nodes in the dorsal attention network, which mediates goal-directed attention and eye movements. (Corbetta & Shulman, 2023; Humphreys et al., 2024) The temporal lobe houses the primary auditory cortex in Heschl's gyrus and supports auditory perception, language comprehension through Wernicke's area, and high-level visual processing in the ventral temporal cortex. Medial temporal structures, including the hippocampus and amygdala, are fundamental to memory formation and emotional processing. The hippocampus specifically mediates the encoding and consolidation of declarative memories and spatial navigation, while the amygdala processes emotional salience and fear conditioning. Recent network analyses demonstrate that temporal regions participate in the semantic network, memory networks, and the ventral attention network. (Ranganath & Ritchey, 2023; Phelps & LeDoux, 2024). The occipital lobe is dominated by visual processing areas, with the primary visual cortex (V1) in the calcarine sulcus receiving direct input from the lateral geniculate nucleus. Visual information flows through a hierarchy of specialized areas organized into dorsal and ventral streams, processing motion and spatial information versus object identity and form, respectively. Occipital regions form the core of visual networks that extend into parietal and temporal cortices. (Wandell & Winawer, 2024; Grill-Spector et al., 2023).

Fig.1. Cerebrum

1. 2. Subcortical Structures and Deep Brain Networks

The basal ganglia comprise a collection of subcortical nuclei, including the caudate nucleus, putamen, globus pallidus, substantia nigra, and subthalamic nucleus, which form recurrent loops with the cortex and thalamus. These structures are essential for motor control, action selection, habit formation, and reward-based learning. Dysfunction of basal ganglia circuits underlies movement disorders such as Parkinson's disease and Huntington's disease, as well as psychiatric conditions including obsessive-compulsive disorder. The basal ganglia participate in cortico-striatal-thalamic loops that integrate information across motor, associative, and limbic domains. (DeLong & Wichmann, 2023; Graybiel & Grafton, 2024) The thalamus serves as a central relay station for sensory information ascending to the cortex, with distinct nuclei dedicated to different sensory modalities. Beyond its relay functions, the thalamus participates in regulating cortical arousal, attention, and consciousness. Thalamocortical networks exhibit synchronized oscillatory activity that varies with behavioral state and supports information integration across cortical areas. The thalamus also receives extensive feedback projections from the cortex, suggesting reciprocal interactions that shape sensory processing. (Halassa & Sherman, 2023; Nakajima & Halassa, 2024). The hypothalamus, despite its small size, exerts profound influence over homeostatic regulation, controlling autonomic functions, endocrine secretion, circadian rhythms, and motivated behaviors including feeding, drinking, and reproduction. Hypothalamic nuclei interface with the pituitary gland to regulate hormonal systems and with brainstem nuclei to control autonomic output. Recent connectomic studies have mapped detailed hypothalamic connectivity patterns, revealing its extensive integration with limbic structures and cortical networks involved in interoception and emotional processing. (Sternson & Eiselt, 2023; Atasoy et al., 2024).

Fig.2. Subcortical brain structures (caudate, putamen, thalamus, globus pallidus, nucleus accumbens, amygdala, and hippocampus) mapped on a human brain

1. 3. The Cerebellum: Beyond Motor Coordination

The cerebellum contains more neurons than the rest of the brain combined, organized into a highly regular architecture of parallel fibers, Purkinje cells, and deep cerebellar nuclei. Traditionally associated with motor coordination, balance, and motor learning, the cerebellum is now recognized to participate in cognitive and emotional processing. Cerebellar regions show functional parcellation that mirrors cortical organization, with distinct areas connected to motor, prefrontal, and posterior parietal cortices. Cerebellar dysfunction produces not only motor symptoms but also cognitive deficits collectively termed "cerebellar cognitive affective syndrome." The cerebellum appears to implement predictive computations and error correction across multiple domains, from movement to language to social cognition. (Koziol et al., 2023; Schmahmann & Guell, 2024).

Fig.3. Cerebellum

1. 4. The Brainstem: Life-Sustaining Networks

The brainstem, comprising the midbrain, pons, and medulla oblongata, contains nuclei that regulate vital autonomic functions including respiration, cardiovascular control, and consciousness. Ascending arousal systems originating in brainstem nuclei, including the locus coeruleus (noradrenergic), raphe nuclei (serotonergic), and ventral tegmental area (dopaminergic), modulate cortical arousal and attention. The reticular formation coordinates multiple sensory and motor systems, while cranial nerve nuclei mediate sensory and motor functions of the head and neck. Brainstem networks exhibit complex connectivity with forebrain structures and play critical roles in sleep-wake regulation, pain modulation, and emotional processing. (Saper & Fuller, 2023; Venner et al., 2024).

Fig.4. Brain Stem

2. The Connectome and Network Neuroscience
   1. Mapping the Human Connectome

The connectome represents the comprehensive structural and functional connectivity architecture of the brain at multiple scales, from synaptic connections between individual neurons to large-scale fiber tracts linking brain regions. The Human Connectome Project has generated high-quality neuroimaging data from hundreds of individuals, enabling systematic characterization of typical connectivity patterns and individual variability. Diffusion MRI tractography reveals white matter pathways, while resting-state fMRI identifies functionally coupled regions based on correlated spontaneous activity. These complementary approaches have converged on a picture of the brain as a complex network with small-world properties, characterized by dense local clustering and short path lengths enabling efficient information transfer. (Van Essen & Glasser, 2023; Sporns & Betzel, 2024). The structural connectome exhibits a modular organization, with densely interconnected communities corresponding to functional systems such as sensory-motor, attention, and default mode networks. Connector hubs link different modules, facilitating integration across specialized systems. The distribution of connectivity follows a heavy-tailed pattern, with a small number of highly connected hub regions that play disproportionate roles in network communication. Damage to these hubs produces more severe cognitive deficits than damage to less connected regions, highlighting the functional significance of network topology. (Avena-Koenigsberger et al., 2023; Breakspear, 2024)

1. 2. Resting-State Networks and Intrinsic Brain Architecture

A groundbreaking discovery in network neuroscience has been the identification of resting-state networks: sets of brain regions showing correlated spontaneous activity in the absence of explicit tasks. These intrinsic networks reveal the brain's functional architecture and account for the majority of brain energy consumption. The Default Mode Network (DMN), comprising medial prefrontal cortex, posterior cingulate cortex, angular gyrus, and medial temporal structures, exhibits high activity during rest and is consistently deactivated during externally focused tasks. The DMN supports self-referential processing, episodic memory retrieval, future planning, and social cognition. (Raichle & Snyder, 2023; Andrews-Hanna et al., 2024) Other prominent resting-state networks include the dorsal attention network (frontoparietal regions supporting goal-directed attention), the ventral attention network (right-lateralized system for stimulus-driven attention), the executive control network (prefrontal and parietal regions mediating cognitive control), the salience network (anterior insula and anterior cingulate cortex detecting behaviorally relevant stimuli), and sensorimotor networks. These networks exhibit characteristic temporal dynamics, including anticorrelations between the DMN and task-positive networks that reflect competition between internal and external attention. (Uddin et al., 2023; Dixon et al., 2024). Resting-state network organization varies systematically across individuals and predicts cognitive abilities, personality traits, and psychiatric symptom profiles. Network dysconnectivity has been implicated in numerous neurological and psychiatric disorders, including Alzheimer's disease, schizophrenia, autism spectrum disorder, and depression. The stability and plasticity of resting-state networks across development and with experience reflect fundamental properties of brain organization. (Finn et al., 2023; Gratton & Nelson, 2024)

1. 3. Meta-Networking and Spatiotemporal Integration

Meta-networking theory proposes that complex cognitive functions emerge from the coordinated interaction of multiple specialized networks operating across different timescales. Rather than attributing functions to single networks, this framework emphasizes dynamic reconfiguration, whereby brain regions flexibly join or leave networks depending on task demands. Network flexibility, measured as the variability in regional network affiliations over time, correlates with cognitive flexibility and learning capacity. (Shine et al., 2023; Cohen & D'Esposito, 2024).  Recent studies employing high-temporal-resolution neuroimaging and computational modeling reveal that brain activity exhibits metastable dynamics, transiently occupying a repertoire of network configurations that facilitate information processing and behavioral adaptation. Critical brain dynamics, positioned at the boundary between order and disorder, may optimize the balance between functional integration and segregation. This perspective links network organization to information-theoretic principles and energy efficiency constraints. (Deco et al., 2024; Mediano et al., 2023).

3. Neuroplasticity and Functional Compensation

The brain demonstrates remarkable capacity for structural and functional reorganization throughout the lifespan, a property termed neuroplasticity. Experience-dependent plasticity enables learning and memory formation through synaptic modifications, including long-term potentiation and depression. At the systems level, training and expertise produce measurable changes in cortical representations and functional connectivity patterns. (Johansen-Berg & Mackey, 2023; Zatorre & Kanwisher, 2024). Following focal brain lesions from stroke or trauma, the brain exhibits compensatory reorganization that supports functional recovery. Perilesional cortex may assume functions previously performed by damaged tissue, while contralesional homologous regions and alternative networks can be recruited to mediate preserved abilities. The degree of recovery depends on lesion characteristics, individual factors, and rehabilitation interventions that promote adaptive plasticity while limiting maladaptive reorganization. Network analyses have revealed that lesions affecting hub regions produce more widespread connectivity disruptions, but also that the brain's network architecture includes multiple redundant pathways that can potentially support functional compensation. (Carrera & Tononi, 2023; Siegel et al., 2024). The principle of degeneracy, whereby multiple neural configurations can produce equivalent functional outcomes, provides a mechanistic basis for compensation and explains individual variability in brain-behavior relationships. This property challenges deterministic structure-function mappings and emphasizes the brain's flexibility in achieving behavioral goals through alternative neural routes. (Friston & Price, 2023; Pessoa, 2024)

4. Glial Cells: Active Participants in Neural Networks

For decades, glial cells were considered passive support elements for neurons, but contemporary research has established their active roles in neural function. Astrocytes, the most abundant glial cell type occupying approximately 25% of brain volume, perform multiple critical functions including neurotransmitter uptake, maintenance of ionic homeostasis, metabolic support for neurons, and regulation of cerebral blood flow. Astrocytes express receptors for neurotransmitters and can modulate synaptic transmission through calcium signaling and gliotransmitter release, contributing to synaptic plasticity. (Verkhratsky & Nedergaard, 2023; Santello et al., 2024). Oligodendrocytes produce myelin sheaths that insulate axons and increase conduction velocity, enabling rapid long-range communication in large brains. Recent studies reveal that myelination patterns are dynamically regulated by neural activity and experience, contributing to circuit refinement and learning. White matter plasticity through activity-dependent myelination represents an underappreciated form of neural plasticity with functional consequences. (Fields & Bukalo, 2023; Mount & Monje, 2024). Microglia serve as the brain's resident immune cells, surveying the neural environment and responding to injury, infection, and pathological protein accumulation. Beyond immune functions, microglia participate in synaptic pruning during development and potentially in adulthood, sculpting neural circuits through selective elimination of synapses. Microglial dysfunction contributes to neurodevelopmental disorders and neurodegenerative diseases, highlighting the importance of neuroimmune interactions. (Prinz et al., 2023; Salter & Stevens, 2024). The concept of the "tripartite synapse," comprising presynaptic and postsynaptic neurons plus astrocytic processes, recognizes glial participation in synaptic function. More broadly, neuron-glia interactions at the network level influence information processing, and glial pathology contributes to network dysfunction in disease states. (Bazargani & Attwell, 2023; Iadecola, 2024).

5. Neurotransmitter Systems and Neuromodulation

Neural communication relies on a diverse array of neurotransmitters that mediate fast synaptic transmission and slow neuromodulation. Glutamate serves as the primary excitatory neurotransmitter in the brain, mediating the majority of excitatory synaptic transmission through AMPA, NMDA, and metabotropic receptors. Glutamatergic transmission is essential for learning and memory, with NMDA receptor-dependent long-term potentiation representing a key mechanism of synaptic plasticity. Excessive glutamate signaling causes excitotoxicity and contributes to neuronal death in acute injuries and chronic neurodegenerative diseases. (Paoletti et al., 2023; Traynelis et al., 2024). GABA (gamma-aminobutyric acid) functions as the major inhibitory neurotransmitter, controlling neuronal excitability and oscillatory activity. GABAergic interneurons exhibit remarkable diversity in their molecular, electrophysiological, and connectivity properties, enabling precise temporal control of principal neuron firing. The balance between excitation and inhibition is critical for normal brain function, and disruptions of this balance have been implicated in epilepsy, autism, and schizophrenia. (Tremblay et al., 2023; Hu et al., 2024). Modulatory neurotransmitter systems, including dopamine, serotonin, norepinephrine, and acetylcholine, originate from small brainstem and basal forebrain nuclei but project widely throughout the brain, regulating cortical state, arousal, attention, and learning. Dopamine, synthesized in the substantia nigra and ventral tegmental area, mediates reward processing, motivation, and motor control. Dopaminergic dysfunction underlies Parkinson's disease and contributes to addiction and schizophrenia. (Berke, 2023; Schultz & Montague, 2024). Serotonin, produced by raphe nuclei, modulates mood, sleep, appetite, and numerous other functions, with serotonergic medications widely prescribed for depression and anxiety disorders. Norepinephrine from the locus coeruleus regulates arousal and attention, with phasic noradrenergic signaling enhancing sensory processing and facilitating learning. Acetylcholine from the basal forebrain promotes cortical activation and attentional processing, while cholinergic deficits characterize Alzheimer's disease. These neuromodulatory systems operate at network scales, influencing the gain and flexibility of neural responses across distributed brain regions. (Paquelet et al., 2023; Ballinger et al., 2024)

6. Recent Anatomical Discoveries

Advancing imaging and histological techniques continue to refine understanding of brain anatomy. A notable recent discovery is the subarachnoid lymphatic-like membrane (SLYM), a thin cellular layer within the subarachnoid space that separates cerebrospinal fluid into compartments and harbors immune cells. This structure, identified through advanced imaging in mice and subsequently observed in human post-mortem tissue, suggests a previously unrecognized organization of the brain's meningeal layers with potential implications for waste clearance, immune surveillance, and the pathophysiology of neurodegenerative diseases. (Møllgård et al., 2023).  The glymphatic system, a brain-wide pathway for cerebrospinal fluid circulation through perivascular spaces, facilitates clearance of metabolic waste including amyloid-beta protein. Glymphatic function is enhanced during sleep and impaired in aging and neurological diseases, linking sleep, neurodegeneration, and brain clearance mechanisms. (Nedergaard & Goldman, 2023; Hablitz & Nedergaard, 2024). High-resolution imaging studies continue to identify previously unknown cell types and refine understanding of neuronal diversity. Single-cell transcriptomic approaches have revealed extensive molecular heterogeneity within traditional cell classes, challenging simple categorical schemes and suggesting a continuum of cell states. These molecular classifications are being integrated with connectivity and functional data to provide comprehensive characterizations of neural cell types. (Yao et al., 2023; Luo et al., 2024).

7. Clinical Implications and Future Directions

The network perspective on brain organization has profound implications for understanding and treating neurological and psychiatric disorders. Rather than attributing disorders to focal pathology, network models emphasize distributed circuit dysfunction. In Alzheimer's disease, pathology preferentially affects DMN hub regions, disrupting network connectivity before substantial neuronal loss. Schizophrenia features dysconnectivity across multiple networks, particularly involving prefrontal-thalamic-cerebellar circuits. Depression involves altered DMN connectivity and reduced functional coupling between prefrontal control systems and limbic regions. (Stam, 2023; Kaiser, 2024).  Therapeutic interventions increasingly target network dynamics. Neuromodulation techniques including transcranial magnetic stimulation and deep brain stimulation can modulate network activity and connectivity. Pharmacological treatments affect neurotransmitter systems that operate at network scales. Behavioral interventions including cognitive training and psychotherapy induce network-level plasticity. Precision medicine approaches aim to characterize individual connectivity profiles to guide personalized interventions. (Fox et al., 2023; Boes et al., 2024).  Future research will continue mapping brain connectivity at finer scales and across diverse populations, characterizing developmental and aging trajectories, and linking connectivity patterns to genetic variants, behavioral phenotypes, and disease risk. Integrating structural and functional connectivity with molecular and cellular data will provide multilevel understanding of brain organization. Advanced computational models will test hypotheses about network dynamics and guide development of circuit-based therapies. (Bullmore & Bassett, 2023; Fornito & Bullmore, 2024).

Table 1: Major Large-Scale Brain Networks and Their Functions