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Dorsolateral prefrontal cortex

The dorsolateral prefrontal cortex (DLPFC) is a key region of the brain's prefrontal cortex, located in the lateral aspect of the frontal lobe, primarily within the superior and middle frontal gyri, and corresponding to Brodmann areas 9 and 46.^[1]^[2]^[3] This area is characterized by its cytoarchitectonic heterogeneity, with subdivisions such as the dorsal (BA9) and ventral (BA46) portions exhibiting distinct structural and functional properties.^[2] It receives inputs from multiple cortical regions via association fibers like the superior and inferior occipitofrontal fasciculi and the uncinate fasciculus, and is supplied by branches of the middle cerebral artery.^[1] The DLPFC serves as a hub for higher-order cognitive processes, particularly executive functions that enable goal-directed behavior and adaptive decision-making.^[4] It is essential for working memory, allowing the temporary storage and manipulation of information to guide actions, as demonstrated in delayed-response tasks.^[1]^[5] Additional roles include planning and strategy formation, abstract reasoning, response inhibition, cognitive flexibility, and attentional selection, which collectively support complex problem-solving and behavioral regulation.^[2]^[6] Through functional connectivity with networks involving the anterior cingulate cortex, anterior insula, and parietal regions, the DLPFC integrates sensory, motor, and emotional information to facilitate cognitive control and allostatic regulation of physiological responses, such as cardiovascular adjustments during uncertainty or effortful tasks.^[4] Dysfunction in this region, often linked to lesions or neuropsychiatric conditions like schizophrenia and depression, impairs these capacities, leading to deficits in context processing, task-switching, and emotional regulation.^[1]

Anatomy

Location and Boundaries

The dorsolateral prefrontal cortex (DLPFC) is a region within the lateral prefrontal cortex of the frontal lobe, primarily encompassing Brodmann areas 9 and 46, with possible extensions into the lateral portions of areas 8 and 10.^[7]^[8] It occupies the middle frontal gyrus and parts of the superior and inferior frontal gyri, contributing to higher-order cognitive processing.^[9] Anatomically, the DLPFC is bounded superiorly (dorsally) by the superior frontal sulcus, inferiorly (ventrally) by the inferior frontal sulcus, anteriorly by the frontomarginal sulcus or frontal pole, and posteriorly by the premotor cortex along the precentral sulcus.^[7]^[9] These sulcal boundaries define its macroscopic position on the lateral surface of the frontal lobe, though individual variability in gyral folding can influence precise demarcation.^[10] While anatomical definitions rely on cytoarchitectonic parcellations like Brodmann's map, functional delineations of the DLPFC often emerge from neuroimaging studies, such as functional magnetic resonance imaging (fMRI), which identify the region based on activation patterns during tasks involving executive control rather than rigid borders.^[2] For instance, meta-analyses of fMRI data reveal consistent DLPFC engagement in cognitive tasks, allowing researchers to map its extent through distributed activation profiles across the middle frontal gyrus.^[11] The DLPFC is present bilaterally in both hemispheres, but exhibits hemispheric asymmetries in function, with the left DLPFC more prominently involved in verbal working memory tasks and the right DLPFC in spatial working memory tasks.^[12] This lateralization is supported by studies using repetitive transcranial magnetic stimulation (rTMS), which demonstrate differential impairments in task performance following unilateral disruption.^[13]

Cytoarchitecture and Subregions

The dorsolateral prefrontal cortex (DLPFC) is characterized by its granular cytoarchitecture, typical of isocortical regions, featuring six distinct layers with a well-developed granular layer IV and a prominent, cell-dense layer II. These features include medium-sized pyramidal cells in layer III, an undivided layer V, and a sharp border between layer VI and the white matter, setting it apart from agranular prefrontal areas such as the orbitofrontal cortex, which lack a prominent layer IV.^[14] This granular organization supports high interconnectivity and is observed consistently across primate species, though with variations in layer thickness and cell density.^[15] The DLPFC exhibits significant heterogeneity in its subregions, as revealed by multi-modal parcellation approaches that integrate cytoarchitecture, connectivity profiles, and functional activation patterns. In the Human Connectome Project multi-modal parcellation, key DLPFC subregions include areas 8Av (dorsal, involved in eye movement control), 8C (caudal), and 9a (rostral), delineated by transitions in myelin content (a proxy for cytoarchitecture) and resting-state functional connectivity.^[16] More recent cytoarchitectonic mapping has identified four anterior subregions: SFS1 and SFS2 in the superior frontal sulcus, and MFG1 and MFG2 in the middle frontal gyrus. SFS1 features a prominent layer IV and layer II with volumes averaging 754 ± 201 mm³, while SFS2 shows a thinner, blurrier layer IV and larger pyramidal cells in layer IIIc, with volumes of 578 ± 142 mm³. MFG1, with a broader layer V and volumes of 1,392 ± 278 mm³, contrasts with MFG2's more homogeneous cell distribution and sharper white matter border, averaging 1,069 ± 281 mm³. These subregions display intersubject variability in size and position but consistent laminar distinctions.^[15] A 2024 study further identified five additional subregions (SFG2, SFG3, SFG4, MFG4, and MFG5) using advanced 3D cytoarchitectonic mapping, highlighting new organizational principles in the DLPFC without following simple gradients.^[17] Phylogenetically, the granular DLPFC represents a late evolutionary specialization unique to anthropoid primates, emerging after the divergence from strepsirrhines and expanding markedly in humans relative to other primates. Single-nucleus transcriptomic analyses reveal increased neuronal diversity, particularly in layers 2-3 intratelencephalic projecting neurons, and human-specific molecular adaptations such as altered neuropeptide expression in interneurons. This expansion contributes to the DLPFC's disproportionately larger volume in humans, supporting advanced cognitive capacities.^[18]

Connectivity

The dorsolateral prefrontal cortex (DLPFC) receives a variety of afferent inputs that integrate sensory, cognitive, and emotional information essential for executive processing. Major inputs originate from sensory association areas, particularly the parietal cortex, which provides spatial and attentional data via reciprocal connections supported by tract-tracing studies in non-human primates.^[19] The mediodorsal nucleus of the thalamus delivers reciprocal projections to the DLPFC, targeting deep layers III and IV to facilitate relay of subcortical signals.^[19] Limbic structures, such as the hippocampus and amygdala, contribute memory- and emotion-related inputs, with projections from the hippocampus aiding episodic memory integration and amygdalar inputs modulating affective context. Efferent outputs from the DLPFC project to regions involved in action execution and evaluation, enabling coordinated behavioral responses. It sends projections to premotor and primary motor cortices for planning and initiating movements, as evidenced by anatomical tracing in macaques showing direct pathways.^[20] Connections to the basal ganglia, particularly the dorsal striatum, form part of cortico-striatal loops that support motor control and habit formation, with outputs targeting the globus pallidus interna. The DLPFC also projects to the orbitofrontal cortex, influencing reward processing and decision valuation through ventrodorsal gradients in frontal connectivity. The DLPFC is a core node in large-scale brain networks, underpinning its role in cognitive integration. It participates in the frontoparietal network for cognitive control, with bidirectional connections to parietal regions facilitating attention and working memory maintenance.^[21] Interactions with the default mode network occur indirectly through hubs like the anterior cingulate cortex, allowing toggling between internal reflection and external task focus. Structurally, these links are mediated by white matter tracts such as the superior longitudinal fasciculus, which bundles fibers connecting the DLPFC to parietal and temporal areas, as confirmed by diffusion tensor imaging in humans. Functional connectivity studies further elucidate the DLPFC's dynamic interactions, revealing bidirectional loops with the anterior cingulate cortex for error monitoring and conflict resolution. Diffusion tensor imaging demonstrates robust white matter integrity in these pathways, correlating with executive performance across individuals. Subregional variations, such as stronger executive hub functions in the middle frontal gyrus (MFG1), modulate these connections but are detailed in cytoarchitectural analyses.

Functions

Executive Functions

The dorsolateral prefrontal cortex (DLPFC) is central to executive functions, a set of high-level cognitive processes that enable the orchestration of goal-directed behavior through mechanisms such as planning, cognitive flexibility, inhibitory control, and attentional set-shifting. These functions allow individuals to formulate strategies, adapt to environmental changes, suppress inappropriate responses, and shift attention between tasks as needed. Seminal models emphasize the DLPFC's role in integrating sensory information with internal goals to guide adaptive actions, distinguishing executive control from habitual or reflexive behaviors.^[22]^[23] Lesion studies provide compelling evidence for the DLPFC's involvement, revealing deficits in impulse control and planning following damage to lateral prefrontal regions, akin to impairments observed in classic cases of frontal lobe injury that disrupt behavioral regulation. For example, patients with DLPFC lesions exhibit reduced strategic planning and increased perseveration on tasks requiring rule adherence. Functional neuroimaging corroborates these findings, demonstrating robust DLPFC activation during the Tower of London task, a paradigm that assesses planning by requiring participants to move disks to match target configurations with minimal moves; meta-analyses show consistent bilateral DLPFC recruitment scaling with task complexity.^[24]^[25]^[26] Lateralization within the DLPFC further refines its contributions, with the right hemisphere predominantly supporting inhibitory control, as evidenced by magnetoencephalography studies of go/no-go tasks where right DLPFC activity predicts successful suppression of prepotent responses to "no-go" stimuli. Conversely, the left DLPFC is implicated in cognitive flexibility, showing greater activation during task-switching paradigms that demand rapid adaptation to shifting attentional sets or rules.^[27]^[28] The DLPFC does not operate in isolation but integrates with adjacent regions like the ventrolateral prefrontal cortex (VLPFC) for effective response inhibition, where the DLPFC exerts top-down modulation of goals and the VLPFC implements stimulus-specific suppression to prevent erroneous actions. This coordinated network ensures precise behavioral control. These executive processes show overlap with working memory maintenance for sustaining task-relevant information.^[29]^[30]

Working Memory

The dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in working memory, which involves the active maintenance and manipulation of information over short periods to guide behavior. According to Baddeley's multicomponent model, working memory comprises the phonological loop for verbal information, the visuospatial sketchpad for spatial and visual data, and the central executive that coordinates attention and integrates inputs from these subsystems.^[31] The central executive is primarily associated with DLPFC functions, enabling the allocation of cognitive resources and control over subordinate storage systems.^[32] At the neural level, the DLPFC supports working memory through persistent neuronal firing during delay periods, where neurons maintain elevated activity to represent information in the absence of stimuli, as demonstrated in seminal studies of prefrontal circuitry.^[33] This mechanism is evident in functional magnetic resonance imaging (fMRI) research using n-back tasks, which require ongoing updating and monitoring of sequential information; these tasks consistently activate the posterior-dorsal DLPFC bilaterally, with load-dependent increases in signal intensity reflecting maintenance and manipulation demands. Working memory capacity is limited to approximately 7 ± 2 items, a constraint originally identified through immediate recall experiments and later linked to DLPFC-mediated processes. Lesion studies in humans reveal that DLPFC damage impairs the manipulation of information—such as rearranging or transforming held items—but spares basic storage, underscoring the region's selective role in executive aspects of working memory rather than passive retention.^[34]^[35] Animal models, particularly in nonhuman primates, provide foundational evidence via single-unit recordings in the monkey DLPFC, showing delay-period neurons with spatially tuned, persistent activity that encodes rule-based representations during oculomotor delayed-response tasks. These recordings highlight how DLPFC cells sustain mnemonic signals tuned to specific rules or locations, supporting flexible working memory operations.

Decision Making

The dorsolateral prefrontal cortex (DLPFC) plays a central role in value-based decision making by evaluating options based on anticipated rewards, risks, and long-term consequences, enabling the selection of actions that maximize utility. This involvement is evident in processes such as risk assessment, where the DLPFC modulates choices under uncertainty by integrating probabilistic information to guide cautious or exploratory behavior. For instance, in tasks requiring the assessment of risky options, the right DLPFC promotes avoidance of high-risk selections in favor of more beneficial outcomes.^[36] In intertemporal choice, the DLPFC contributes to delay discounting, the tendency to devalue rewards that are delayed in time, by encoding the subjective value of future outcomes and facilitating choices that prioritize larger but postponed rewards over immediate smaller ones. Neuroimaging studies show that activity in the DLPFC, particularly the left hemisphere, correlates with reduced discounting rates, reflecting its role in sustaining attention to delayed benefits during decision processes.^[37] Reversal learning, another key process, relies on the DLPFC to detect shifts in reward contingencies and update behavioral strategies accordingly, with neural activity in this region predicting the timing of adaptive switches in probabilistic environments.^[38] Empirical evidence from the Iowa Gambling Task (IGT) highlights the DLPFC's activation during complex decision making, where it integrates reward signals from the orbitofrontal cortex to accumulate evidence for advantageous choices amid uncertain outcomes. Computational models, such as the drift-diffusion model, further illustrate this by positing that DLPFC activity reflects the gradual accumulation of decision-relevant evidence, influencing choice thresholds and response times in value-based selections.^[39]^[40] Social decision making engages the DLPFC in moral judgments, particularly in impersonal dilemmas like the trolley problem, where it supports utilitarian choices by overriding emotional responses to maximize overall welfare. Disruption of right DLPFC activity via transcranial magnetic stimulation shifts judgments toward less utilitarian outcomes, underscoring its causal role in deliberative moral reasoning.^[41] Impairments from DLPFC lesions manifest as perseveration in probabilistic learning tasks, where individuals fail to adapt to changing reward probabilities and rigidly repeat suboptimal responses, as seen in elevated perseverative errors on the Wisconsin Card Sorting Test. Such deficits highlight the DLPFC's necessity for flexible updating in uncertain decision contexts.^[25]

Neurobiology

Neurotransmitter Systems

The dorsolateral prefrontal cortex (DLPFC) exhibits particular sensitivity to dopamine levels, where optimal working memory performance follows an inverted-U shaped dose-response curve, with both deficient and excessive dopamine impairing function.^[42] Dopamine D1 receptors in the DLPFC promote persistent neuronal firing essential for maintaining information during working memory tasks, while D2 receptors facilitate cognitive flexibility by modulating network dynamics.^[43] Unlike subcortical regions, the DLPFC has a scarcity of dopamine transporters, leading to prolonged extracellular dopamine signaling that amplifies the impact of even modest release.^[44] Norepinephrine modulates DLPFC activity primarily through alpha-2A adrenergic receptors, which enhance cognitive control by improving the signal-to-noise ratio of neuronal representations, thereby sharpening attentional focus and reducing distractibility.^[42] Glutamate serves as the primary excitatory neurotransmitter in the DLPFC, driving activity in pyramidal neurons, while GABA provides inhibition via interneurons to maintain excitatory-inhibitory balance critical for stable network operations.^[45] NMDA receptors, a subtype of glutamate receptors, are vital for synaptic plasticity in these circuits, enabling long-term potentiation that supports learning and memory consolidation in the DLPFC.^[46] Serotonin influences DLPFC function by regulating mood states that indirectly shape decision-making processes, with serotonergic projections modulating risk assessment and emotional biases in cognitive choices.^[47]

Development and Plasticity

The dorsolateral prefrontal cortex (DLPFC) exhibits a protracted developmental trajectory compared to other cortical regions, with myelination occurring last among association areas and reaching full maturity in the early 20s. Synaptogenesis in the DLPFC begins prenatally but follows a plateau until approximately 3 years, followed by a peak around age 3.5 years, after which synaptic pruning intensifies during adolescence and continues into the third decade of life, reducing synaptic density by up to 40% in layer III pyramidal neurons. This pruning process, which refines neural circuits for executive functions, aligns with increases in white matter volume and dendritic complexity throughout childhood and adolescence.^[48] Critical periods for DLPFC development occur primarily in early childhood, rendering it particularly vulnerable to environmental stressors that can disrupt executive function trajectories into adulthood. Chronic stress during this window impairs DLPFC connectivity and reduces dendritic spine density, leading to long-term deficits in working memory and cognitive flexibility. For instance, early-life adversity has been shown to alter glucocorticoid signaling, which hinders the refinement of prefrontal circuits essential for self-regulation.^[49]^[50] Plasticity in the DLPFC is mediated by mechanisms such as long-term potentiation (LTP), which depends on N-methyl-D-aspartate (NMDA) receptor activation to sustain persistent neuronal firing during working memory tasks. NMDA receptors, particularly those containing NR2B subunits in layer III synapses, facilitate calcium influx critical for LTP induction and synaptic strengthening. Experience-dependent rewiring further supports adaptability, as learning induces dendritic spine growth and stabilization; for example, reward-related expectations trigger rapid spine formation on pyramidal neurons, enhancing circuit efficiency.^[51]^[52] In aging, the DLPFC undergoes structural decline, accompanied by reduced dendritic spine density and myelin integrity. This atrophy contributes to cognitive impairments, yet older adults often exhibit compensatory hyperactivity in the DLPFC during tasks requiring executive control, such as working memory, to maintain performance despite underlying neural inefficiency. Such increased activation, observed via functional imaging, reflects recruitment of additional resources but may not fully offset age-related losses.^[53]

Clinical Significance

Psychiatric Disorders

The dorsolateral prefrontal cortex (DLPFC) exhibits dysfunction across several psychiatric disorders, often manifesting as hypoactivity, structural alterations, or connectivity disruptions that contribute to core symptoms like cognitive impairment and emotional dysregulation.^[54] In schizophrenia, reduced DLPFC activation during working memory tasks supports the hypofrontality hypothesis, where impaired prefrontal efficiency underlies cognitive deficits.^[55] Grey matter loss in the DLPFC, particularly in Brodmann area 46, correlates with symptom severity and positive symptoms.^[56] Genetic factors, such as variants in the DISC1 gene, are linked to decreased prefrontal cortical thickness and altered neural efficiency in affected individuals.^[57] Major depressive disorder involves decreased DLPFC volume and reduced functional connectivity, which correlate with anhedonia and persistent rumination.^[54] These structural changes contribute to cognitive biases, such as negative attentional selectivity, by impairing top-down regulation of emotional processing.^[58] Hypoactivation of the DLPFC during cognitive control tasks further exacerbates these biases in depressed patients.^[59] Anxiety disorders feature DLPFC hyperactivity during threat processing, reflecting heightened vigilance and difficulty in disengaging from potential dangers.^[60] In posttraumatic stress disorder (PTSD), impaired DLPFC function disrupts extinction recall, leading to persistent fear responses and re-experiencing symptoms.^[61] Attention-deficit/hyperactivity disorder (ADHD) is characterized by delayed DLPFC maturation, contributing to executive function deficits like poor inhibitory control and working memory.^[62] The right DLPFC plays a key role in attentional regulation, with dysfunction in this region linked to inattention and impulsivity symptoms.^[63] In autism spectrum disorder (ASD), atypical DLPFC metabolic profiles and functional connectivity abnormalities contribute to deficits in executive function, social cognition, and inhibitory control. Studies show altered glutamate/glutamine levels in the left DLPFC and aberrant peak connectivity toward default mode network regions, correlating with symptom severity. Therapeutic interventions like transcranial direct current stimulation (tDCS) targeting the DLPFC have demonstrated potential in modulating excitatory-inhibitory balance and improving behavioral outcomes in ASD.^[64]^[65]

Neurological and Other Conditions

In Parkinson's disease (PD), dopamine depletion in the dorsolateral prefrontal cortex (DLPFC) contributes to executive function deficits, including impairments in working memory and cognitive flexibility.^[66] This depletion arises from the progressive loss of dopaminergic neurons in the substantia nigra, which disrupts frontostriatal circuits and leads to reduced DLPFC activation during tasks requiring set-shifting and planning.^[67] Deep brain stimulation (DBS) of the subthalamic nucleus can modulate these deficits by altering DLPFC activity; for instance, DBS-induced changes in cortical blood flow within the DLPFC correlate with variability in cognitive performance, sometimes improving executive control while occasionally exacerbating subtle impairments in select patients.^[68]^[69] Chronic stress impairs DLPFC plasticity through elevated cortisol levels acting on glucocorticoid receptors, resulting in dendritic retraction and reduced spine density that compromise working memory capacity.^[70] This glucocorticoid-mediated effect disrupts synaptic remodeling in the DLPFC, leading to persistent deficits in executive processes such as attention allocation and response inhibition under prolonged stress exposure.^[71] Over time, these changes contribute to a vulnerability in prefrontal circuits, where heightened cortisol signaling suppresses neurogenesis and enhances vulnerability to cognitive decline.^[72] In substance use disorders, alcohol consumption induces DLPFC volume reduction and hypoactivation, particularly during decision-making tasks, which correlates with impaired impulse control and risk assessment.^[73]^[74] Chronic alcohol exposure leads to gray matter atrophy in the DLPFC, diminishing its role in suppressing reward-driven choices and exacerbating maladaptive behaviors.^[75] Similarly, cocaine disrupts DLPFC dopamine modulation by eliciting abnormal cue-induced dopamine release, which overrides normal inhibitory signaling and promotes compulsive drug-seeking through altered frontostriatal balance.^[76] This dysregulation weakens DLPFC-mediated cognitive control, facilitating persistent addiction cycles.^[75] Traumatic brain injury (TBI) involving focal lesions to the DLPFC often results in perseverative errors on planning tasks, such as the Tower of London, due to disrupted rule maintenance and behavioral flexibility.^[25] These lesions impair the DLPFC's capacity to internally represent and update task goals, leading to repetitive, inflexible responses that hinder adaptive problem-solving.^[77] Post-injury, such deficits manifest as elevated perseveration rates, particularly in right prefrontal damage, underscoring the region's critical role in overriding habitual actions during complex planning.^[78] In Alzheimer's disease (AD), DLPFC exhibits structural atrophy, increased cortical excitability, and deficits in neuroplasticity, contributing to executive dysfunction and global cognitive impairment. Recent spatial transcriptomic analyses as of 2025 reveal subcellular-resolution changes in the prefrontal cortex, highlighting disrupted gene expression patterns in DLPFC associated with AD progression. High-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the DLPFC has shown promise in improving cognitive function and modulating functional connectivity in AD patients.^[79]^[80]

Therapeutic Interventions

Pharmacological interventions targeting the dorsolateral prefrontal cortex (DLPFC) primarily involve stimulants and antidepressants that modulate neurotransmitter systems to address dysfunctions associated with disorders like attention-deficit/hyperactivity disorder (ADHD) and depression. Stimulants such as methylphenidate enhance DLPFC function in ADHD by increasing dopamine and norepinephrine levels, which stimulate D1 dopamine receptors and α2-adrenoceptors to improve working memory performance.^[81] Moderate doses of methylphenidate (0.1–1.2 mg/kg) optimize signal-to-noise ratios in DLPFC networks, reducing perseverative errors and enhancing cognitive control, as demonstrated in primate models and human functional imaging studies.^[81] These effects are particularly evident in tasks requiring sustained attention, where methylphenidate upregulates dopamine signaling in prefrontal circuits innervating subcortical regions.^[82] Antidepressants like selective serotonin reuptake inhibitors (SSRIs) indirectly influence DLPFC activity through serotonin modulation, normalizing hypoactivity observed in major depressive disorder. After eight weeks of SSRI treatment, patients with depression exhibit significantly increased DLPFC activation during emotional interference tasks, approaching levels seen in healthy controls.^[83] This enhancement correlates with reduced amygdala hyperactivity and improved emotional regulation, suggesting SSRIs promote DLPFC-mediated top-down control over limbic responses.^[83] Sertraline, for instance, is associated with volume increases in the left DLPFC, reflecting structural adaptations that support antidepressant efficacy.^[84] Non-invasive brain stimulation techniques, particularly repetitive transcranial magnetic stimulation (rTMS), directly modulate DLPFC excitability to treat conditions like treatment-resistant depression. High-frequency rTMS (10 Hz) applied to the left DLPFC, delivering 3,000 pulses per session at 120% of resting motor threshold, was FDA-approved in 2008 based on randomized controlled trials showing response rates of 40–50% and remission rates of 25–30%.^[85] This protocol, lasting 37.5 minutes per session over four to six weeks, enhances cortical excitability and connectivity within frontostriatal networks, leading to sustained symptom relief in major depressive disorder.^[85] Intermittent theta-burst stimulation (iTBS), a faster variant using 600 pulses in three minutes, has since been approved as non-inferior, offering similar outcomes with reduced treatment time.^[85] Neurofeedback approaches, such as real-time functional magnetic resonance imaging (rt-fMRI), enable voluntary upregulation of DLPFC activity to promote cognitive enhancement. In training protocols combining rt-fMRI neurofeedback of the left DLPFC with n-back working memory tasks over five sessions, participants achieve learned control over DLPFC BOLD signals, resulting in focal neuroplastic changes confined to the target region.^[86] These adaptations manifest as increased activation during cognitive load, with closed-loop feedback matching open-loop performance by the final session and yielding improvements in executive function without widespread network alterations.^[86] Connectivity-based rt-fMRI neurofeedback further strengthens DLPFC-anterior cingulate cortex coupling, supporting applications in cognitive rehabilitation.^[87] Emerging therapeutic strategies leverage advanced technologies for precise DLPFC modulation. Optogenetics in animal models, such as rhesus macaques, enables cell-type-specific targeting of DLPFC circuits using machine learning-identified enhancers to drive optogenetic expression in layer-specific neurons, facilitating high-resolution studies of cognitive processes like decision-making.^[88] Post-2022 advancements have refined these tools for dissecting prefrontal hierarchies, with optogenetic inhibition revealing causal roles of DLPFC subpopulations in hierarchical control and behavioral flexibility.^[89] In parallel, AI-guided TMS personalizes DLPFC stimulation based on individual connectivity profiles derived from fMRI and diffusion tensor imaging, improving response prediction with areas under the curve up to 0.87.^[90] Connectivity-guided targeting, focusing on subregions anticorrelated with the subgenual anterior cingulate, boosts remission rates by over 30% in treatment-resistant depression compared to standard methods.^[90] As of 2025, precision neuronavigated rTMS targeting the right DLPFC (MNI coordinates: 40,39,11) has shown significant reductions in insomnia symptoms and mood disturbances in preliminary trials. High-definition tDCS (HD-tDCS) over the left DLPFC, applied for 12 days in moderate to severe depression, significantly improved mood scores in randomized controlled trials. Additionally, tDCS protocols targeting DLPFC are being explored for chronic low back pain, enhancing activity and functional connectivity to alleviate pain-related cognitive interference.^[91]^[92]^[93]

References

[1]
Neuroanatomy, Prefrontal Cortex - StatPearls - NCBI Bookshelf
In this roundabout way we have begun to understand some of its functions; for example, the dorsolateral PFC tends to be associated with planning, strategy, and ...
[2]
Is the Dorsolateral Prefrontal Cortex Actually Several Different Brain ...
Aug 17, 2022 · Its involvement has been shown in a variety of executive functions such as abstract reasoning (Bernardi et al., 2020), response inhibition ( ...
[3]
MeSH Browser - NIH
It is involved in EXECUTIVE FUNCTION. Entry Term(s): Brodmann Area 46: Brodmann Area 9: Brodmann Area 9 and 46: Brodmann Areas 9 and 46: Brodmann's Area 46 ...
[4]
The Dorsolateral Prefrontal Cortex: A High-level Hub for Allostatic ...
The dlPFC is part of a larger functionally connected network responsible for general cognitive control, also including the anterior insular cortex, the anterior ...
[5]
Differential contributions of dorsolateral and frontopolar cortices to ...
Oct 29, 2015 · Substantial evidence indicates that dorsolateral PFC (dlPFC) is an important structure for maintaining information across delays.
[6]
Functional coupling underlying motor and cognitive ... - PubMed
Mar 2, 2009 · The dorsolateral prefrontal cortex (dlPFC) is likely responsible for attentional selection, which orients organisms' mental resources to ...
[7]
Dorsolateral Prefrontal Cortex - an overview | ScienceDirect Topics
1. Anatomically, it spans the superior, middle, and inferior frontal gyri, bounded anteriorly by the frontal pole, posteriorly by motor areas, dorsally by the ...
[8]
Subregions of DLPFC Display Graded yet Distinct Structural and ...
Apr 13, 2022 · The dorsolateral prefrontal cortex (DLPFC) approximately corresponds to Brodmann area (BA)9 and BA46 and consists of the lateral part of ...
[9]
Dorsolateral Prefrontal Cortex (Areas 9, 46) - Radiology Key
Mar 13, 2021 · Boundaries. • Rostral: Frontal pole; • Caudal: Caudal portion of middle frontal gyrus; • Lateral and ventral: Inferior frontal sulcus; • Medial ...
[10]
An MRI-based approach for the measurement of the dorsolateral ...
The DLPFC is located on the lateral and dorsal part of the medial convexity of the frontal lobe and comprises Brodmann's areas 9 and 46 and a few transitional ...
[11]
Is There “One” DLPFC in Cognitive Action Control? Evidence for ...
The dorsolateral prefrontal cortex (DLPFC) has consistently been ... activation patterns across fMRI experiments in the BrainMap database. In a ...<|control11|><|separator|>
[12]
Causal Evidence Supporting Functional Dissociation of Verbal and ...
One study (Sandrini et al. 2008) found evidence of lateralized dlPFC function from directly comparing left and right stimulation on verbal and spatial n-back ...2.3 The 3-Back Task Of... · 3 Results · 4 Discussion
[13]
[PDF] Age Differences in the Frontal Lateralization of Verbal and Spatial ...
The asymmetrical organization of verbal and spatial working memory has been largely corroborated by neuroimaging studies of healthy, young right-handed adults, ...
[14]
Dorsolateral prefrontal cortex: comparative cytoarchitectonic ...
The cytoarchitecture of the human and the macaque monkey dorsolateral prefrontal cortex has been examined in a strictly comparative manner.
[15]
Cytoarchitecture, intersubject variability, and 3D mapping of four ...
Aug 10, 2022 · Adapted cytoarchitectonic maps showing the dorsolateral prefrontal cortex (DLPFC, bold black lines) and frontal pole (Fp, magenta) as segmented ...Abstract · Introduction · Results · Discussion
[16]
A multi-modal parcellation of human cerebral cortex - PubMed Central
Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas.Missing: DLPFC | Show results with:DLPFC
[17]
Molecular and cellular evolution of the primate dorsolateral ...
Aug 25, 2022 · The granular dorsolateral prefrontal cortex (dlPFC) is an evolutionary specialization of primates that is centrally involved in cognition.
[18]
https://www.science.org/doi/10.1126/science.abo7257
[19]
https://doi.org/10.1002/cne.902280110
[20]
https://doi.org/10.1523/JNEUROSCI.2419-07.2007
[21]
The role of prefrontal cortex in cognitive control and executive function
Aug 18, 2021 · Concepts of cognitive control (CC) and executive function (EF) are defined in terms of their relationships with goal-directed behavior versus habits.
[22]
Executive Functions - PMC - PubMed Central - NIH
Executive functions (EFs) make possible mentally playing with ideas; taking the time to think before acting; meeting novel, unanticipated challenges; resisting ...
[23]
Executive functions after orbital or lateral prefrontal lesions
Jun 25, 2012 · The dorsolateral PFC (DLPFC) is primarily associated with cognitive executive functions such as controlled attention, working memory, strategic ...Participants · Table Iii · Discussion<|separator|>
[24]
Insights into Human Behavior from Lesions to the Prefrontal Cortex
We provide a broad overview of PFC functions based upon behavioral and neural changes resulting from damage to PFC in both human patients and non-human ...<|control11|><|separator|>
[25]
A Meta‐analysis on the neural basis of planning: Activation ... - NIH
We report a quantitative meta‐analysis with activation likelihood estimation based on 31 functional neuroimaging datasets on the ToL.
[26]
Magnetoencephalographic signatures of right prefrontal cortex ...
In complex go‐nogo tasks, the right dorsolateral prefrontal cortex is considered to be important for guiding the response inhibition. However, little is ...
[27]
The neural substrates of cognitive flexibility are related to individual ...
Results indicated that left DLPFC activation was associated with cognitive flexibility and positively correlated with irritability. Right DLPFC activation ...
[28]
The contribution of ventrolateral and dorsolateral prefrontal cortex to ...
Studies investigating response reversal consistently implicate regions of medial and lateral prefrontal cortex when reinforcement contingencies change.
[29]
Brain regions underlying response inhibition and interference ...
Aug 7, 2025 · The inhibition of (motor) responses has been attributed to a fronto-parietal network encompassing the dorsolateral and ventrolateral prefrontal ...
[30]
Working Memory - ScienceDirect.com
The chapter presents a series of experiments on the role of memory in reasoning, language comprehension, and learning.
[31]
Working Memory in the Prefrontal Cortex - PMC - PubMed Central
Therefore, the central executive of Baddeley's model is thought to reflect functions of the prefrontal cortex. In fact, the term “executive function” is ...
[32]
Review Cellular basis of working memory - ScienceDirect.com
Neuron Volume 14, Issue 3, March 1995, Pages 477-485 Review Cellular basis of working memory Author links open overlay panel PS Goldman-RakicMissing: URL | Show results with:URL
[33]
[PDF] The Magical Number Seven, Plus or Minus Two - UT Psychology Labs
The Magical Number Seven, Plus or Minus Two: Some Limits on our Capacity for. Processing Information[1]. George A. Miller (1956). Harvard University. First ...
[34]
Dorsolateral Prefrontal Contributions to Human Working Memory
DlPFC damage was associated with deficits in the manipulation of verbal and spatial knowledge, with left dlPFC necessary for manipulating information in working ...
[35]
A Causal Role for the Right Dorsolateral Prefrontal Cortex in ...
Mar 15, 2021 · The right DLPFC directs behaviour to avoid risky choices and adopt more cautious but beneficial choices.
[36]
Prefrontal Coding of Temporally Discounted Values during Inter ...
In the present study, we focused on whether and how the dorsolateral prefrontal cortex (DLPFC) is involved in temporal discounting and inter-temporal choice.
[37]
Prefrontal Cortex Predicts State Switches during Reversal Learning
Jun 17, 2020 · The dorsal-lateral prefrontal cortex (dlPFC) integrates information carried by reward circuits, which can be used to infer the current state of ...
[38]
A Causal Role for the Right Dorsolateral Prefrontal Cortex ... - PubMed
Mar 15, 2021 · We provide evidence for the role of the DLPFC in value-independent, directed exploration on the Iowa Gambling Task (IGT) and we describe a new ...
[39]
Evidence accumulation, not 'self-control', explains dorsolateral ...
Sep 8, 2022 · An evidence accumulation model (drift diffusion model [DDM]) can be used to simulate decision making for any self-control context requiring ...
[40]
Disrupting the right prefrontal cortex alters moral judgement
Apr 22, 2011 · Our study explored the consequence of a localized disruption of right DLPFc activity in the context of moral dilemma evaluation. Moral ...
[41]
Catecholamine Influences on Dorsolateral Prefrontal Cortical ...
Apr 13, 2011 · The dorsolateral PFC is especially sensitive to levels of norepinephrine and dopamine, whereby either too little or too much markedly impairs PFC function.
[42]
Monoaminergic Modulation of Learning and Cognitive Function in ...
Sep 6, 2024 · The dlPFC supports the active retention and processing of task-relevant information, facilitating complex behaviors and future-oriented actions.Monoaminergic Modulation Of... · 2. Monoamines And The... · 3. Monoamines And Behavior...
[43]
Prefrontal cortical alterations of glutamate and GABA ...
The density of EAAT2 at the synaptic membrane also appears to shift with changes to the excitatory/inhibitory balance as it can be increased or decreased, ...
[44]
Article NMDA Receptors Subserve Persistent Neuronal Firing during ...
Feb 20, 2013 · Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task.
[45]
Serotonin and decision making processes - ScienceDirect.com
The aim of the present essay is to review the role of 5-HT in various types of decision making processes. 5-HT, a highly conserved monoamine neuromodulator, ...
[46]
Development of prefrontal cortex | Neuropsychopharmacology
Oct 13, 2021 · Prefrontal synaptogenesis starts prenatally and peaks postnatally followed by a process called pruning or refinement of synaptic connections, ...
[47]
The Brain on Stress: Vulnerability and Plasticity of the Prefrontal ...
Jul 10, 2013 · This Review focuses primarily on stress-related effects upon the PFC because of its importance in working memory and self-regulatory and goal-directed ...
[48]
Early Adversity and Critical Periods: Neurodevelopmental ...
Children exposed to adverse life events in the first years of life are at increased risk for a variety of neural, behavioral and psychological sequelae.Early Adversity And Critical... · Adversity As A Violation Of... · Figure 4. Sequelae Of...
[49]
https://www.sciencedirect.com/science/article/pii/S0896627313005448
[50]
Contribution of NMDA receptors to dorsolateral prefrontal cortical ...
Cognitive disorders such as schizophrenia and Alzheimer's disease are associated with dysfunction of the highly evolved dorsolateral prefrontal cortex ...
[51]
Lateral prefrontal activity as a compensatory strategy for deficits of ...
Aug 3, 2017 · On the other hand, the activity in dlPFC related to inhibitory control seems to decrease with age. This change can be interpreted as a ...
[52]
Age-Related Differences in Prefrontal Cortex Activity during ...
Apr 17, 2012 · Older adults instead exhibited high levels of DLPFC activity for all of these conditions, and activity was greater than younger adults even when ...Missing: hyperactivity | Show results with:hyperactivity
[53]
Prefrontal cortex and depression - PMC - PubMed Central - NIH
Treatment-resistant depression (TRD) was characterized by decreased global connectivity within the right dlPFC and bilateral dmPFC (including the dACC) [76].Issues Of Translatability · Mdd And Chronic Stress... · Anhedonia
[54]
Executive Function, Neural Circuitry, and Genetic Mechanisms in ...
Functional hypofrontality and working memory ... Re-evaluating dorsolateral prefrontal cortex activation during working memory in schizophrenia.
[55]
Magnetic Resonance Imaging in Studying Schizophrenia, Negative ...
Apr 3, 2014 · Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. ... dorsolateral prefrontal cortex in schizophrenia ...
[56]
DISC1 is associated with cortical thickness and neural efficiency - NIH
Prefrontal cortex dysfunction during working memory ... DISC1 is associated with prefrontal cortical gray matter and positive symptoms in schizophrenia.
[57]
Precision psychiatry: a neural circuit taxonomy for depression and ...
Apr 14, 2016 · This state of intrinsic hyperconnectivity is thought to drive rumination and the negative attributions that underlie negative biases.A Neural Circuit Approach To... · Putative Biotype 2: Anxious... · Cognitive Control Circuit
[58]
Defining biotypes for depression and anxiety based on large-scale ...
Hypo-activation of the DLPFC and dorsal anterior cingulate cortex (dACC) during cognitive tasks, and in stress-induced situations, has been found in depressed ...Neural Circuit Selection · Results · Table 1<|separator|>
[59]
Neural circuits in anxiety and stress disorders: a focused review - PMC
Decreased activation in mPFC was observed consistently in PTSD and GAD, with mixed findings in SAD. In contrast, dlPFC hyperactivation to threat was observed in ...Fear Versus Anxiety · Emotion Modulation Regions · Medial Prefrontal Cortex
[60]
Prefrontal cortex, amygdala, and threat processing: implications for ...
Sep 20, 2021 · The dlPFC, vmPFC/IL, and hippocampus show impaired functioning with PTSD, whereas the amygdala and dACC/PL are enhanced. Disrupted connections ...
[61]
Lag in maturation of the brain's intrinsic functional architecture in ...
It was proposed that individuals with attention-deficit/hyperactivity disorder (ADHD) exhibit delays in brain maturation. In the last decade, resting state ...
[62]
Dorsolateral prefrontal cortex dysfunction caused by a go/no-go task ...
Mar 28, 2023 · Our results indicate that brain dysfunction in children with ADHD is related to functional impairments in the dorsolateral prefrontal cortex.
[63]
Prefrontal dopaminergic receptor abnormalities and executive ... - NIH
... Parkinson's disease (PD) includes deficits of executive functions. These ... Dopamine deficiency in the cerebral cortex in Parkinson disease. Neurology ...
[64]
Executive dysfunction in Parkinson's disease: From neurochemistry ...
... dopamine dysfunction are associated with executive deficits in Parkinson's disease with mild cognitive impairment ... depletion in patients with Parkinson ...
[65]
Neural correlates of STN DBS-induced cognitive variability in ...
These results demonstrate that variability in the effects of STN DBS on cognitive performance relates to STN DBS-induced cortical blood flow changes in DLPFC ...
[66]
Deep Brain Stimulation of the Subthalamic Nucleus Alters Frontal ...
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). The STN may represent an important ...
[67]
Brain On Stress: Vulnerability and Plasticity of the Prefrontal Cortex ...
This review focuses primarily on stress-related effects upon the PFC because of its importance in working memory, self regulatory and goal-directed behaviors.Missing: cortisol | Show results with:cortisol
[68]
Prefrontal cortical trkB, glucocorticoids, and their interactions in ...
This review examines the literature regarding developmental and stress-induced changes in receptors for two potent modulators of dendritic spines and synaptic ...4. Bdnf-Trkb Regulation Of... · 6.1. Trkb In The Pfc Across... · 9. Bdnf-Trkb And Gr Systems...
[69]
Chronic Stress in Adolescents and Its Neurobiological and ...
Importantly, glucocorticoids can cross the blood–brain barrier, act on receptors, and regulate genes involved in neurogenesis, neuroplasticity, and ...Chronic Stress And... · Table 2 · Discussion<|control11|><|separator|>
[70]
ALCOHOL AND THE PREFRONTAL CORTEX - PubMed Central - NIH
Chronic alcohol use is associated with reduced white matter volume throughout the cortex (de la Monte, 1988). ... The acute effect of alcohol on decision making ...Missing: DLPFC | Show results with:DLPFC
[71]
Prefrontal hypoactivation during cognitive control in early abstinent ...
These preliminary findings suggest that hypofunction in cortical areas that are important for executive function underlies cognitive control deficits ...
[72]
Dysfunction of the prefrontal cortex in addiction - NIH
The loss of control over drug intake that occurs in addiction was initially believed to result from disruption of subcortical reward circuits.
[73]
Cocaine cue–induced dopamine release in the human prefrontal ...
Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers.
[74]
Model-based lesion mapping of cognitive control using the ...
Jan 3, 2019 · Our results reveal that lesions in the right prefrontal cortex are associated with elevated perseverative errors and reductions in the model ...
[75]
Insights into Human Behavior from Lesions to the Prefrontal Cortex
Sep 3, 2014 · Human lesion studies have reinforced the notion that DLPFC is essential for working memory function (Barbey et al., 2013, Manes et al., 2002 ...
[76]
Methylphenidate and Atomoxetine Enhance Prefrontal Function ...
This study examined the effects of the attention-deficit/hyperactivity disorder treatments, methylphenidate (MPH) and atomoxetine (ATM), on prefrontal cortex ( ...
[77]
Neuropharmacological effect of methylphenidate on attention ... - NIH
These results are consistent with the neuropharmacological effects of methylphenidate to upregulate the dopamine system in the prefrontal cortex innervating ...
[78]
Antidepressant treatment normalizes hypoactivity in dorsolateral ...
Results: After eight weeks of SSRI antidepressant treatment, patients with depression showed significantly increased DLPFC activity to unattended fear-related ...
[79]
Antidepressant effects of sertraline associated with volume ...
2013年4月25日 · Effective antidepressant treatment with sertraline is associated with left DLPFC volume increases. These volume increases may reflect cortical architectural ...
[80]
Repetitive transcranial magnetic stimulation for major depressive ...
The first approved FDA protocol involved 10 Hz stimulation (3000 pulses, 37.5 min duration) at an intensity of 120% rMT to the left DLPFC. Deep TMS was ...
[81]
Combining Real-Time fMRI Neurofeedback Training of the DLPFC ...
Jun 28, 2016 · The advent of real-time fMRI has enabled a new method to systematically alter brain activity across space and time using neurofeedback training ...
[82]
Using connectivity-based real-time fMRI neurofeedback to modulate ...
The current study examined the potential of connectivity-based real-time functional magnetic imaging neurofeedback (rt-fMRI-nf) for enhancing DLPFC – ACC ...
[83]
Machine learning identification of enhancers in the rhesus macaque ...
May 21, 2025 · We trained machine-learning models to rank those OCRs according to their potential as cell-type-specific enhancers for cells in the dorsolateral prefrontal ...
[84]
Distinct role of primate DLPFC and LIP in hierarchical control of ...
Dec 26, 2024 · ... dorsolateral prefrontal cortex (DLPFC), the supplementary eye field ... The burgeoning application of optogenetics in non-human ...
[85]
Precision TMS through the integration of neuroimaging and machine ...
Personalized connectivity-guided DLPFC-TMS for depression: Advancing computational feasibility, precision and reproducibility. Hum. Brain Mapp. 42 4155–4172 ...