Schizophrenia is a severe psychiatric disorder characterised by positive symptoms such as auditory hallucinations, delusions and thought disorganisation, as well as negative and cognitive symptoms including social withdrawal, anhedonia, working-memory deficits and impaired executive function.
Within the framework of the Excitability-Margin Hypothesis (EMH), chronic stress and repeated emotional activation progressively narrow the ventral CA1 hippocampal excitability margin (ΔVmargin)—the voltage difference between the resting membrane potential and action-potential threshold. This loss of “safety margin” destabilises hippocampal circuits, leading to spontaneous replay of emotional memory traces and the emergence of intrusive “voices” or internally generated perceptions.
At the molecular level, schizophrenia is associated with down-regulation of the potassium-chloride cotransporter KCC2, up-regulation of NKCC1, and a depolarising shift in the GABAergic equilibrium potential (EGABA). These chloride-gradient disturbances weaken inhibitory control, causing hippocampal hyperexcitability and excessive gamma-frequency oscillations observed in MEG and EEG recordings. Parallel reductions in Na⁺/K⁺-ATPase activity, alterations in GIRK and TASK leak potassium currents, and dysfunction of PV-positive (parvalbumin) interneurons amplify the excitability imbalance.
Stress hormones further aggravate this process: hypothalamic–pituitary–adrenal (HPA) axis dysregulation, elevated cortisol and dopaminergic hyperactivity in the mesolimbic pathway create a feed-forward loop. Increased dopamine release in the striatum drives positive psychotic symptoms, while cortical hypodopaminergia contributes to negative and cognitive deficits.
Oxidative stress adds another layer: reactive oxygen species (ROS) accumulation and glutathione (GSH) depletion damage PV interneurons and impair NMDA-receptor-mediated synaptic plasticity, mechanisms consistently linked to schizophrenia pathophysiology.
Genetic studies reinforce this multifactorial model. Risk variants in CACNA1C, SCN2A, GRIN2A, DISC1 and COMT converge on calcium and sodium channel regulation, NMDA receptor signalling, and dopamine metabolism, aligning with the EMH prediction that diverse molecular insults ultimately erode the vCA1 excitability buffer.
Environmental factors—prenatal infection, perinatal hypoxia, urban upbringing, high-sugar or high-fat diet, chronic psychosocial stress, and cannabis or psychostimulant exposure—act as additional triggers that accelerate ΔVmargin collapse.
Clinically, this cascade explains hallmark findings:
auditory hallucinations arising from uncontrolled hippocampal replay of fear or emotionally charged engrams,
hyper-gamma activity on EEG/MEG,
enlarged lateral ventricles, reduced hippocampal volume, and fronto-temporal dysconnectivity on MRI and DTI,
impaired working memory and executive dysfunction linked to prefrontal cortical hypoactivation.
From a therapeutic perspective, the EMH highlights potential biomarkers and intervention targets: restoring KCC2 function, boosting Na⁺/K⁺-ATPase activity, reducing ROS, normalising PV interneuron firing, and modulating gamma oscillations.
These approaches complement current antipsychotic strategies aimed at dopamine D2 receptor blockade, and open avenues for novel treatments such as chloride-homeostasis modulators, antioxidants (N-acetylcysteine), 40 Hz gamma entrainment protocols, and stress-reduction interventions.
By integrating genetic risk, molecular neurobiology, stress physiology, and circuit-level oscillatory dynamics, the Excitability-Margin Hypothesis provides a single, falsifiable mechanistic framework linking the diverse clinical manifestations of schizophrenia to a measurable collapse of the vCA1 safety margin.
Post-traumatic Stress Disorder is a chronic psychiatric condition that develops after exposure to life-threatening events, combat, assault, accidents or repeated early-life trauma. Core features include intrusive flashbacks, nightmares, hyperarousal, avoidance behaviour, sleep disturbances and negative alterations in mood and cognition.
Within the Excitability-Margin Hypothesis (EMH), these symptoms originate when repeated or severe stress progressively narrows the ventral CA1 (vCA1) hippocampal excitability margin (ΔVmargin)—the voltage gap between resting potential and action-potential threshold. Once ΔVmargin falls below a critical ~5 mV, hippocampal circuits become unstable and are prone to spontaneous replay of emotional memory traces, experienced clinically as intrusive recollections and vivid re-experiencing.
At the cellular level, sustained activation of the hypothalamic–pituitary–adrenal (HPA) axis drives prolonged cortisol release and noradrenaline (norepinephrine) surges from the locus coeruleus. These stress hormones disrupt ionic homeostasis by down-regulating KCC2, up-regulating NKCC1, and shifting the GABA equilibrium potential (EGABA) toward depolarising values. The resulting loss of inhibitory tone allows hippocampal hyperexcitability and promotes theta–gamma coupling abnormalities commonly observed in EEG and MEG recordings of trauma survivors.
Simultaneously, Na⁺/K⁺-ATPase impairment, reductions in GIRK and TASK leak K⁺ currents, and parvalbumin-positive (PV) interneuron vulnerability further erode the ΔVmargin. Repeated re-activation of fear-related engrams generates reactive oxygen species (ROS) and accelerates glutathione (GSH) depletion, causing oxidative damage that perpetuates PV-interneuron dysfunction.
This self-reinforcing loop—stress → ΔVmargin collapse → spontaneous emotional replay → ROS generation → interneuron injury—explains the clinical persistence of nightmares, hypervigilance and intrusive memories long after the original trauma.
Functional imaging studies show hyperactivity of the amygdala, reduced prefrontal inhibition, and hippocampal volume loss, matching EMH predictions of a chronically unstable vCA1 network. Genetic and epigenetic factors—such as FKBP5 polymorphisms, BDNF methylation changes, and variants in stress-response genes—interact with environmental triggers (childhood adversity, repeated trauma, chronic inflammation) to lower the threshold for ΔVmargin collapse.
Clinically, EMH unifies diverse observations:
high basal cortisol and exaggerated startle responses,
altered gamma/theta oscillatory patterns,
impaired extinction of fear memories,
and long-term structural changes in hippocampus and medial prefrontal cortex.
Therapeutic implications extend beyond standard psychotherapy and SSRIs. EMH highlights potential benefit from interventions that restore chloride homeostasis (for example KCC2 enhancers), reduce oxidative stress (N-acetylcysteine, antioxidant micronutrients), modulate gamma oscillations (e.g. 40 Hz sensory stimulation), and down-regulate HPA axis overdrive through mindfulness, vagus-nerve stimulation or controlled breathing protocols.
By integrating stress endocrinology, ionic neurophysiology, oscillatory network dynamics and genetic vulnerability, the Excitability-Margin Hypothesis offers a single mechanistic explanation for the hallmark phenomena of PTSD—persistent intrusive memories and heightened arousal—linking them to a measurable, reversible collapse of the hippocampal safety margin.
Major depressive disorder (MDD) is characterised by persistent low mood, anhedonia, fatigue, sleep and appetite disturbance, cognitive slowing, and in many cases suicidal ideation.
Within the Excitability-Margin Hypothesis (EMH), these core symptoms emerge when chronic stress progressively narrows the ventral CA1 (vCA1) excitability margin (ΔVmargin)—the voltage difference between resting potential and the action-potential threshold. When ΔVmargin drops below a critical ~5 mV, hippocampal network instability disrupts both mood-regulating circuits and monoaminergic balance, setting the stage for depressive phenotypes.
HPA axis hyperactivity: Persistent psychosocial or inflammatory stress drives excess corticotropin-releasing hormone (CRH) and sustained cortisol elevation, which in turn down-regulates KCC2, up-regulates NKCC1, and shifts GABA equilibrium potential (E_GABA) toward depolarisation.
Loss of inhibitory control: Reduced KCC2 function and parvalbumin-positive (PV) interneuron dysfunction weaken GABAergic inhibition, allowing excessive dendritic plateau bursts and aberrant theta–gamma coupling, patterns repeatedly observed in EEG/MEG studies of depression.
Na⁺/K⁺-ATPase impairment and decreased GIRK/TASK leak currents further erode the ΔVmargin, reinforcing vCA1 hyperexcitability.
vCA1 instability projects to ventral tegmental area (VTA), dorsal raphe nucleus and locus coeruleus, disrupting dopaminergic, serotonergic and noradrenergic tone. The result is the classic monoaminergic dysregulation:
dopamine down-regulation → anhedonia and reduced motivation,
serotonin deficits → negative affect and ruminative thought patterns,
noradrenaline imbalance → fatigue and impaired stress resilience.
Repeated replay of negative emotional engrams generates reactive oxygen species (ROS), depleting glutathione (GSH) and damaging PV interneurons. This reduces brain-derived neurotrophic factor (BDNF) signalling and contributes to hippocampal atrophy, a robust structural finding in MRI studies of MDD.
Variants in SLC6A4 (serotonin transporter), BDNF Val66Met, FKBP5, and CACNA1C interact with early-life adversity and chronic stress to lower the threshold for ΔVmargin collapse and to amplify HPA axis dysregulation.
The EMH unifies diverse biomarkers of depression:
elevated basal cortisol and flattened diurnal rhythm,
gamma/theta oscillatory abnormalities,
reduced hippocampal volume,
blunted dopaminergic reward signalling.
Beyond conventional SSRIs and SNRIs, the model suggests benefit from interventions that:
restore chloride homeostasis (e.g. experimental KCC2 enhancers, NKCC1 blockers such as bumetanide),
reduce oxidative stress (N-acetylcysteine, omega-3 fatty acids, antioxidant vitamins),
stimulate BDNF and neurogenesis (exercise, enriched-environment protocols, 40 Hz sensory stimulation),
and modulate HPA activity through mindfulness, vagus-nerve stimulation, or cognitive behavioural therapies.
By linking stress endocrinology, ionic physiology, monoamine regulation and network oscillations, the Excitability-Margin Hypothesis provides a single mechanistic framework that explains how chronic stress translates into the emotional, cognitive and biological hallmarks of major depression.
Post-traumatic stress disorder (PTSD) emerges after exposure to severe or repeated trauma and is defined by intrusive memories, flashbacks, hyperarousal, nightmares, avoidance behaviours, and often co-morbid depression or anxiety.
Within the Excitability-Margin Hypothesis (EMH), these features reflect a chronic narrowing of the ventral CA1 (vCA1) excitability margin (ΔVmargin)—the voltage gap between neuronal resting potential and spike threshold—caused by prolonged stress and repeated fear-memory reactivation.
Locus coeruleus hyperactivity → sustained noradrenaline (norepinephrine) release, heightening arousal and reinforcing traumatic engrams.
HPA axis dysregulation: fluctuating cortisol levels impair KCC2 chloride extrusion, up-regulate NKCC1, and destabilise GABAergic inhibition, pushing E_GABA toward depolarising values.
PV-interneuron stress vulnerability and Na⁺/K⁺-ATPase down-regulation reduce leak conductances and shrink ΔVmargin by ~10–12 mV.
When ΔVmargin falls below ~5 mV:
theta–gamma coupling in vCA1 becomes unstable, producing spontaneous replay of fear engrams, experienced clinically as flashbacks or intrusive memories.
amygdala–hippocampus circuits receive aberrant high-frequency bursts, maintaining a state of hypervigilance and exaggerated startle reflex.
prefrontal cortex hypoactivity limits top-down inhibition of fear networks.
Persistent reactive oxygen species (ROS) production depletes glutathione (GSH) and damages PV interneurons, further weakening inhibitory control. Neuroimaging studies consistently show reduced hippocampal volume, amygdala hyperactivity, and anterior cingulate cortex (ACC) dysconnectivity—all consistent with EMH predictions.
Variants in FKBP5, COMT Val158Met, SLC6A4, and ADCYAP1R1, combined with early-life stress, increase HPA reactivity and lower the threshold for ΔVmargin collapse. Trauma-related DNA methylation changes in stress-regulatory genes reinforce long-term vulnerability.
EMH integrates well-known PTSD biomarkers:
elevated noradrenaline, altered cortisol rhythms,
EEG gamma/theta abnormalities,
hippocampal and prefrontal structural changes,
and high comorbidity with major depression (35–68 %).
Therapeutic strategies that may counteract ΔVmargin narrowing include:
noradrenergic modulation (e.g., prazosin),
GABAergic support / KCC2 enhancement (experimental bumetanide, neurosteroids such as allopregnanolone),
antioxidant supplementation (N-acetylcysteine, omega-3 fatty acids),
trauma-focused psychotherapies (CBT, EMDR) which help extinguish maladaptive engrams.
By unifying stress endocrinology, fear-circuit neurophysiology, and ionic homeostasis, the Excitability-Margin Hypothesis explains how traumatic stress imprints persistent hyper-excitability of hippocampal–amygdala networks, driving the hallmark symptoms of PTSD.
Attention-deficit/hyperactivity disorder (ADHD) is characterised by inattention, impulsivity, hyperactivity, and deficits in working memory and executive function.
Within the Excitability-Margin Hypothesis (EMH) these behavioural traits reflect a developmental narrowing of the ventral CA1 (vCA1) excitability margin (ΔVmargin) together with impaired top–down regulation from prefrontal cortex (PFC).
Catecholaminergic imbalance – hypoactive dopamine and noradrenaline signalling in PFC and hippocampus disrupts maintenance of stable resting membrane potential (Vrest) and weakens the Na⁺/K⁺-ATPase drive that supports the ΔVmargin.
Delayed GABAergic maturation – reduced KCC2 expression and elevated NKCC1 activity during childhood keep GABA signalling more depolarising, shrinking ΔVmargin by several mV in vCA1 and dentate gyrus.
Chronic low-grade neuroinflammation – IL-6, TNF-α and microglial activation generate reactive oxygen species (ROS), further impairing PV-interneuron function and gamma-rhythm stability.
When ΔVmargin is chronically reduced:
theta–gamma phase coupling between vCA1 and medial PFC becomes noisy, weakening working-memory replay and attention gating.
PV-interneuron hypoactivity diminishes gamma-band synchrony, producing the EEG signatures of increased slow-wave power and reduced frontal gamma commonly reported in ADHD.
Dysregulated hippocampal replay contributes to distractibility and impulsive decision-making.
Variants in DAT1 (SLC6A3), DRD4 7-repeat, CACNA1C, SCN2A, and ANK3 affect dopamine transport, calcium and sodium channel kinetics—each capable of tightening the excitability margin.
Prenatal stress, maternal smoking, and early-life hypoxia elevate cortisol and impair GABAergic maturation, amplifying ΔVmargin vulnerability.
Neuroimaging consistently shows reduced hippocampal and PFC volumes, fronto-hippocampal dysconnectivity, and altered default-mode network activity—all compatible with EMH predictions.
Effective treatments—psychostimulants (methylphenidate, amphetamine), atomoxetine, and behavioral interventions—increase catecholamine tone and help restore stable PFC–hippocampal gating, indirectly widening ΔVmargin.
Adjunctive strategies aimed at GABAergic support, KCC2 up-regulation, or antioxidant therapy (e.g., N-acetylcysteine) represent promising research avenues.
By framing ADHD as a disorder of fronto-hippocampal excitability-margin insufficiency, the Excitability-Margin Hypothesis links classic ADHD biomarkers—dopaminergic deficits, immature inhibitory circuits, and abnormal gamma–theta coupling—to a single quantitative bottleneck in vCA1–PFC network stability.
Obsessive–compulsive disorder (OCD) is marked by intrusive, repetitive thoughts (obsessions) and compulsive behaviours aimed at reducing anxiety.
Within the Excitability-Margin Hypothesis (EMH) these symptoms arise when the ventral CA1 (vCA1) excitability margin (ΔVmargin = Vrest – Vthr) becomes critically narrowed and interacts with the cortico-striato-thalamo-cortical (CSTC) loop, allowing unwanted hippocampal replay to repeatedly trigger maladaptive behavioural programs.
GABA–glutamate imbalance – multiple studies show reduced GABA and excess glutamate in orbitofrontal cortex and hippocampus.
↓ KCC2 / ↑ NKCC1 shifts GABAergic currents toward depolarisation, reducing ΔVmargin in vCA1 and in striatal interneurons.
Dopaminergic hyper-responsivity in striatum and serotonergic dysregulation (5-HT2A/5-HT1B) further destabilise inhibitory control.
ROS accumulation and microglial activation – elevated IL-6, TNF-α weaken PV-interneuron gamma pacing, promoting noisy theta–gamma coupling.
With ΔVmargin < ~5 mV, hippocampal replay bursts spontaneously arise and entrain CSTC circuits, making intrusive thoughts self-perpetuating.
Orbitofronto-striatal loops receive repeated “false alarms,” driving compulsive checking and ritualised behaviours.
EEG/MEG studies show increased frontal theta and aberrant gamma, consistent with impaired PV-interneuron synchrony predicted by EMH.
Variants in SLC1A1 (glutamate transporter), GRIN2B (NMDA receptor subunit), CACNA1C and SCN2A influence excitatory drive and ion-channel kinetics, predisposing to ΔVmargin narrowing.
Perinatal hypoxia, childhood stress, and autoimmune basal ganglia inflammation (PANDAS) can exacerbate GABAergic immaturity and oxidative stress.
MRI consistently reports orbitofrontal cortex hyperactivity, hippocampal volume reductions, and increased functional connectivity in CSTC loops—all compatible with vCA1-driven replay instability.
First-line therapies—SSRIs and exposure-response prevention (ERP)—reduce intrusive thought frequency; adjunctive glutamate modulators (e.g., N-acetylcysteine, riluzole) and deep-brain stimulation of the anterior limb of the internal capsule may further stabilise E/I balance.
Emerging approaches that up-regulate KCC2 or support PV-interneuron antioxidant defences (e.g., NAC, sulforaphane) directly target the EMH bottleneck.
By viewing OCD as a vCA1-initiated replay disorder superimposed on CSTC circuit vulnerability, the Excitability-Margin Hypothesis unifies its core phenomena—persistent intrusive thoughts, compulsive acts, frontal hyperactivity, and GABA/glutamate dysregulation—within a single quantitative mechanism of excitability-margin collapse.
Alzheimer’s disease (AD) is characterised by progressive memory loss, cognitive decline and cortical–hippocampal network disintegration.
Within the Excitability-Margin Hypothesis (EMH), these features emerge when ventral CA1 (vCA1) neurons experience a critical narrowing of the excitability margin (ΔVmargin = Vrest – Vthr), making hippocampal replay bursts unstable and impairing long-term memory consolidation.
Amyloid-β oligomers and hyperphosphorylated tau elevate intracellular Ca²⁺, activate NMDA receptors and disrupt K⁺ leak channels (GIRK/TASK), progressively depolarising Vrest.
KCC2 down-regulation / NKCC1 up-regulation diminishes GABAergic inhibition, shifting inhibitory postsynaptic potentials toward excitation and further reducing ΔVmargin.
Oxidative stress and microglial activation (↑ IL-6, TNF-α, ROS) damage PV-interneurons, weakening gamma-frequency pacing that normally stabilises theta–gamma coupling.
With ΔVmargin < ~5 mV, hippocampal replay bursts become erratic, impairing episodic memory encoding and retrieval.
MEG/EEG studies show slowed theta rhythms, reduced gamma coherence and hypersynchronous sharp-wave ripples, matching EMH predictions of unstable vCA1 oscillatory dynamics.
Functional MRI reveals early default-mode network hyperconnectivity followed by disconnection, consistent with replay-driven noise and subsequent synaptic exhaustion.
APOE-ε4, TREM2 variants and mitochondrial DNA haplogroups increase vulnerability to oxidative stress and ion-channel dysfunction.
Type-2 diabetes, high-sugar diets, chronic sleep deprivation and mid-life hypertension exacerbate ROS production and ΔVmargin narrowing.
MRI shows progressive hippocampal atrophy, particularly in CA1, the very subfield implicated in EMH.
Cognitive symptoms—anterograde amnesia, spatial disorientation, executive decline—mirror predicted failure of stable hippocampal replay.
Therapeutic strategies that restore inhibitory tone—e.g. GABA agonists, KCC2 enhancers, 40 Hz gamma entrainment, antioxidants (N-acetylcysteine, sulforaphane)—directly address the excitability-margin bottleneck.
Lifestyle interventions (aerobic exercise, ketogenic or Mediterranean diet, sleep optimisation) reduce neuroinflammation and support PV-interneuron resilience.
Framing AD within the Excitability-Margin Hypothesis unifies amyloid/tau pathology, oxidative stress, and network oscillation deficits into a single quantitative mechanism—critical ΔVmargin collapse in vCA1—offering testable targets for prevention and early therapeutic modulation.
Channelopathies are neurological disorders caused by pathogenic variants in genes encoding voltage-gated or ligand-gated ion channels.
Examples include SCN2A‐related epileptic encephalopathy, CACNA1A‐associated familial hemiplegic migraine, KCNQ2/3 epilepsies, and KCNT1, KCNA1 or GABRG2 variants seen across epilepsy and neurodevelopmental syndromes.
Within the Excitability-Margin Hypothesis (EMH) these apparently diverse syndromes share a single quantitative fault line: critical narrowing of the excitability margin (ΔVmargin = Vrest – Vthr) in hippocampal and cortical circuits, especially ventral CA1 (vCA1).
Gain-of-function sodium channel mutations (SCN2A, SCN8A) increase persistent Na⁺ currents, depolarising resting membrane potential (Vrest) and reducing ΔVmargin.
Loss-of-function K⁺ channel mutations (KCNQ2/3, KCNA1) diminish repolarising currents and TASK/GIRK leak conductance, again shrinking the safety buffer between Vrest and firing threshold.
Chloride transporter variants (SLC12A5/KCC2, SLC12A2/NKCC1) impair GABAergic inhibition by shifting ECl, so inhibitory postsynaptic potentials become less hyperpolarising, functionally equivalent to ΔVmargin narrowing.
A reduced ΔVmargin (< ~5 mV) renders gamma–theta oscillations unstable, promoting pathological replay bursts and paroxysmal discharges—the electrophysiological hallmarks of many epilepsies.
In cognitive channelopathies (e.g., SCN2A autism spectrum, CACNA1C bipolar risk), unstable vCA1 replay compromises episodic memory consolidation and emotional regulation, paralleling deficits seen in schizophrenia, MDD and PTSD.
Epileptic phenotypes: focal seizures, temporal-lobe epilepsy, generalized epileptic encephalopathies.
Neuropsychiatric overlap: intellectual disability, autism spectrum traits, migraine, episodic ataxia, and mood disorders.
Shared findings—hippocampal hyperexcitability, abnormal EEG gamma bursts, altered MEG theta–gamma coupling—mirror EMH predictions.
Precision medicine: sodium-channel blockers (e.g., phenytoin, carbamazepine) or K⁺-channel openers (retigabine) effectively re-widen ΔVmargin in gain-of-function contexts.
GABAergic modulators (benzodiazepines, neurosteroids) and KCC2 enhancers strengthen inhibitory tone, stabilising network oscillations.
Adjuncts—antioxidants (N-acetylcysteine, sulforaphane) and lifestyle measures reducing systemic inflammation—help preserve PV-interneuron function and gamma-rhythm integrity.
The Excitability-Margin Hypothesis therefore provides a unifying framework: seemingly distinct **ion-channel mutations converge on a single electrophysiological bottleneck—critical ΔVmargin collapse—linking classical channelopathies with epilepsy, migraine, autism spectrum disorders and even the shared circuitry vulnerabilities seen in schizophrenia, depression and PTSD.
Migraine is now recognised as a complex neurovascular and neuroinflammatory brain disorder, often overlapping genetically and mechanistically with epilepsy and other excitability syndromes.
Within the Excitability-Margin Hypothesis (EMH), migraine attacks arise when the ventral CA1 (vCA1) hippocampal and cortical circuits experience a critical reduction in excitability margin (ΔVmargin = Vrest – Vthr), predisposing to sudden, large-scale network events such as cortical spreading depolarisation (CSD).
Ion-channel variants (e.g., CACNA1A, ATP1A2, SCN1A) and Na⁺/K⁺-ATPase dysfunction decrease the separation between resting potential and firing threshold, directly narrowing ΔVmargin.
KCC2 down-regulation and NKCC1 up-regulation shift GABAergic inhibition towards depolarising, weakening inhibitory control over pyramidal cells.
Glial and vascular inflammatory mediators (IL-6, TNF-α, CGRP) further disturb extracellular K⁺ buffering and glutamate clearance, amplifying excitability.
A ΔVmargin collapse below ~5 mV makes gamma–theta oscillations unstable and lowers the threshold for CSD initiation, the electrophysiological substrate of migraine aura.
Hippocampal–thalamic circuitry hyperexcitability helps explain prodromal cognitive symptoms, heightened sensory gain, and the frequent comorbidity of migraine with temporal-lobe epilepsy and mood disorders.
Migraine frequently coexists with epilepsy, depression, anxiety and bipolar spectrum disorders, conditions likewise linked to hippocampal hyperexcitability and ΔVmargin instability.
Shared endophenotypes include abnormal gamma power on EEG/MEG, HPA-axis dysregulation, and PV-interneuron vulnerability, paralleling observations in schizophrenia, MDD and PTSD.
Ion-channel–targeted therapies—calcium-channel blockers (verapamil), sodium-channel inhibitors (lamotrigine) and emerging K⁺-channel openers—can re-expand the excitability margin.
CGRP antagonists, anti-inflammatory nutraceuticals (e.g., omega-3, N-acetylcysteine) and lifestyle interventions that reduce systemic inflammation further protect against vCA1 hyperexcitability.
Through the EMH lens, migraine is not merely a vascular headache disorder but a paradigmatic channelopathy of excitability, converging mechanistically with epilepsy and psychiatric illnesses via critical ΔVmargin narrowing in hippocampal and cortical circuits.
Chronic migraine and episodic migraine are strongly influenced by environmental and lifestyle triggers. Sleep deprivation, high-sugar diet, chronic stress, caffeine overuse and even microplastic exposure elevate circulating IL-6, TNF-α and other pro-inflammatory cytokines. These factors promote oxidative stress, disrupt KCC2/NKCC1 chloride homeostasis and impair Na⁺/K⁺-ATPase activity, driving the same ΔVmargin narrowing described in the Excitability-Margin Hypothesis.
Clinically, many patients report “brain fog”, attention deficits and episodic memory disturbances during migraine prodrome or post-drome. These hippocampal-related cognitive symptoms mirror those observed in schizophrenia, depression and PTSD, supporting the concept of a shared vCA1 excitability bottleneck across migraine and psychiatric disorders. Recognition of these hippocampal features underscores the need for integrated therapeutic strategies—addressing sleep hygiene, anti-inflammatory nutrition and targeted modulation of hippocampal network excitability.
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