Seizure is a common neurological disorder that affects approximately 1% of the population worldwide. Frontal lobe epilepsy (FLE) is the second most prevalent type of seizure, but detecting seizure onset in FLE is difficult. Most seizures are detectable because epileptic currents pass through brain areas that are involved in motor or language processing. Limbic seizures are difficult to study because the symptoms in these patients are usually related to alterations in motivational, social, and cognitive function (Csernansky et al., 1990; Levin and Duchowny, 1991). These subtle symptoms are sometimes difficult to detect unless the seizure activity spreads to other brain regions. The ACC is considered a part of the limbic cortex, and the ACC is one of the most difficult brain regions in which to detect seizure onset. This is because the ACC is not readily accessible for routine electrographic investigations using scalp electrodes (Quesney, 1986), and the close proximity between the right and left ACC also increases the difficulty in identifying where seizures actually initiate (Mazars, 1970; Geier et al., 1977; Nadkarni and Devinsky, 2009). Invasive electrodes only provide limited sampling. The dense venous drainage over the medial surface of the hemisphere hinders electrode placement in the ACC. Despite these limitations, clinical studies have provided insights into ACC function, and basic research has revealed the mechanism of epileptic synchronization and how ACC seizures are modulated. Cingulate epilepsy was first characterized and defined in 1970 using an intracerebral-depth electrode (Mazars, 1970) and such seizures are usually classified as simple partial (Nadkarni and Devinsky, 2009).

The ACC can be subdivided into affective and cognitive parts (Bush et al., 2000; Vogt, 2005). The affective part is connected to the periaqueductal gray, amygdala, anterior insula, and nucleus accumbens (Devinsky et al., 1995). The affective pathway is involved in endocrine and autonomic function (Critchley et al., 2005). The cognitive part is interconnected with the parietal cortex, lateral prefrontal cortex, and premotor and supplementary motor areas (Devinsky et al., 1995; Bush et al., 2000). Investigations of seizures can provide additional insights into brain function. The symptoms of ACC seizures are closely associated with interactions between the ACC and other brain regions.

In the pre-magnetic resonance imaging (MRI) era, clinical studies of ACC seizures were primarily retrospective. The data were obtained from patients with ACC seizures who underwent anterior cingulotomy. Patients who were free from seizures after anterior cingulotomy strongly suggested that the seizure originated in the ACC. With the invention of MRI, magneto encephalogram (MEG), intracranial electrodes, and single-photon emission computed tomography (CT), clinicians were able to more precisely locate the seizure onset in the ACC.

Cingulate epilepsies were first characterized by MRI and CT in 1970 (Mazars, 1970). In 1989, the International League Against Epilepsy included cingulate epilepsy as a type of FLE. The ACC epilepsy was classified as a type of FLE by ILAE in 1989. However, the term “ACC epilepsy” is controversial because the symptoms of ACC epilepsies may overlap with other types of FLE (Williamson et al., 2000). Some researchers have attempted to distinguish cingulate gyrus epilepsy from FLE by examining semiological patterns (Williamson et al., 2000). Other researchers considered that seizures caused by lesions in the cingulate cortex are more specific and can be classified as ACC seizures (Alkawadri et al., 2011).

Patients with ACC seizures fall into two categories: (1) patients with lesions in the ACC, which also includes cortical dysplasia in the ACC that causes focal seizures (Biraben et al., 2001; Nobili et al., 2007), and patients with ACC neoplasms, but this condition is quite rare (Zaatreh et al., 2002); (2) patients with no lesions in the ACC and a normal MRI that reveals only non-specific findings. Most focal ACC epilepsies are believed to be idiopathic and cryptogenic. Clinically, these lesional ACC seizures are often characterized by an early onset, drug resistance, and behavioral disturbances (Biraben et al., 2001; Zaatreh et al., 2002).

Anterior cingulate seizures have a broad range of clinical manifestations. The age of onset of ACC seizures is usually early in life (Williamson et al., 1985). However, ACC seizures may also start in adulthood. ACC seizures mostly occur during sleep and can be misdiagnosed as parasomnias. The common symptoms of ACC seizures include emotional outbursts. Autonomic symptoms are also common (Devinsky et al., 1995; Nadkarni and Devinsky, 2009). In adults, the aggressive features and psychotic symptoms of ACC seizure are overt, but a case report of young children showed intact intellect and normal behavioral ability (De Rose et al., 2009).

These clinical symptoms have been described as seizures that originate in the frontal lobe, and these symptoms are the hallmark of seizures that affect area 24. Despite clinical evidence that demonstrates that the ACC is involved in frontal lobe epileptic disorders, few basic research studies have reported the mechanism of seizure synchronization in the ACC.

There are clinical limitations on identifying seizure onset within ACC. Although an invasive depth and subdural electrodes increase spatial resolution in identifying seizure onset, they only provide limited sampling (Quesney, 1986; Quesney et al., 1992). Therefore, animals models are needed to conduct ACC epilepsy research. The first animal model of anterior cingulate seizure was established by (Andy and Chinn, 1957). Threshold and suprathreshold electrical stimulation of the ACC was used to induce epileptic afterdischarges in unanesthetized freely moving cats. The afterdischarges invariably propagated to the contralateral ACC. The propagation between the left and right ACC was faster than between the ACC and posterior cingulate gyrus. The propagation of the cingulate epileptic afterdischarges also passed through various brain structures, such as the sensory cortex basal ganglia, cerebellum, hypothalamus, and mesencephalic structure. Afterdischarges also propagated to the motor cortex but less frequently. Behavioral changes were minimal during cingulate gyrus afterdischarges and only one cat showed extremely aggressive behavior during afterdischarges (Andy and Chinn, 1957).

The kindling (i.e., motor seizure development) model was first established in rodents (Racine, 1975). Kindling in the ACC requires a mean of 11.6 s stimulation. The initial discharges in the frontal-cingulate regions were short in duration, with an average of 10.6 s. The seizures that arose from the ACC showed strong transhemispheric propagation. The electroencephalographic spike of the first afterdischarge was usually simple, with a frequency of 1–3 Hz in the ACC. Approximately 75% of the rodents with seizures that arose from cingulate kindling exhibited an immediate loss of postural control without rearing during the first and subsequent afterdischarges. Approximately 50% of the rodents exhibited these symptoms in the second to fourth afterdischarge. The behavioral seizure response was a mixture of both neocortical and limbic types (Racine, 1975).

Repetitive electrical stimulation of the ACC in baboons (Papio papio) also induced cingulate seizures. The symptoms that arose from ACC kindling had protracted non-convulsive seizure state features, such as flexion of the neck, widening of the eyelids, rapid bilateral spread, and eventually secondary generalization. Kindling of the ACC evolves into convulsive seizures after epileptiform activity propagates to the frontal central cortex. Focal epileptogenesis on one side of the ACC was shown to interfere with seizure development on the contralateral side (Wada and Tsuchimochi, 1995). These authors later showed that cingulate kindling can lead to the prolonged inhibition of kindling at a homotopic secondary site. This antiepileptic effect is not specific to primates because it was also shown to occur in cats. They also showed that the antiepileptic effect was not confined to the contralateral homotopic site, and the antiepileptic effect is presumably attributable to an enhanced intrinsic inhibitory mechanism in the mammalian brain (Wada and Hirayasu, 2004).

The basic synchronization mechanism of cingulate epileptiform activity has been studied in vitro (Panuccio et al., 2008a, 2009; Chang et al., 2011, 2013). The convulsant 4-aminopyridine (4-AP) induces epileptic discharges in humans (Lundh et al., 1984) and other mammals (Glover, 1982). In vitro studies showed that 4-AP could induce epileptic events in different brain regions, such as the cingulate cortex (Panuccio et al., 2009), amygdala (Klueva et al., 2003), and parahippocampal cortex (Avoli et al., 1996). 4-AP is a potassium channel blocker that affects A-type and D-type K⁺ currents (Ulbricht and Wagner, 1976; Storm, 1988). 4-AP-induced seizures are sensitive to anticonvulsants, and pharmacoresistant activity can be induced by combining the GABA_A receptor antagonist bicuculline with 4-AP (Bruckner et al., 1999). Bath application of 50 μM 4-AP in coronal ACC slices elicited epileptiform synchronization that was composed of interictal and ictal events. The glutamatergic system is involved in the epileptic synchronization of cingulate epilepsy. In a 4-AP-induced seizure model, bath application of the N-methyl-D-aspartate (NMDA) receptor antagonist CPP (10 μM) abolished ictal events but did not affect interictal events. Concomitant application of the AMPA/kainate receptor antagonist CNQX (10 μM) abolished ictal events and reduced the amplitude of interictal events (Panuccio et al., 2009). In a 4-AP + bicuculline-induced drug-resistant seizure model, the application of the NMDA receptor antagonist APV (50 μM) shortened the duration and amplitude of clonic phase discharge. Concomitant application of the AMPA/kainate receptor antagonist CNQX (20 μM) completely suppressed tonic- and clonic-phase seizures (Chang et al., 2011; Figure 1).

Application of the GABA_A and GABA_B receptor antagonists PTX (50 μM) and CGP55845 (4 μM), respectively, abolished ictal events induced by 4-AP and transformed the epileptiform activity into recurrent synchronous discharges. The results showed that GABA_A transmission contributed to the synchronization of epileptic discharges in the ACC (Panuccio et al., 2009). The paradoxical GABA-mediated excitatory mechanism may result from a shift of GABA_A receptor reversal potential (Staley and Proctor, 1999) or a transient increase in [K⁺]₀, which in turn enhances synchronization through a synaptic or non-synaptic mechanism (Avoli et al., 1996; Kohling et al., 2000; Gigout et al., 2006). The synchronization of ACC seizures is also mediated by gap junctions (Panuccio et al., 2008a; Chang et al., 2013). The application of a gap junction blocker significantly decreased the amplitude and duration of epileptiform activity. Epileptic synchronization in the ACC is also subjected to opioid modulation. Application of 10 μM DAGO significantly abolished ictal discharges induced by 4-AP (Panuccio et al., 2009).

In cortical areas, the lateral propagation of electrical activity is under tight control because unrestrained, laterally propagated electrical activity easily leads to epileptiform activity. Epileptiform activity in neocortical areas is restrained by surrounding inhibition (Prince, 1967), and a decrease in surrounding inhibition causes the spread of epileptiform activity (Pinto et al., 2005). The development of interneurons in the ACC was altered in mice with targeted mutation of the gene that encodes urokinase plasminogen activator receptor (μPAR). The ACC and parietal cortical areas showed 50% fewer GABAergic interneurons in a μPAR^-/- mouse strain compared with wildtype littermates. The numbers of interneurons in other cortical areas did not differ from wildtype mice. The μPAR^-/- strain displayed spontaneous seizures and a lower seizure threshold when challenged with pentylenetetrazol (Powell et al., 2003). Although seizure onset was not determined, the μPAR^-/- strain may serve as an animal model for investigating the importance of GABAergic interneurons in ACC seizures.

Epileptiform activity that initiates in the ACC showed strong trans-hemispheric propagation. To test whether left and right ACC epileptic discharges synchronize through the corpus callosum, a modified slice cutting method was established to preserve the corpus callosum between the left and right ACC (Walker et al., 2012). Seizure-like activity could be induced by the bath or local application of bicuculline and in a zero-magnesium solution. Seizure-like activity could be regulated by the corpus callosum, demonstrated by an incision of the callosum in vitro. An incision of the callosum diminished bilateral propagation. Interestingly, patch-clamp recordings showed that inhibitory postsynaptic currents (IPSCs) were increased by the focal application of bicuculline in the contralateral ACC. No GABAergic projection was found between the left and right ACC, and the authors concluded that the callosal projection has a strong effect on local GABAergic interneurons (Walker et al., 2012).

Most ACC seizures in clinical cases result from lesions. The remainder of ACC seizures are sporadic, and the pathophysiological mechanisms appear to be similar to those affect the cerebral cortex. Cortical epilepsies can result from extracellular ionic fluctuations (Taylor and Dudek, 1982), the dysfunction of energy metabolism (Cavus et al., 2005), channelopathies (Kullmann, 2002), and alterations in transmitter uptake (Chapman, 1998; Rainesalo et al., 2004). Although the pathophysiological mechanisms may have major differences, the outcome of the hypersynchronous bursting of cortical neurons and the concomitant phenotype are similar if the same brain regions are involved.

Clinical electroencephalographic and functional MRI (fMRI) data suggest that autosomal-dominant frontal lobe epilepsy (ADFLE) may have a mesial frontal origin (So, 1998). ADFLE often involves complex motor movements and vocalizations. The gene loci that encode the nicotinic acetylcholine receptor α and β subunits CHRNA4, CHRNB2, and CHRNA2 are involved in ADFLE (Steinlein et al., 1995; Bertrand et al., 1998; De Fusco et al., 2000). Two mouse strains that carry mutant alleles of the α4 subunit of the nicotinic acetylcholine receptor display spontaneous seizures. In vitro recordings of neocortical pyramidal neurons showed that nicotine-evoked GABAergic inhibition is significantly increased. Spontaneous seizures could be blocked by the application of a low dose of the GABA_A receptor antagonist picrotoxin. These results suggest that excessive GABAergic transmission is involved in the epileptogenesis of ACC seizures. Epilepsy that occurs in the ACC may be attributable to enhanced GABAergic function (Engel, 1996; Mann and Mody, 2008; Panuccio et al., 2008b). The application of the GABA_A receptor antagonist picrotoxin inhibited epileptic discharges (Klaassen et al., 2006). The possible mechanisms of GABAergic inhibition that contribute to epileptogenesis include the resetting of synchronization (Klaassen et al., 2006), the direct excitatory effects of axo-axonic interneurons in layer II/III pyramidal cells (Szabadics et al., 2006), or changes in GABA reversal potential (Marty and Llano, 2005).

The dysregulation of interneuron development might also contribute to abnormal epileptic discharges (Levitt et al., 2004). The μPAR^-/- mouse strain exhibited a specific reduction of parvalbumin-positive interneurons in the ACC and parietal cortex and displayed spontaneous seizures. Previous studies showed that the hypersynchrony of GABAergic transmission is involved in ACC seizures (Panuccio et al., 2009). These results indicate that the balance between excitatory and inhibitory transmission is very important in seizure control, and the dysregulation of GABAergic transmission is one of the factors of the epileptogenesis of ACC seizures.

The synchronization mechanism of ACC epileptic discharges is largely attributable to the dysregulation of interneuronal networks. Spontaneous seizures are caused by excessive GABAergic transmission, such as in the case of the ADFLE and 4-AP-induced epilepsy models. The reduction of GABAergic transmission in the ACC might also cause seizures, such as the spontaneous seizures found in the μPAR^-/- mouse strain. To fully understand the role of inhibitory interneurons in ACC seizures, one must precisely control the activity of interneuronal networks by either enhancing or suppressing interneurons. Based on the basic research, the ACC seizure could be modulated by gap junction. Application of gap junction uncoupler decrease the duration of seizure-like activities, while gap coupler enhance seizures. The μ-opioid receptors are also involved in the pathogenesis of ACC seizure, as μ-opioid agonist DAMGO reduced the ictal discharge. The ACC seizure is also subjected to the modulation by thalamic inputs. Removing or inactivating thalamus enhanced seizure-like activities in ACC.

To fully understand the role of inhibitory interneurons in ACC seizures, one must precisely control the activity of interneuronal networks by either enhancing or suppressing interneurons. Optogenetics is the integration of optics and genetics to allow the expression of light-sensitive channels, such as channel rhodopsin-2 (ChR2) and Halorhodopsin from Natronomonas (NpHR) in certain groups of neurons (Nagel et al., 2003; Boyden et al., 2005; Zhang et al., 2006). Using blue light to activate ChR2 can trigger action potentials in neurons. Using yellow light to activate NpHR can hyperpolarize neurons. Many knock-in mouse lines are available to specifically and robustly increase the Cre-dependent expression of ChR2 and other light-sensitive proteins (Madisen et al., 2012). By combining hundreds of available Cre lines, ChR2 or NpHR can be expressed in different subtypes of interneurons, and these knock-in mice will facilitate investigations of the function of neural circuits with high fidelity and accuracy.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.