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Neuromodulation

Neuromodulation encompasses both physiological processes and therapeutic interventions that alter neural activity within the nervous system. In neuroscience, it refers to the regulation of neural and synaptic function by extrinsic or intrinsic neuromodulatory substances, which modify the efficacy of synaptic transmission, neuronal excitability, and overall network computation in response to behavioral states or task demands.^[1] Therapeutically, neuromodulation is defined as the alteration of nerve activity through targeted delivery of stimuli, such as electrical stimulation or chemical agents, to specific neurological sites in the central, peripheral, or autonomic nervous systems, aiming to achieve clinical benefits for various disorders.^[2] In physiological contexts, neuromodulation plays a critical role in adapting brain function to environmental and internal changes, influencing processes like attention, learning, mood, and arousal. Key neuromodulators include monoamines such as dopamine, serotonin, and norepinephrine, as well as acetylcholine, histamine, and various neuropeptides, which are released from specialized neurons and diffuse widely to affect multiple targets over extended timescales compared to fast synaptic transmission.^[1] These substances enable flexible neural processing by altering ion channel conductances, second messenger systems, and synaptic plasticity, thereby fine-tuning information flow across brain circuits.^[1] Dysfunctions in endogenous neuromodulation are implicated in disorders like Parkinson's disease, depression, and schizophrenia, highlighting its foundational importance in systems neuroscience.^[3] Therapeutic neuromodulation has evolved into a multidisciplinary field combining neuroscience, engineering, and medicine, with applications spanning chronic pain management, movement disorders, psychiatric conditions, and epilepsy. Common techniques include invasive methods like deep brain stimulation (DBS), which delivers electrical pulses via implanted electrodes to modulate dysfunctional circuits in conditions such as Parkinson's disease and essential tremor, and non-invasive approaches like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) for treating depression and stroke rehabilitation.^[3] Spinal cord stimulation and vagus nerve stimulation represent peripheral neuromodulation strategies effective for neuropathic pain and epilepsy, respectively, while emerging bioelectronic medicines target autonomic functions for hypertension and heart failure.^[4] These interventions restore or normalize aberrant neural activity, offering alternatives to pharmacological treatments with potentially fewer systemic side effects, and continue to advance through innovations in device miniaturization and closed-loop systems.^[3]

Fundamentals

Definition and Scope

Neuromodulation is the physiological process by which neurons release neuromodulators—such as monoamines and neuropeptides—to modify the excitability, synaptic efficacy, or firing patterns of broad populations of neurons over extended timescales, distinct from the rapid, point-to-point signaling of classical neurotransmission.^[5] This process enables neural circuits to adapt dynamically, reconfiguring their output to support behavioral flexibility across diverse contexts.^[6] The scope of neuromodulation extends to both the central and peripheral nervous systems, where it regulates essential functions including arousal, mood, learning, and homeostasis.^[7] Endogenous neuromodulators, including biogenic amines like dopamine, serotonin, and norepinephrine, as well as peptides, diffuse through extracellular spaces via volume transmission to influence widespread neural activity, contrasting with the localized, fast actions of neurotransmitters such as glutamate or GABA.^[6] For instance, neuromodulation governs neural circuits in sleep-wake transitions, reward processing, and sensory gating, ensuring coordinated responses to environmental demands.^[5] At the molecular level, neuromodulators predominantly engage G-protein-coupled receptors (GPCRs), triggering intracellular second messenger cascades—such as those involving cyclic AMP (cAMP) or inositol trisphosphate (IP3)—that phosphorylate ion channels, receptors, or synaptic proteins to alter neuronal properties.^[7] These mechanisms allow for persistent changes in circuit dynamics, promoting plasticity and state-dependent modulation without directly evoking action potentials.^[6]

Historical Development

The foundations of neuromodulation trace back to early 20th-century investigations into chemical neurotransmission. In 1921, Otto Loewi demonstrated that stimulation of the vagus nerve in isolated frog hearts released a substance—later identified as acetylcholine—that slowed the heartbeat of a second heart, providing the first evidence for chemical synaptic transmission.^[8] This discovery shifted the field from electrical to chemical signaling paradigms. Building on this, the mid-20th century saw the identification of monoamines as key signaling molecules; notably, in the 1950s, Arvid Carlsson established dopamine as an independent neurotransmitter in the brain, distinct from its role as a norepinephrine precursor, through pharmacological assays showing its depletion by reserpine and restoration by L-DOPA.^[9] The term "neuromodulation" emerged from Edward A. Kravitz's work in the early 1970s describing the modulatory effects of amines, such as octopamine and serotonin, on excitatory and inhibitory transmission at lobster neuromuscular junctions, highlighting their role in altering synaptic efficacy rather than directly eliciting responses.^[5] The 1970s marked a pivotal recognition of neuromodulation's slower dynamics. Researchers observed slow synaptic potentials lasting seconds to minutes, mediated by monoamines and peptides, which contrasted with fast ionotropic transmission and influenced neuronal excitability over extended periods.^[10] Concurrently, Luigi F. Agnati and Kjell Fuxe advanced the concept of volume transmission in the 1970s and 1980s, proposing that monoamines like dopamine diffuse through extracellular spaces and cerebrospinal fluid to act on distant targets via varicose fibers, as evidenced by fluorescence histochemistry and immunohistochemistry revealing non-synaptic transmitter-receptor mismatches.^[11] Advances in the late 20th century integrated imaging and modeling techniques. In the 1980s, positron emission tomography (PET) enabled in vivo mapping of dopamine receptors using radioligands like [11C]methylspiperone, allowing noninvasive visualization of dopaminergic systems in humans and baboons, which linked receptor densities to neuropsychiatric conditions.^[12] By the 1990s, computational models began elucidating neuromodulation's role in plasticity; for instance, simulations of dopamine's influence on reinforcement learning demonstrated how it gates synaptic changes in decision-making circuits, providing a framework for understanding adaptive behaviors.^[13] In the 2010s and 2020s, large-scale initiatives like the Human Connectome Project have connected neuromodulatory networks to brain disorders, using diffusion MRI and functional imaging to map altered connectivity in conditions such as schizophrenia and depression, where dopaminergic and serotonergic imbalances disrupt circuit dynamics.^[14] Recent efforts emphasize multi-omics approaches to dissect modulator interactions; for example, integrated genomic, transcriptomic, and proteomic analyses in major depressive disorder have revealed how serotonin and dopamine pathways intersect with inflammatory and epigenetic factors, informing personalized therapeutic strategies.^[15]

Biological Mechanisms

Distinction from Classical Neurotransmission

Classical synaptic neurotransmission, often referred to as fast neurotransmission, involves the rapid release of neurotransmitters from presynaptic terminals into a narrow synaptic cleft, where they bind to ionotropic receptors on the postsynaptic membrane, leading to quick changes in membrane potential that can directly trigger action potentials.^[16] This process operates on very short timescales, typically 1-10 milliseconds, and is highly localized, occurring point-to-point between precisely connected neurons.^[17] For instance, glutamate binding to AMPA receptors exemplifies this mechanism, facilitating excitatory postsynaptic potentials through direct ion flux.^[18] In contrast, neuromodulation employs slower signaling pathways, where neuromodulators are released from varicosities or synaptic terminals to diffuse more broadly, influencing receptors on multiple neurons over larger volumes.^[6] These effects are mediated primarily by metabotropic G-protein-coupled receptors (GPCRs), which activate intracellular second messenger systems rather than directly opening ion channels, resulting in timescales ranging from hundreds of milliseconds to hours.^[7] This diffuse mode, often involving volume transmission, allows neuromodulators to exert widespread influence without strict synaptic alignment.^[6] Functionally, classical neurotransmitters drive immediate neural communication by eliciting fast excitatory or inhibitory responses that propagate signals across circuits.^[16] Neuromodulators, however, do not typically evoke direct postsynaptic potentials; instead, they fine-tune neuronal and synaptic properties by altering excitability, synaptic efficacy, or plasticity through mechanisms like protein phosphorylation.^[18] For example, activation of GPCRs can increase cyclic AMP (cAMP) levels, leading to phosphorylation of ion channels such as hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which modulates intrinsic neuronal excitability without generating action potentials.^[19] A notable illustration of these distinctions is the dual role of acetylcholine, which acts as a fast neurotransmitter at the neuromuscular junction via ionotropic nicotinic receptors to directly trigger muscle contraction, but functions as a neuromodulator in the cerebral cortex through slower metabotropic muscarinic receptors, influencing attention and plasticity.^[20] Similarly, dopamine enhances [long-term potentiation](/page/Long-term_p potentiation) (LTP) in the hippocampus by gating synaptic strengthening mechanisms via D1-like receptors, without causing direct neuronal excitation.^[21] These examples highlight how neuromodulation adapts circuit dynamics over extended periods, complementing the rapid signaling of classical neurotransmission.^[7]

Volume Transmission

Volume transmission refers to the non-synaptic diffusion of neuromodulators from release sites to receptors located at considerable distances, facilitating widespread modulation of neural circuits rather than point-to-point signaling. This process allows neuromodulators, such as monoamines and neuropeptides, to act as paracrine signals in the extracellular fluid, influencing multiple target cells simultaneously. The concept was first proposed by Agnati et al. in 1986 as a complement to traditional wired synaptic transmission, highlighting its role in slower, more diffuse forms of intercellular communication in the central nervous system. Neuromodulators are released from axonal varicosities—beaded swellings along axons that lack the specialized synaptic clefts of classical synapses—enabling free diffusion into the extracellular space. This diffusion follows concentration gradients, with the spread of molecules governed by factors including molecular size, extracellular volume fraction, and tortuosity of the diffusion path. Clearance mechanisms, such as reuptake via transporters like the dopamine transporter (DAT), rapidly terminate signaling by removing neuromodulators from the extracellular milieu, while the extracellular matrix acts as a structural barrier that can impede or channel diffusion, influencing the spatial extent of the signal.^[22]^[6] Physiologically, volume transmission enables the integration of neuromodulatory signals across extended neural populations, such as modulating activity throughout cortical layers to coordinate broader circuit functions like attention or arousal. Extrasynaptic receptors, including D2 autoreceptors on dopaminergic terminals, sense ambient neuromodulator levels in the extracellular space and provide feedback to regulate release rates, thereby maintaining homeostasis and preventing overstimulation. This diffuse signaling contrasts with the localized precision of synaptic transmission, allowing neuromodulators to exert prolonged, integrative effects on network excitability.^[23]^[24] Supporting evidence for volume transmission derives from microdialysis techniques, which measure extracellular neuromodulator levels and reveal that dopamine released in the striatum can diffuse over distances of 100–500 μm, encompassing volumes far exceeding single synaptic domains and influencing remote neuronal ensembles. These findings underscore the spatial scale of neuromodulatory influence, consistent with observations of non-synaptic release sites and extrasynaptic receptor activation.^[25]

Neuromodulatory Systems

Noradrenergic System

The noradrenergic system, centered on norepinephrine (NE) as its primary neurotransmitter, originates predominantly from the locus coeruleus (LC), a compact nucleus of noradrenergic neurons located bilaterally in the pontine tegmentum of the brainstem.^[26] The LC sends extensive axonal projections throughout the central nervous system, including dense innervations to the cerebral cortex, hippocampus, thalamus, cerebellum, and spinal cord, enabling widespread modulation of neural activity.^[27] These projections interact with postsynaptic adrenergic receptors, primarily α1- and α2-adrenoceptors, which are G-protein-coupled, and β-adrenoceptors, which are also G-protein-coupled but mediate distinct signaling pathways such as cyclic AMP production.^[28] Functionally, the noradrenergic system plays a critical role in enhancing vigilance and arousal, facilitating adaptive responses to environmental demands through LC-mediated NE release.^[29] It contributes to the stress response by activating sympathetic-like mechanisms that heighten physiological readiness, while also supporting memory consolidation, particularly in the hippocampus, where NE strengthens synaptic plasticity during emotionally salient events.^[30] Additionally, the system modulates sensory processing by improving signal-to-noise ratios in cortical and subcortical circuits, achieved through variations in LC firing patterns that prioritize relevant stimuli over background noise.^[31] Pharmacologically, the noradrenergic system is targeted by various agents that alter NE availability or receptor activity. α2-Adrenergic agonists like clonidine reduce NE release by providing presynaptic feedback inhibition at α2 autoreceptors on LC neurons, often used to manage hyperactivity.^[32] In contrast, α1-antagonists such as prazosin block postsynaptic α1-receptors, attenuating NE-mediated vasoconstriction and arousal effects.^[33] Selective norepinephrine reuptake inhibitors (NRIs), exemplified by reboxetine, enhance synaptic NE levels by blocking its reuptake via the norepinephrine transporter, proving effective in treating depression by bolstering mood regulation.^[34] Dysfunctions in the noradrenergic system are implicated in several psychiatric and neurodegenerative conditions. Hypoactivity or dysregulation contributes to attention-deficit/hyperactivity disorder (ADHD), where impaired NE signaling disrupts vigilance and executive function, as evidenced by the efficacy of NRIs and stimulants that boost NE transmission.^[35] Similarly, excessive LC-NE activity is linked to anxiety disorders, amplifying threat detection and autonomic arousal.^[36] In Alzheimer's disease, early LC degeneration leads to NE depletion, exacerbating tau pathology, neuroinflammation, and cognitive decline; recent 2025 research highlights potential neuroprotective strategies targeting LC restoration to mitigate these effects.^[37]^[38]

Dopaminergic System

The dopaminergic system originates primarily from midbrain nuclei, including the substantia nigra pars compacta (SNpc) and the ventral tegmental area (VTA), which give rise to key pathways such as the nigrostriatal, mesolimbic, and mesocortical projections.^[39] The nigrostriatal pathway innervates the dorsal striatum, facilitating motor control, while the mesolimbic pathway targets the nucleus accumbens and associated limbic structures to modulate reward processing, and the mesocortical pathway extends to the prefrontal cortex, influencing executive functions.^[40] Dopamine release in these pathways often occurs via volume transmission in regions like the striatum, allowing diffuse modulation beyond synaptic clefts.^[41] Dopamine exerts its effects through five receptor subtypes divided into D1-like (D1 and D5) and D2-like (D2, D3, D4) families, which couple to distinct G-protein signaling pathways.^[42] D1-like receptors are primarily excitatory, activating adenylyl cyclase to increase cyclic AMP levels and enhance neuronal excitability, whereas D2-like receptors are generally inhibitory, inhibiting adenylyl cyclase or modulating potassium channels to reduce firing rates.^[43] This dichotomy enables balanced modulation of downstream circuits, with D1-like receptors often promoting locomotion and motivation, and D2-like receptors regulating inhibition and autoregulation of dopamine release.^[44] In terms of functions, the dopaminergic system is central to reward prediction error signaling, where phasic bursts of dopamine neurons encode discrepancies between expected and actual rewards to drive learning and reinforcement.^[45] These phasic signals, lasting 100-200 milliseconds, highlight salient environmental stimuli, promoting motivation and goal-directed behavior, while tonic dopamine levels maintain baseline arousal.^[46] Additionally, the nigrostriatal pathway supports motor initiation by facilitating movement selection and execution through direct and indirect striatal pathways.^[47] Pharmacologically, dopamine agonists like L-DOPA, a precursor converted to dopamine in the brain, are the cornerstone for treating dopaminergic deficits, restoring motor function in conditions of depletion by increasing striatal dopamine availability.^[48] Conversely, antipsychotics such as haloperidol act as D2 receptor antagonists, with high binding affinity (Ki ≈ 0.35 nM) to block hyperactive signaling and alleviate positive symptoms of psychosis.^[49] Dopamine itself binds D2 receptors with moderate affinity in the high-affinity state (Ki ≈ 20 nM), underscoring the precision of antagonists in therapeutic targeting.^[50] Dysfunctions in the dopaminergic system underlie several disorders, notably Parkinson's disease, characterized by the progressive loss of SNpc neurons leading to nigrostriatal denervation and motor impairments like bradykinesia.^[51] In schizophrenia, mesolimbic hyperactivity contributes to positive symptoms such as hallucinations, driven by excessive dopamine release in limbic regions.^[52] Recent advances include 2025 gene therapy trials aimed at dopaminergic restoration; for instance, a Phase I trial using human embryonic stem cell-derived dopaminergic neurons demonstrated safe engraftment and functional dopamine production in Parkinson's patients, improving motor scores without tumor formation.^[53] Similarly, a Phase I/II trial with induced pluripotent stem cell-derived dopaminergic progenitors reported sustained neuron survival and dopamine release up to 24 months post-transplantation.^[54]

Serotonergic System

The serotonergic system originates primarily from clusters of neurons in the raphe nuclei, located along the midline of the brainstem from the medulla to the midbrain. These nuclei, including the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN), project extensively to the forebrain structures such as the cortex, hippocampus, and amygdala, as well as to the brainstem and spinal cord, forming a diffuse network that modulates widespread neural activity.^[55]^[56] The system features over 14 receptor subtypes classified into seven families (5-HT1 through 5-HT7), with the majority, particularly the 5-HT1 and 5-HT5 families, coupling to inhibitory Gi/o proteins that suppress adenylyl cyclase activity and reduce cyclic AMP levels.^[57]^[58] Serotonin (5-HT) released from these projections plays a key role in mood regulation by influencing emotional processing in limbic regions, promoting emotional stability and resilience to stress. It also contributes to impulse control, dampening impulsive behaviors through inhibitory effects on prefrontal circuits, and helps maintain circadian rhythms by synchronizing suprachiasmatic nucleus activity with environmental light cues. Additionally, serotonergic terminals in the forebrain modulate aggression and anxiety, with reduced activity linked to heightened aggressive responses and anxiogenic states in animal models.^[59]^[60]^[61] Pharmacologically, selective serotonin reuptake inhibitors (SSRIs) like fluoxetine target the serotonin transporter (SERT), blocking 5-HT reuptake into presynaptic neurons and thereby elevating extracellular 5-HT levels; fluoxetine exhibits high affinity for SERT with inhibition kinetics reflecting SERT's endogenous substrate affinity (Km ≈ 0.3 μM). Psychedelics such as psilocybin act as agonists at 5-HT2A receptors, particularly in cortical pyramidal neurons, inducing altered perception and neuroplasticity through downstream signaling cascades like β-arrestin recruitment. These interventions enhance serotonergic transmission, with SSRIs providing sustained elevation and psychedelics offering acute, receptor-specific activation.^[62]^[63]^[64] Dysfunctions in the serotonergic system are implicated in major depressive disorder via the low 5-HT hypothesis, which posits that diminished serotonergic signaling contributes to mood deficits, as evidenced by the efficacy of SSRIs in restoring balance. In obsessive-compulsive disorder (OCD), aberrant 5-HT signaling in cortico-striatal circuits underlies compulsive behaviors, with high-dose SSRIs alleviating symptoms by normalizing impulse control. By 2025, advances in rapid-acting antidepressants, such as 5-HT1A biased agonists like NLX-101, have targeted specific serotonergic circuits to produce antidepressant effects within hours, offering alternatives to traditional SSRIs for treatment-resistant depression.^[65]^[66]^[67]

Additional Neuromodulators

Cholinergic System

The cholinergic system exerts dual roles in the central nervous system, functioning as both a fast-acting neurotransmitter and a key neuromodulator, with its modulatory influences primarily arising from widespread projections originating in the basal forebrain and brainstem. Cholinergic neurons in the basal forebrain, particularly within the nucleus basalis of Meynert, send diffuse, branched projections to the neocortex, hippocampus, and other subcortical structures, enabling broad regulation of cortical activity.^[68] In the brainstem, cholinergic cells in the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDT) project to thalamic, hypothalamic, and brainstem targets, contributing to arousal and sleep-wake transitions.^[69] These projections release acetylcholine (ACh), which binds to nicotinic receptors—ionotropic ligand-gated ion channels that permit rapid cation influx for excitatory synaptic transmission—and muscarinic receptors, G-protein-coupled metabotropic receptors that trigger slower intracellular signaling cascades.^[70] In its neuromodulatory capacity, the cholinergic system plays essential roles in attention, learning, and memory by dynamically altering neuronal excitability and synaptic efficacy across cortical networks. Activation of M1 muscarinic receptors on pyramidal neurons enhances intrinsic excitability through suppression of potassium conductances and promotes long-term potentiation (LTP), a cellular correlate of learning, by facilitating calcium-dependent signaling pathways.^[71] This modulation sharpens sensory processing and supports adaptive behaviors during tasks requiring focused attention.^[72] Brainstem cholinergic projections are particularly vital for promoting rapid eye movement (REM) sleep, where increased ACh release desynchronizes cortical EEG activity and inhibits motor tone via interactions with pontine circuits.^[73] Overall, these functions underscore the system's capacity to coordinate state-dependent plasticity, with tonic ACh release sustaining baseline vigilance and phasic bursts driving task-specific enhancements.^[20] Pharmacological interventions targeting the cholinergic system leverage its receptors and synthetic enzymes to address cognitive impairments. Acetylcholinesterase inhibitors, such as donepezil, elevate synaptic ACh levels by preventing its breakdown, thereby improving attention and memory in Alzheimer's disease patients through enhanced muscarinic and nicotinic signaling.^[74] Muscarinic antagonists like scopolamine block these receptors centrally and peripherally, reducing vestibular-induced nausea and serving as a standard treatment for motion sickness.^[75] For subtype-specific modulation, partial agonists at α7 nicotinic receptors have been investigated to enhance cognitive domains like working memory by amplifying glutamatergic transmission, though advanced clinical trials have not confirmed consistent efficacy.^[76] Cholinergic dysfunctions prominently feature in neurodegenerative and psychiatric disorders, with selective neuronal loss disrupting modulatory balance. In Alzheimer's disease, degeneration of basal forebrain cholinergic neurons leads to profound ACh deficits, correlating with cognitive decline and forming the basis of the cholinergic hypothesis.^[77] Similarly, in schizophrenia, reduced expression of muscarinic and nicotinic receptors impairs attentional gating and sensory processing, as evidenced by neuroimaging and postmortem studies.^[78] As of 2025, research continues to explore α7 nicotinic agonists for schizophrenia despite challenges in advanced clinical trials.^[76]

GABAergic and Glutamatergic Modulation

GABAergic modulation extends beyond phasic synaptic events to include tonic inhibition mediated by extrasynaptic GABAA receptors, which are particularly prominent in the hippocampus and incorporate the δ-subunit for sustained control of neuronal excitability.^[79] These receptors respond to ambient GABA levels, generating a persistent inhibitory conductance that helps maintain circuit homeostasis by dampening overall network activity without relying on discrete synaptic inputs.^[80] Neurosteroids, such as allopregnanolone, act as positive allosteric modulators of these δ-containing GABAA receptors, enhancing tonic inhibition and thereby reducing neuronal excitability in a region-specific manner.^[81] In the context of anxiety regulation, tonic GABAergic inhibition in limbic structures like the amygdala plays a critical role, where its disruption leads to heightened fear responses and emotional dysregulation.^[82] Glutamatergic modulation involves metabotropic glutamate receptors (mGluR1-8), a family of G-protein-coupled receptors that fine-tune neuronal excitability through second-messenger signaling pathways, influencing synaptic plasticity and network stability independent of ionotropic fast transmission.^[83] These receptors respond to glutamate spillover or ambient levels, which are regulated by transporters such as EAAT2 on astrocytes, thereby modulating mood-related circuits in the prefrontal cortex and limbic system.^[84] Ambient glutamate dynamics, in particular, contribute to circuit homeostasis by preventing excitotoxicity while supporting adaptive changes in connectivity, as seen in synaptic scaling mechanisms where postsynaptic glutamate receptor density adjusts globally to preserve firing rates across the neuron.^[85] Dysfunctions in these systems underlie several neuropsychiatric disorders; for instance, hypoactivity of GABAergic tonic inhibition is implicated in epilepsy, where reduced extrasynaptic GABAA receptor function leads to unchecked hyperexcitability and seizure propagation in hippocampal networks.^[86] Similarly, glutamatergic hypofunction, particularly involving impaired metabotropic receptor signaling and elevated ambient glutamate clearance deficits, contributes to schizophrenia by disrupting prefrontal dopamine-glutamate interactions and cognitive processing.^[87] Advances in precision medicine as of 2025 include subtype-selective allosteric modulators targeting δ-GABAA receptors (e.g., neurosteroid derivatives like zuranolone) for anxiety and mood disorders such as postpartum depression, and preclinical studies suggest mGluR2/3 positive allosteric modulators may restore glutamatergic balance in schizophrenia, though clinical trials have shown mixed results.^[88]^[89]

Neuropeptides and Endocannabinoids

Neuropeptides serve as key neuromodulators in the central nervous system, often co-released with classical neurotransmitters from large dense-core vesicles in response to high-frequency or sustained neuronal activity.^[90] This co-release enables neuropeptides to exert slower, longer-lasting effects on synaptic transmission and neuronal excitability compared to fast-acting transmitters stored in small clear vesicles.^[91] Unlike classical neurotransmission, neuropeptide signaling frequently involves volume transmission, where peptides diffuse over distances of several microns to influence broader neural ensembles.^[6] Prominent examples of neuropeptides include orexin, which promotes arousal and wakefulness by exciting monoaminergic and cholinergic neurons in the hypothalamus and brainstem.^[92] Substance P, an 11-amino-acid peptide, plays a central role in pain transmission and sensitization by activating neurokinin-1 receptors on sensory neurons and in the spinal cord, enhancing nociceptive signaling.^[93] Endogenous opioid neuropeptides, such as enkephalins and endorphins, mediate analgesia through μ-opioid receptors, inhibiting pain pathways in the spinal cord and brainstem while also modulating reward circuits, often in concert with dopamine for reinforcement learning.^[94] Endocannabinoids, lipid-derived signaling molecules like 2-arachidonoylglycerol (2-AG) and anandamide, function primarily through retrograde signaling, where they are synthesized postsynaptically in response to calcium influx and diffuse backward to activate presynaptic CB1 receptors.^[95] This activation suppresses the release of neurotransmitters such as glutamate and GABA, facilitating forms of synaptic plasticity like depolarization-induced suppression of inhibition or excitation.^[96] 2-AG, in particular, acts as the primary endocannabinoid for activity-dependent retrograde modulation across various brain synapses.^[97] Both neuropeptides and endocannabinoids fine-tune emotional responses, such as fear and anxiety, by integrating with limbic circuits to regulate stress reactivity and extinction learning.^[98] In feeding behavior, orexin and endocannabinoids promote appetite and energy homeostasis; for instance, endocannabinoids enhance orexigenic signaling in the hypothalamus to increase food intake.^[99] Their volume diffusion allows modulation over extended spatial scales, influencing network-level dynamics in regions like the amygdala and nucleus accumbens.^[6] Endocannabinoids also interact briefly with dopaminergic reward pathways to shape motivational states.^[100] Dysfunctions in these systems contribute to neuropsychiatric disorders; CB1 receptor dysregulation disrupts endocannabinoid tone, promoting addiction vulnerability by altering reward sensitivity and impulse control in mesolimbic circuits.^[100] Chronic opioid exposure leads to tolerance in neuropeptide-mediated analgesia, involving receptor desensitization and upregulated inflammatory mediators that exacerbate pain hypersensitivity.^[101] As of 2025, a clinical trial of fatty acid amide hydrolase inhibitors to elevate anandamide levels found no significant augmentation of exposure-based cognitive behavioral therapy for PTSD symptoms compared to therapy alone.^[102]

Transmission Modes

Tonic Transmission

Tonic transmission refers to the sustained, low-level release of neuromodulators that maintains baseline states in neural circuits, providing a continuous modulatory tone essential for network stability.^[103] This mode of signaling contrasts with more transient forms by operating on longer timescales, typically seconds to minutes, to regulate overall circuit excitability and responsiveness.^[6] The mechanism of tonic transmission involves continuous basal release of neuromodulators from varicosities—specialized swellings along unmyelinated axons of neuromodulatory neurons—without reliance on traditional synaptic vesicles or action potential-evoked bursts.^[17] These varicosities enable diffuse diffusion of the neuromodulator into the extracellular space, where it is primarily detected by extrasynaptic receptors located on neuronal somata, dendrites, or even non-neuronal cells.^[104] Release rates are tightly regulated by presynaptic autoreceptors, which exert negative feedback to prevent excessive accumulation, and by high-affinity uptake transporters that rapidly clear the neuromodulator from the synaptic cleft and extracellular milieu; for instance, the norepinephrine transporter (NET) efficiently reuptakes norepinephrine, maintaining low ambient levels. This dynamic balance ensures that tonic levels remain within a narrow physiological range, shaped further by enzymatic degradation and diffusion.^[17] Functionally, tonic transmission establishes a foundational level of global excitability across neural populations, influencing baseline synaptic efficacy and plasticity thresholds.^[105] A representative example is ambient dopamine in the prefrontal cortex, where concentrations of approximately 1–5 nM—measured under resting conditions in rodent models—stabilize working memory performance by preferentially activating D1-like receptors, which exhibit an inverted-U dose-response curve for optimal cognitive function.^[106]^[107] Such sustained modulation supports persistent neural representations without overwhelming the system, allowing circuits to remain poised for adaptive responses. Tonic neuromodulator levels are commonly measured using microdialysis, a technique that samples extracellular fluid over intervals of several minutes to capture steady-state concentrations, revealing basal profiles that reflect ongoing release and clearance dynamics.^[108] This method has demonstrated consistent tonic elevations or depletions in various brain regions, providing insights into homeostatic regulation, though it lacks the temporal resolution for detecting rapid fluctuations.^[109] Dysregulation of tonic transmission contributes to neuropsychiatric disorders, as seen in depression where reduced tonic serotonin levels impair mood regulation and emotional processing.^[110] Low ambient serotonin diminishes postsynaptic signaling through 5-HT1A autoreceptors and transporters, perpetuating a hypoactive state in serotonergic pathways.^[111] Tonic transmission often leverages volume transmission for its spatial reach, allowing neuromodulators to influence distant targets via extracellular diffusion.^[6]

Phasic Transmission

Phasic transmission refers to the brief, stimulus-evoked release of neuromodulators, characterized by high-amplitude bursts triggered by action potentials in presynaptic terminals, leading to rapid diffusion and activation of nearby receptors.^[6] This mode contrasts with tonic transmission by producing transient extracellular concentrations that decay quickly, often within hundreds of milliseconds, due to efficient clearance mechanisms such as reuptake by transporters.^[112] For instance, in dopaminergic systems, phasic bursts generate dopamine transients lasting approximately 100 ms, primarily cleared by the dopamine transporter (DAT), which limits spatial spread to tens of micrometers around release sites.^[113] Similar dynamics occur in noradrenergic transmission from the locus coeruleus (LC), where phasic firing synchronizes across neurons to release norepinephrine in localized bursts.^[6] Across neuromodulators like acetylcholine and serotonin, phasic release follows comparable principles, with action potential-driven exocytosis enabling precise, event-locked signaling.30011-4) Functionally, phasic transmission signals salient events such as novelty or rewards, facilitating adaptive behavioral responses and synaptic plasticity. In the LC-noradrenergic system, phasic bursts enhance attention shifts by amplifying sensory processing and orienting responses to unexpected stimuli, as evidenced by increased pupil dilation and cortical arousal linked to these firing patterns.^[114] Dopaminergic phasic signals, particularly in the midbrain, encode reward prediction errors, promoting reinforcement learning by strengthening synapses associated with positive outcomes.00734-X) This mode also drives plasticity mechanisms, such as long-term potentiation (LTP); for example, phasic dopamine release coincides with pauses in cholinergic interneurons to induce LTP at corticostriatal synapses, enabling associative learning.^[115] In broader neuromodulatory contexts, phasic acetylcholine transients support working memory by modulating cortical excitability during task-relevant events.^[116] Electrophysiological and electrochemical techniques provide key evidence for phasic transmission. Fast-scan cyclic voltammetry (FSCV) detects subsecond dopamine peaks reaching micromolar concentrations (up to 1-10 μM) in striatal regions during burst firing, confirming the rapid onset and clearance of these signals.^[117] In vivo recordings from LC neurons reveal phasic bursts of 3-10 action potentials at frequencies exceeding 10 Hz, synchronized by shared inputs and correlating with behavioral salience.^[6] Computational models, including temporal difference (TD) learning frameworks, integrate these observations by positing phasic dopamine as a teaching signal that updates value predictions, with burst activity aligning firing rates to prediction errors for efficient learning.^[118] Such evidence underscores phasic transmission's role in dynamic network modulation across species and brain regions. Dysfunctions in phasic transmission contribute to neuropsychiatric disorders, notably addiction. In cocaine self-administration models, repeated exposure blunts phasic dopamine release in the nucleus accumbens, reducing signaling amplitude by up to 50% and impairing reward sensitivity, which perpetuates compulsive behavior.^[119] This attenuation disrupts TD error computation, leading to aberrant habit formation as phasic signals fail to reinforce adaptive choices.^[120] Similar impairments in LC phasic firing have been linked to attentional deficits in disorders like ADHD, highlighting the conserved vulnerability of phasic modes to pathological alterations.00819-7) Tonic and phasic modes interact dynamically to fine-tune neural signaling. For example, elevated tonic dopamine levels can suppress phasic release through activation of D2 autoreceptors on dopaminergic neurons, preventing overstimulation and maintaining signaling fidelity. Conversely, phasic bursts can transiently alter local tonic levels, influencing subsequent baseline excitability. This interplay is critical for adaptive behaviors and is disrupted in conditions like Parkinson's disease and addiction.^[121]

Therapeutic Applications

Electrical and Magnetic Stimulation

Electrical and magnetic stimulation techniques represent cornerstone methods in therapeutic neuromodulation, utilizing implanted or external devices to deliver targeted electrical impulses or induced magnetic fields that modulate neural activity in the central and peripheral nervous systems. These approaches are particularly effective for disorders involving dysregulated neural circuits, such as movement disorders and mood dysregulation, by altering neuronal firing patterns and synaptic transmission without relying on pharmacological agents. Deep brain stimulation (DBS) exemplifies invasive electrical neuromodulation, where electrodes are surgically implanted into specific brain nuclei to deliver high-frequency pulses, while transcranial magnetic stimulation (TMS) offers a non-invasive alternative by generating magnetic fields that induce electrical currents in superficial cortical regions. Both methods have garnered FDA approvals for clinical use, demonstrating their safety and efficacy in alleviating symptoms of refractory conditions. Deep brain stimulation for Parkinson's disease targets the subthalamic nucleus (STN) with high-frequency stimulation, typically at 130 Hz, to suppress pathological oscillations and restore balanced motor control. This technique involves implanting leads into the STN connected to a chest-mounted pulse generator, which delivers continuous biphasic pulses that modulate basal ganglia circuits implicated in dopamine pathway dysregulation. The primary mechanism involves high-frequency DBS inducing synaptic depression and altering neuronal firing patterns, effectively inhibiting excessive beta-band activity (13-35 Hz) associated with bradykinesia and rigidity, rather than simple depolarization blockade. FDA approval for DBS was granted in 1997 for unilateral thalamic stimulation to treat essential tremor, with expansions in 2002 to bilateral STN targeting for advanced Parkinson's symptoms. Transcranial magnetic stimulation, particularly repetitive TMS (rTMS), employs rapidly changing magnetic fields to induce focal electrical currents in the brain, targeting the left dorsolateral prefrontal cortex (DLPFC) for major depressive disorder. High-frequency rTMS (e.g., 10-20 Hz) over the DLPFC enhances cortical excitability and promotes neuroplasticity, potentially by increasing glutamatergic transmission and modulating default mode network connectivity to alleviate anhedonia and cognitive deficits. Unlike invasive methods, TMS requires no surgery, with sessions lasting 20-40 minutes over several weeks, and it received FDA clearance in 2008 for treatment-resistant depression in adults. Beyond movement and mood disorders, electrical neuromodulation extends to epilepsy via vagus nerve stimulation (VNS), where an implanted device delivers intermittent pulses to the left vagus nerve to reduce seizure frequency by desynchronizing cortical activity. VNS was FDA-approved in 1997 as an adjunctive therapy for refractory partial-onset seizures in patients over 12 years old, with mechanisms involving afferent projections to brainstem nuclei that inhibit epileptogenic foci. For chronic pain, spinal cord stimulation (SCS) involves epidural electrode arrays that deliver low-voltage pulses to the dorsal columns, gating nociceptive signals via the gate control theory and reducing perceived pain intensity. SCS systems received initial FDA approvals between 1981 and 1984 for intractable trunk and limb pain, with modern iterations providing paresthesia-free stimulation for conditions like failed back surgery syndrome. Recent advancements as of 2025 emphasize closed-loop DBS systems, which adapt stimulation parameters in real-time based on detected neural biomarkers, such as pathological beta oscillations, to optimize therapeutic efficacy and minimize side effects. These adaptive systems, incorporating onboard sensing electrodes, have shown superior motor symptom control in Parkinson's patients compared to continuous stimulation, with clinical trials demonstrating reduced energy consumption and improved quality of life in ambulatory settings.

Pharmacological Interventions

Pharmacological interventions in neuromodulation involve the use of chemical agents to modulate neurotransmitter systems, primarily by mimicking, enhancing, or inhibiting the activity of endogenous neuromodulators such as serotonin, dopamine, and norepinephrine, thereby altering neural signaling for therapeutic purposes. These drugs target specific receptor subtypes or transporters to influence synaptic transmission and plasticity in brain circuits associated with mood, attention, and cognition. For instance, selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, block the serotonin transporter (SERT), increasing extracellular serotonin levels and enhancing serotonergic signaling across various receptor subtypes like 5-HT1A and 5-HT2A. This mechanism promotes neuroplasticity and is foundational in treating disorders involving dysregulated serotonin modulation.^[122] Reuptake inhibitors represent a key class of pharmacological agents, including norepinephrine-dopamine reuptake inhibitors (NDRIs) like bupropion, which selectively inhibit the norepinephrine transporter (NET) and dopamine transporter (DAT), elevating synaptic levels of these catecholamines without significant serotonergic effects. Bupropion's dual action enhances dopaminergic and noradrenergic transmission in prefrontal and limbic regions, contributing to its efficacy in depression and smoking cessation by modulating reward and motivational pathways. Similarly, serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, inhibit both SERT and NET, providing broader neuromodulation for conditions like major depressive disorder where multiple monoamine systems are implicated. These agents typically have half-lives ranging from 5 to 24 hours, allowing once- or twice-daily dosing, though individual pharmacokinetics vary based on metabolism via cytochrome P450 enzymes.^[123]^[124] Agonists and antagonists further refine neuromodulation by directly interacting with receptors; for example, buspirone acts as a partial agonist at postsynaptic 5-HT1A receptors, reducing anxiety by dampening excessive serotonergic hyperactivity in the amygdala and hippocampus without the sedative effects of benzodiazepines. In attention-deficit/hyperactivity disorder (ADHD), atomoxetine, a selective NET inhibitor, increases norepinephrine and indirectly dopamine in prefrontal cortex circuits, improving executive function and inhibitory control as evidenced by enhanced activation in the right inferior frontal gyrus during cognitive tasks. Clinical applications extend to depression, where SNRIs alleviate symptoms by restoring monoamine balance, though potential side effects include serotonin syndrome—a potentially life-threatening condition characterized by hyperthermia, autonomic instability, and neuromuscular abnormalities arising from excessive serotonergic activity, particularly when combining multiple agents.^[125]^[126]^[127] As of 2025, advances in pharmacological neuromodulation include psychedelic-assisted therapies, with psilocybin emerging as a promising agent for treatment-resistant depression through its agonism at 5-HT2A receptors, promoting rapid synaptic remodeling and emotional processing in guided sessions. Clinical trials have demonstrated sustained antidepressant effects lasting up to a year following a single dose, with Compass Pathways' COMP360 formulation showing positive phase 3 results in double-blinded studies, positioning it for potential FDA approval within the next two years. These interventions highlight the shift toward targeted, receptor-specific modulation to address unmet needs in psychiatric care.^[128]

Emerging Non-Invasive Techniques

Transcranial direct current stimulation (tDCS) applies weak electrical currents, typically 1-2 mA, via scalp electrodes to modulate neuronal excitability without inducing action potentials. Anodal tDCS enhances cortical activity by subthreshold depolarization of the resting membrane potential, promoting neuronal firing, while cathodal stimulation suppresses it through hyperpolarization. Post-2020 advancements have refined tDCS for cognitive enhancement, with randomized trials demonstrating improved working memory and attention in healthy adults and individuals with mild cognitive impairment, often with effects lasting beyond the stimulation session. High-definition tDCS configurations achieve more focal targeting, reducing diffuse effects compared to conventional montages.^[129]^[130]^[131] Low-intensity focused ultrasound (LIFU) provides non-invasive access to deep brain regions by delivering acoustic pressure waves that activate mechanosensitive ion channels, such as Piezo1, to alter neuronal membrane conductance and firing patterns without incision or thermal ablation. Operating at frequencies of 250 kHz to several MHz, LIFU offers millimeter-scale spatial resolution, enabling precise modulation of subcortical structures inaccessible to surface-based methods. Since 2020, clinical studies have validated its neuromodulatory effects, including suppression of aberrant activity in epilepsy models and enhancement of prefrontal function in decision-making tasks, with no reported seizures across human trials involving thousands of pulses.^[132]^[133]^[134] In substance use disorders (SUD), repetitive transcranial magnetic stimulation (rTMS), an evolution of classical transcranial magnetic stimulation, targets the dorsolateral prefrontal cortex to reduce cravings, with meta-analyses of post-2020 trials showing significant decreases in alcohol and cocaine cue reactivity. For obsessive-compulsive disorder (OCD), 2025 clinical trials are evaluating non-invasive modulation of alpha oscillations via transcranial alternating current stimulation (tACS) to normalize frontostriatal circuits, yielding preliminary reductions in Yale-Brown Obsessive Compulsive Scale scores. These techniques complement established electrical methods by emphasizing portability and personalization.^[135]^[136]^[137] Recent innovations include battery-powered portable tDCS devices that facilitate home-based administration, achieving comparable efficacy to clinic settings in cognitive rehabilitation without increased risks. Artificial intelligence-driven protocols optimize stimulation parameters by integrating real-time EEG feedback, boosting response rates in cognitive tasks by up to 20% in personalized applications. Funding from the BRAIN Initiative has accelerated these developments, supporting tools for enhanced spatiotemporal precision in non-invasive neuromodulation.^[138]^[139]^[140]

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