Comparison of monkey and human retrosplenial neurocytology.

Retrosplenial cortex (RSC) has unique problems for human neuroimaging studies as its divisions are small, at the lower end of functional scanner spatial resolution, and it is buried in the callosal sulcus. The present study sought to define the cytoarchitecture of RSC in human and monkey brains along its entire anteroposterior extent. The results show anterior extensions, a newly defined dichotomy of area 30, a new area p30, and an area p29v in monkey that differentiates into three divisions in human. Accordingly, anterior (a), intermediate (i), and posterior (p) divisions of areas 29l, 29m, 30l, and 30m were identified. Posterior area 29 has higher neuron packing in the granular layer than anterior and intermediate divisions of area 29. A newly detected dysgranular area p30 has larger neurons in layers II-IIIab than a30 and i30 and with substantially higher NFP expression  in layer IIIab of posterior areas than areas a30 and i30. Medial area 30 has larger pyramids and higher NFP expression in all layers than area 30l. The new area p30 was seen between areas p29m and p30I in both species. Finally, a ventral area p29v is present in monkeys. This latter area appears to differentiate into three divisions in human with the most extensive granular layer adjacent to layer I in p29vm and p29vl. Functional imaging has identified pRSC as part of a cognitive map which is engaged in spatial navigation and localization of personally relevant objects.

Structural Degradation in Midcingulate Cortex Is Associated with Pathological Aggression in Mice.

Pathological aggression is a debilitating feature of many neuropsychiatric disorders, and cingulate cortex is one of the brain areas centrally implicated in its control. Here we explore the specific role of midcingulate cortex (MCC) in the development of pathological aggression. To this end, we investigated the structural and functional degeneration of MCC in the BALB/cJ strain, a mouse model for pathological aggression. Compared to control animals from the BALB/cByJ strain, BALB/cJ mice expressed consistently heightened levels of aggression, as assessed by the resident-intruder test. At the same time, immunohistochemistry demonstrated stark structural degradation in the MCC of aggressive BALB/cJ mice: Decreased neuron density and widespread neuron death were accompanied by increased microglia and astroglia concentrations and reactive astrogliosis. cFos staining indicated that this degradation had functional consequences: MCC activity did not differ between BALB/cJ and BALB/cByJ mice at baseline, but unlike BALB/cByJ mice, BALB/cJ mice failed to activate MCC during resident-intruder encounters. This suggests that structural and functional impairments of MCC, triggered by neuronal degeneration, may be one of the drivers of pathological aggression in mice, highlighting MCC as a potential key area for pathologies of aggression in humans.

A central role for anterior cingulate cortex in the control of pathological aggression.

Controlling aggression is a crucial skill in social species like rodents and humans and has been associated with anterior cingulate cortex (ACC). Here, we directly link the failed regulation of aggression in BALB/cJ mice to ACC hypofunction. We first show that ACC in BALB/cJ mice is structurally degraded: neuron density is decreased, with pervasive neuron death and reactive astroglia. Gene-set enrichment analysis suggested that this process is driven by neuronal degeneration, which then triggers toxic astrogliosis. cFos expression across ACC indicated functional consequences: during aggressive encounters, ACC was engaged in control mice, but not BALB/cJ mice. Chemogenetically activating ACC during aggressive encounters drastically suppressed pathological aggression but left species-typical aggression intact. The network effects of our chemogenetic perturbation suggest that this behavioral rescue is mediated by suppression of amygdala and hypothalamus and activation of mediodorsal thalamus. Together, these findings highlight the central role of ACC in curbing pathological aggression.

Where is Cingulate Cortex? A Cross-Species View.

To compare findings across species, neuroscience relies on cross-species homologies, particularly in terms of brain areas. For cingulate cortex, a structure implicated in behavioural adaptation and control, a homologous definition across mammals is available - but currently not employed by most rodent researchers. The standard partitioning of rodent cingulate cortex is inconsistent with that in any other model species, including humans. Reviewing the existing literature, we show that the homologous definition better aligns results of rodent studies with those of other species, and reveals a clearer structural and functional organisation within rodent cingulate cortex itself. Based on these insights, we call for widespread adoption of the homologous nomenclature, and reinterpretation of previous studies originally based on the nonhomologous partitioning of rodent cingulate cortex.

Cingulate cortex in Parkinson's disease.

Once a diagnosis of Parkinson's disease (PD) has been made, even in its earliest prodromal form of subjective memory impairment, cognitive impairment has begun and involves anterior cingulate cortex (ACC). While the Braak staging scheme showed mid- to later-stage PD progression from cingulate allocortex adjacent to the corpus callosum and progressing into its neocortical moieties, the last decade has produced substantial information on the role of cingulate cortex in multiple symptoms, not just global measures of cognition. Voxel-based morphometry has been used in many studies of mild cognitive impairment (MCI) in PD to show reduced thickness in ACC and posterior cingulate cortex (PCC). Regional cerebral blood flow is altered in association with verbal IQ in all the PCC and anterior midcingulate cortex and executive impairments in ACC. Diffusion tensor imaging shows reduced fractional anisotropy throughout the entire cingulum bundle. Amnestic MCI is associated with reduced dopamine-2 receptor binding in ACC and, even in cognitively normal PD cases, dopaminergic pathways in ACC are impaired early in association with executive and language functions. The cholinergic system also has substantial changes in nicotinic and muscarinic receptor binding, and therapy with donepezil improves Mini-Mental State Exam scores and metabolism in pACC and dPCC. Cingulate cortex is also engaged in two critical symptoms: apathy and visual hallucinations. Finally, one can be optimistic that cingulate cortex will play an important role in developing new biomarkers of early PD. These methods have already been shown to be useful in cingulate cortex and include magnetic resonance spectroscopy, next-generation gene expression, and the new α-synuclein proximity ligation assay that specifically recognizes α-synuclein oligomers. Thus the future is bright for developing multivariate, multimodal biomarkers that include cingulate cortex.

Cingulate impairments in ADHD: Comorbidities, connections, and treatment.

The entire cingulate cortex is engaged in the structure/function abnormalities found in attention-deficit/hyperactivity disorder (ADHD). In ADHD, which is the most common developmental disease, impaired impulse control and cognition often trace to anterior midcingulate cortex (aMCC) in Go/No-go tests, decoding and reading, the Stroop Color and Word Test, and the Wisconsin Card Sorting Test (WCST), with volume deficits in anterior cingulate cortex (ACC) and posterior midcingulate cortex (pMCC). Volumes in pMCC correlate positively with the WCST and negatively with total and nonperseverative errors on the WCST. Activation and connectivity on N-back tests show connections for high and low spatial working memory, but patients have increased activation in PCC and decreased connectivity between MCC and PCC for high load. Students struggle in class due to malfunctioning aMCC, pregenual anterior cingulate cortex (pACC), and dorsal posterior cingulate cortex (dPCC), and to core deficits in response/task switching in aMCC. Gene mutations are found in the DA transporter and DA4 and DA5 receptors. Methylphenidate decreases hyperactivity in aMCC. The DA system is controlled by cholinergic receptors in the daMCC and genetics show nAChR mutations in alpha 3, 4, and 7 receptors. At 25 years, a modified Eriksen flanker/No-go task and voxel-based morphometry (VBM) show prenatal smoking, lifetime smoking at 13 years, and novelty seeking. Prenatal exposure to nicotine exhibits weaker responses in aMCC during cognitive tasks for hyperactivity/impulsiveness but not inattention. AZD1446 (ɑ4ß2 nAChR agonist) improves the Groton Maze task due to high nAChR in dPCC/RSC engaged in spatial orientation. Environmental factors associated with childhood ADHD relate to pesticides, organochlorine, and air pollutants. Network connection segregation shows increased amygdala local nodal, but decreased ACC and PCC connections, reflecting emphasis on local periamygdala connections at the expense of cortical connections. Thus, ADHD children/adolescents respond impulsively to the significance of stimuli without having cortical inhibition. Finally, controls show negative relationships between aMCC and the default mode network, and ADHD compromises this relationship, showing decreased connectivity between ACC and precuneus/PCC.

The cingulate cortex in neurologic diseases: History, Structure, Overview.

A brief review of the history of key observations of cingulate organization, particularly in the limbic system framework, is presented from 1907 to the present. The reasons why it has not played a significant role in neurology reflect the fact that its arterial supply is complex and no cingulate syndrome has been identified. A flat map of its eight subregions and areas is presented as a basis for many subsequent chapters in this volume. Along with this is a summary of current functional attributes of many of its divisions including cognitive, emotion, mental (Theory of Mind), skeletomotor, and autonomic output and various models of its function based on connectivity studies.

Cingulate cortex in the three limbic subsystems.

Broca's (1878) definition of the limbic lobe referred to its being located at the edge of the cerebral cortex, and Papez (1937) and MacLean (1990) welded a series of medial surface structures into what we now know as the limbic system. The last four decades of research have provided a wealth of detailed information on the connectivity and functions of the limbic system and one can only conclude that it is not a uniform and single system. The cingulate cortex itself has three major divisions: anterior primarily for emotion, middle mainly for response selection and feedback-guided decision making, and posterior/retrosplenial cortices for visuospatial orientation and assessing the self-relevance of objects and events. Each of these divisions has a different cytoarchitecture and set of connections. The cingulate observations lead to a new framework of limbic organization: three limbic subsystems that include the amygdala, orbitofrontal cortex, the insula, the hippocampus, and, of course, the cingulate cortex. This concept is expanded in terms of connectivity among them and the underlying functions of each subsystem. The three limbic subsystems considered here are the "anterior emotional subsystem," the "middle sensorimotor subsystem," and the "posterior cognitive spatial map subsystem" for localizing personally relevant objects and episodes. A defining characteristic of the anterior emotional subsystem is its input from the amygdala. Another interesting outcome of this analysis is that the middle hippocampus and anterior midcingulate cortex share a role in approach-avoidance decision making suggesting a potential for connectional synergy. Thus, the concept of "a" limbic system needs radical revision to accommodate a minimum of three limbic subsystems. As this approach was initiated by the three-part composition of the cingulate cortex, a finer-grain analysis of the cingulate region shows that six limbic subsystems may be a more accurate reflection of limbic organization.

A nociceptive stress model of adolescent physical abuse induces contextual fear and cingulate nociceptive neuroplasticities.

Adolescent physical abuse impairs emotional development and evokes cingulate pathologies, but its neuronal and circuit substrates are unknown. Conditioning adolescent rabbits with noxious colorectal distension for only 2 h over 3 weeks simulated the human child abuse in amplitude, frequency, and duration. Thermal withdrawal thresholds were unchanged suggesting that sensitized spinal mechanisms may not be operable. Unchanged weight, stools, colorectal histology, and no evidence of abdominal pain argue against tissue injury or irritable bowel syndrome. Contextual fear was amplified as they avoided the site of their abuse. Conditioning impacted anterior cingulate and anterior midcingulate (ACC, aMCC) neuron excitability: (1) more neurons responded to cutaneous and visceral (VNox) noxious stimuli than controls engaging latent nociception (present but not manifest in controls). (2) Rear paw stimulation increased responses over forepaws with shorter onsets and longer durations, while forepaw responses were of higher amplitude. (3) There were more VNox responses with two excitatory phases and longer durations. (4) Some had unique three-phase excitatory responses. (5) Long-duration VNox stimuli did not inhibit neurons as in controls, suggesting the release of an inhibitory circuit. (6) aMCC changes in cutaneous but not visceral nociception confirmed its role in cutaneous nociception. For the first time, we report neuroplasticities that may be evoked by adolescent physical abuse and reflect psychogenic pain: i.e., no ongoing peripheral pain and altered ACC nociception. These limbic responses may be a cognitive trace of abuse and may shed light on impaired human emotional development and sexual function.

Midcingulate cortex: Structure, connections, homologies, functions and diseases.

Midcingulate cortex (MCC) has risen in prominence as human imaging identifies unique structural and functional activity therein and this is the first review of its structure, connections, functions and disease vulnerabilities. The MCC has two divisions (anterior, aMCC and posterior, pMCC) that represent functional units and the cytoarchitecture, connections and neurocytology of each is shown with immunohistochemistry and receptor binding. The MCC is not a division of anterior cingulate cortex (ACC) and the "dorsal ACC" designation is a misnomer as it incorrectly implies that MCC is a division of ACC. Interpretation of findings among species and developing models of human diseases requires detailed comparative studies which is shown here for five species with flat maps and immunohistochemistry (human, monkey, rabbit, rat, mouse). The largest neurons in human cingulate cortex are in layer Vb of area 24 d in pMCC which project to the spinal cord. This area is part of the caudal cingulate premotor area which is involved in multisensory orientation of the head and body in space and neuron responses are tuned for the force and direction of movement. In contrast, the rostral cingulate premotor area in aMCC is involved in action-reinforcement associations and selection based on the amount of reward or aversive properties of a potential movement. The aMCC is activated by nociceptive information from the midline, mediodorsal and intralaminar thalamic nuclei which evoke fear and mediates nocifensive behaviors. This subregion also has high dopaminergic afferents and high dopamine-1 receptor binding and is engaged in reward processes. Opposing pain/avoidance and reward/approach functions are selected by assessment of potential outcomes and error detection according to feedback-mediated, decision making. Parietal afferents differentially terminate in MCC and provide for multisensory control in an eye- and head-centric manner. Finally, MCC vulnerability in human disease confirms the unique organization of MCC and supports the predictive validity of the MCC dichotomy. Vulnerability of aMCC is shown in chronic pain, obsessive-compulsive disorder with checking symptoms and attention-deficit/hyperactivity disorder and methylphenidate and pain medications selectively impact aMCC. In contrast, pMCC vulnerabilities are for progressive supranuclear palsy, unipolar depression and posttraumatic stress disorder. Thus, there is an emerging picture of the organization, functions and diseases of MCC. Future work will take this type of modular analysis to individual areas of which there are at least 10 in MCC.

Cytoarchitecture and neurocytology of rabbit cingulate cortex.

The rabbit cingulate cortex is highly differentiated in contrast to rodents and numerous recent advances suggest the rabbit area map needs revision. Immunohistochemistry was used to assess cytoarchitecture with neuron-specific nuclear binding protein (NeuN) and neurocytology with intermediate neurofilament proteins, parvalbumin and glutamic acid decarboxylase. Key findings include: (1) Anterior cingulate cortex (ACC) area 32 has dorsal and ventral divisions. (2) Area 33 is part of ACC. (3) Midcingulate cortex (MCC) has anterior and posterior divisions and this was verified with extensive quantitative analysis and a horizontal series of sections. (4) NeuN, also known as Fox-3, is not limited to somata and formed nodules, granular clusters and striations in the apical dendrites of pyramidal neurons. (5) Area 30 forms a complex of anterior and posterior parts with further medial and lateral divisions. (6) Area 29b has two divisions and occupies substantially more volume than in rat. (7) Area 29a begins with a subsplenial component and extends relatively further caudal than in rat. As similar areal designations are often used among species, direct comparisons were made of rabbit areas with those in rat and monkey. The dichotomy of MCC is of particular interest to studies of pain as anterior MCC is most frequently activated in human acute pain studies and the rabbit can be used to study this subregion. Finally, the area 30 complex is not primarily dysgranular as in rat and is more differentiated than in any other mammal including human. The large and highly differentiated rabbit cingulate cortex provides a unique model for assessing cingulate cortex, pain processing and RNA splicing functions.

Functional organization of human subgenual cortical areas: Relationship between architectonical segregation and connectional heterogeneity.

Human subgenual anterior cingulate cortex (sACC) is involved in affective experiences and fear processing. Functional neuroimaging studies view it as a homogeneous cortical entity. However, sACC comprises several distinct cyto- and receptorarchitectonical areas: 25, s24, s32, and the ventral portion of area 33. Thus, we hypothesized that the areas may also be connectionally and functionally distinct. We performed structural post mortem and functional in vivo analyses. We computed probabilistic maps of each area based on cytoarchitectonical analysis of ten post mortem brains. Maps, publicly available via the JuBrain atlas and the Anatomy Toolbox, were used to define seed regions of task-dependent functional connectivity profiles and quantitative functional decoding. sACC areas presented distinct co-activation patterns within widespread networks encompassing cortical and subcortical regions. They shared common functional domains related to emotion, perception and cognition. A more specific analysis of these domains revealed an association of s24 with sadness, and of s32 with fear processing. Both areas were activated during taste evaluation, and co-activated with the amygdala, a key node of the affective network. s32 co-activated with areas of the executive control network, and was associated with tasks probing cognition in which stimuli did not have an emotional component. Area 33 was activated by painful stimuli, and co-activated with areas of the sensorimotor network. These results support the concept of a connectional and functional specificity of the cyto- and receptorarchitectonically defined areas within the sACC, which can no longer be seen as a structurally and functionally homogeneous brain region.

Subspecialization in the human posterior medial cortex.

The posterior medial cortex (PMC) is particularly poorly understood. Its neural activity changes have been related to highly disparate mental processes. We therefore investigated PMC properties with a data-driven exploratory approach. First, we subdivided the PMC by whole-brain coactivation profiles. Second, functional connectivity of the ensuing PMC regions was compared by task-constrained meta-analytic coactivation mapping (MACM) and task-unconstrained resting-state correlations (RSFC). Third, PMC regions were functionally described by forward/reverse functional inference. A precuneal cluster was mostly connected to the intraparietal sulcus, frontal eye fields, and right temporo-parietal junction; associated with attention and motor tasks. A ventral posterior cingulate cortex (PCC) cluster was mostly connected to the ventromedial prefrontal cortex and middle left inferior parietal cortex (IPC); associated with facial appraisal and language tasks. A dorsal PCC cluster was mostly connected to the dorsomedial prefrontal cortex, anterior/posterior IPC, posterior midcingulate cortex, and left dorsolateral prefrontal cortex; associated with delay discounting. A cluster in the retrosplenial cortex was mostly connected to the anterior thalamus and hippocampus. Furthermore, all PMC clusters were congruently coupled with the default mode network according to task-unconstrained but not task-constrained connectivity. We thus identified distinct regions in the PMC and characterized their neural networks and functional implications.

Cytoarchitecture of mouse and rat cingulate cortex with human homologies.

A gulf exists between cingulate area designations in human neurocytology and those used in rodent brain atlases with a major underpinning of the former being midcingulate cortex (MCC). The present study used images extracted from the Franklin and Paxinos mouse atlas and Paxinos and Watson rat atlas to demonstrate areas comprising MCC and modifications of anterior cingulate (ACC) and retrosplenial cortices. The laminar architecture not available in the atlases is also provided for each cingulate area. Both mouse and rat have a MCC with neurons in all layers that are larger than in ACC and layer Va has particularly prominent neurons and reduced neuron densities. An undifferentiated ACC area 33 lies along the rostral callosal sulcus in rat but not in mouse and area 32 has dorsal and ventral subdivisions with the former having particularly large pyramidal neurons in layer Vb. Both mouse and rat have anterior and posterior divisions of retrosplenial areas 29c and 30, although their cytology is different in rat and mouse. Maps of the rodent cingulate cortices provide for direct comparisons with each region in the human including MCC and it is significant that rodents do not have a posterior cingulate region composed of areas 23 and 31 like the human. It is concluded that rodents and primates, including humans, possess a MCC and this homology along with those in ACC and retrosplenial cortices permit scientists inspired by human considerations to test hypotheses on rodent models of human diseases.

Cingulate area 32 homologies in mouse, rat, macaque and human: cytoarchitecture and receptor architecture.

Homologizing between human and nonhuman area 32 has been impaired since Brodmann said he could not homologize with certainty human area 32 to a specific cortical domain in other species. Human area 32 has four divisions, however, and two can be structurally homologized to nonhuman species with cytoarchitecture and receptor architecture: pregenual (p32) and subgenual (s32) in human and macaque monkey and areas d32 and v32 in rat and mouse. Cytoarchitecture showed that areas d32/p32 have a dysgranular layer IV in all species and that areas v32/s32 have large and dense neurons in layer V, whereas a layer IV is not present in area v32. Areas v32/s32 have the largest neurons in layer Va. Features unique to humans include large layer IIIc pyramids in both divisions, sparse layer Vb in area p32, and elongated neurons in layer VI, with area s32 having the largest layer Va neurons. Receptor fingerprints of both subdivisions of area 32 differed between species in size and shape, although AMPA/GABAA and NMDA/GABAA ratios were comparable among humans, monkeys, and rats and were significantly lower than in mice. Layers I-III of primate and rodent area 32 subdivisions share more similarities in their receptor densities than layers IV-VI. Monkey and human subdivisions of area 32 are more similar to each other than to rat and mouse subdivisions. In combination with intracingulate connections, the location, cytoarchitecture, and ligand binding studies demonstrate critical homologies among the four species.

Cyto- and receptor architecture of area 32 in human and macaque brains.

Human area 32 plays crucial roles in emotion and memory consolidation. It has subgenual (s32), pregenual (p32), dorsal, and midcingulate components. We seek to determine whether macaque area 32 has subgenual and pregenual subdivisions and the extent to which they are comparable to those in humans by means of NeuN immunohistochemistry and multireceptor analysis of laminar profiles. The macaque has areas s32 and p32. In s32, layer IIIa/b neurons are larger than those of layer IIIc. This relationship is reversed in p32. Layer Va is thicker and Vb thinner in s32. Area p32 contains higher kainate, benzodiazepine (BZ), and serotonin (5-HT)1A but lower N-methyl-D-aspartate (NMDA) and α2 receptor densities. Most differences were found in layers I, II, and VI. Together, these differences support the dual nature of macaque area 32. Comparative analysis of human and macaque s32 and p32 supports equivalences in cyto- and receptor architecture. Although there are differences in mean areal receptor densities, there are considerable similarities at the layer level. Laminar receptor distribution patterns in each area are comparable in the two species in layers III-Va for kainate, NMDA, γ-aminobutyric acid (GABA)B , BZ, and 5-HT1A receptors. Multivariate statistical analysis of laminar receptor densities revealed that human s32 is more similar to macaque s32 and p32 than to human p32. Thus, macaque 32 is more complex than hitherto known. Our data suggest a homologous neural architecture in anterior cingulate s32 and p32 in human and macaque brains.

Social context induces two unique patterns of c-Fos expression in adolescent and adult rats.

The study assessed possible age differences in brain activation patterns to low dose ethanol (.5 g/kg intraperitoneally) and the influence of social context on this activation. Early adolescent or young adult male Sprague-Dawley rats were placed either alone or with an unfamiliar partner of the same age and sex following saline or ethanol administration. c-Fos protein immunoreactivity was used to index neuronal activation in 15 regions of interest. Ethanol had little effect on c-Fos activation. In adolescents, social context activated an "autonomic" network including the basolateral and central amygdala, bed nucleus of the stria terminalis, lateral hypothalamus, and lateral septum. In contrast, when adult rats were alone, activation was evident in a "reward" network that included the substantia nigra, nucleus accumbens, anterior cingulate and orbitofrontal cortices, lateral parabrachial nucleus, and locus coeruleus.

Spatiotemporal organization and thalamic modulation of seizures in the mouse medial thalamic-anterior cingulate slice.

PURPOSE: Seizure-like activities generated in anterior cingulate cortex (ACC) are usually classified as simple partial and are associated with changes in autonomic function, motivation, and thought. Previous studies have shown that thalamic inputs can modulate ACC seizure, but the exact mechanisms have not been studied thoroughly. Therefore, we investigated the role of thalamic inputs in modulating ACC seizure-like activities. In addition, seizure onset and propagation are difficult to determine in vivo in ACC. We studied the spatiotemporal changes in epileptiform activity in this cortex in a thalamic-ACC slice to clearly determine seizure onset. METHODS: We used multielectrode array (MEA) recording and calcium imaging to investigate the modulatory effect of thalamic inputs in a thalamic-ACC slice preparation. KEY FINDINGS: Seizure-like activities induced with 4-aminopyridine (4-AP; 250 µm) and bicuculline (5-50 µm) in ACC were attenuated by glutamate receptor antagonists, and the degree of disinhibition varied with the dose of bicuculline. Seizure-like activities were decreased with 1 Hz thalamic stimulation, whereas corpus callosum stimulation could increase ictal discharges. Amplitude and duration of cingulate seizure-like activities were augmented after removing thalamic inputs, and this effect was not observed with those induced with elevated bicuculline (50 µm). Seizure-like activities were initiated in layers II/III and, after thalamic lesions, they occurred mainly in layers V/VI. Two-dimensional current-source density analyses revealed sink signals more frequently in layers V/VI after thalamic lesions, indicating that these layers produce larger excitatory synchronization. Calcium transients were synchronized after thalamic lesions suggesting that ACC seizure-like activities are subjected to desynchronizing modulation by thalamic inputs. Therefore, ACC seizure-like activities are subject to desynchronizing modulation from medial thalamic inputs to deep layer pyramidal neurons. SIGNIFICANCE: Cingulate seizure-like activities were modulated significantly by thalamic inputs. Repeated stimulation of the thalamus efficiently inhibited epileptiform activity, demonstrating that the desynchronization was pathway-specific. The clinical implications of deep thalamic stimulation in the modulation of cingulate epileptic activity require further investigation.