To define further the electroclinical manifestations of frontal lobe epilepsy (FLE), we studied 150 seizures manifested by 24 patients; 18 patients had subdural electrode arrays (SEA). The findings in these patients clearly overlapped presumably reflecting the interconnections between functionally related frontal zones; yet the manner in which the symptoms clustered and the sequence in which they occurred generally indicated the anatomic site of the epileptogenic zone. We divided the patients into three major groups: (a) those with supplementary motor seizures, (b) those with focal motor seizures, and (c) those with complex partial seizures (CPS, psychomotor seizures). Supplementary motor seizures began with tonic posturing of the extremities. Focal motor seizures generally began with conscious contralateral version or unilateral clonic focal motor activity; tonic posturing was noted only late in the seizure. CPS (psychomotor) began with unresponsiveness at onset, followed by staring or unconscious contraversion. We compared frontal lobe seizures with temporal lobe seizures reported previously; oral-alimentary automatisms, repetitive hand movements, or looking around, were more common in temporal lobe seizures, whereas tonic posturing and bicycling movements were more common in frontal lobe psychomotor seizures.

Examination of associations between specific disorders and physical properties of functionally relevant frontal lobe sub-regions is a fundamental goal in neuropsychiatry. Here, we present and evaluate automated methods of frontal lobe parcellation with the programs FreeSurfer(FS) and TOADS-CRUISE(T-C), based on the manual method described in Ranta et al. [2009]: Psychiatry Res 172:147-154 in which sulcal-gyral landmarks were used to manually delimit functionally relevant regions within the frontal lobe: i.e., primary motor cortex, anterior cingulate, deep white matter, premotor cortex regions (supplementary motor complex, frontal eye field, and lateral premotor cortex) and prefrontal cortex (PFC) regions (medial PFC, dorsolateral PFC, inferior PFC, lateral orbitofrontal cortex [OFC] and medial OFC). Dice's coefficient, a measure of overlap, and percent volume difference were used to measure the reliability between manual and automated delineations for each frontal lobe region. For FS, mean Dice's coefficient for all regions was 0.75 and percent volume difference was 21.2%. For T-C the mean Dice's coefficient was 0.77 and the mean percent volume difference for all regions was 20.2%. These results, along with a high degree of agreement between the two automated methods (mean Dice's coefficient = 0.81, percent volume difference = 12.4%) and a proof-of-principle group difference analysis that highlights the consistency and sensitivity of the automated methods, indicate that the automated methods are valid techniques for parcellation of the frontal lobe into functionally relevant sub-regions. Thus, the methodology has the potential to increase efficiency, statistical power and reproducibility for population analyses of neuropsychiatric disorders with hypothesized frontal lobe contributions.

Concepts from cognitive neuroscience strongly suggest that the prefrontal cortex (PFC) plays a crucial role in the cognitive functions necessary for creative thinking. Functional imaging studies have repeatedly demonstrated the involvement of PFC in creativity tasks. Patient studies have demonstrated that frontal damage due to focal lesions or neurodegenerative diseases are associated with impairments in various creativity tasks. However, against all odds, a series of clinical observations has reported the facilitation of artistic production in patients with neurodegenerative diseases affecting PFC, such as frontotemporal dementia (FTD). An exacerbation of creativity in frontal diseases would challenge neuroimaging findings in controls and patients, as well as the theoretical role of prefrontal functions in creativity processes. To explore this paradox, we reported the history of a FTD patient who exhibited the emergence of visual artistic productions during the course of the disease. The patient produced a large amount of drawings, which have been evaluated by a group of professional artists who were blind to the diagnosis. We also reviewed the published clinical cases reporting a change in the artistic abilities in patients with neurological diseases. We attempted to reconcile these clinical observations to previous experimental findings by addressing several questions raised by our review. For instance, to what extent can the cognitive, conative, and affective changes following frontal damage explain changes in artistic abilities? Does artistic exacerbation truly reflect increased creative capacities? These considerations could help to clarify the place of creativity-as it has been defined and explored by cognitive neuroscience-in artistic creation and may provide leads for future lesion studies.

Analysis of FDG-PET imaging commonly shows that hypometabolism extends into extra-epileptogenic zones (extra-EZ). This study investigates the distribution patterns of hypometabolism in frontal lobe epilepsy (FLE) originating in different frontal regions.

The frontal aslant tract (FAT) is a white-matter tract connecting the inferior frontal gyrus (IFG) and the supplementary motor complex (SMC). Damage to either component of the network causes spontaneous speech dysfluency, indicating its critical role in language production. However, spontaneous speech dysfluency may stem from various lower-level linguistic deficits, precluding inferences about the nature of linguistic processing subserved by the IFG-SMC network. Since the IFG and the SMC are attributed a role in conceptual and lexical selection during language production, we hypothesized that these processes rely on the IFG-SMC connectivity via the FAT. We analysed the effects of FAT volume on conceptual and lexical selection measures following frontal lobe stroke. The measures were obtained from the sentence completion task, tapping into conceptual and lexical selection, and the picture-word interference task, providing a more specific measure of lexical selection. Lower FAT volume was not associated with lower conceptual or lexical selection abilities in our patient cohort. Current findings stand in marked discrepancy with previous lesion and neuroimaging evidence for the joint contribution of the IFG and the SMC to lexical and conceptual selection. A plausible explanation reconciling this discrepancy is that the IFG-SMC connectivity via the FAT does contribute to conceptual and/or lexical selection but its disrupted function undergoes reorganisation over the course of post-stroke recovery. Thus, our negative findings stress the importance of testing the causal role of the FAT in lexical and conceptual selection in patients with more acute frontal lobe lesions.

Advances in our understanding of sensory-motor integration suggest a unique role of the frontal lobe circuits in cognition and behaviour. Long-range afferent connections convey higher order sensory information to the frontal cortex, which in turn responds to internal and external stimuli with flexible and adaptive behaviour. Long-range connections from and to frontal lobes have been described in detail in monkeys but little is known about short intralobar frontal connections mediating local connectivity in humans. Here we used spherical deconvolution diffusion tractography and post-mortem dissections to visualize the short frontal lobe connections of the human brain. We identified three intralobar tracts connecting: i) posterior Broca's region with supplementary motor area (SMA) and pre-supplementary motor area (pre-SMA) (i.e., the frontal 'aslant' tract - FAT); ii) posterior orbitofrontal cortex with anterior polar region (i.e., fronto-orbitopolar tract - FOP); iii) posterior pre-central cortex with anterior prefrontal cortex (i.e., the frontal superior longitudinal - FSL faciculus system). In addition more complex systems of short U-shaped fibres were identified in the regions of the central, pre-central, perinsular and fronto-marginal sulcus (FMS). The connections between Broca and medial frontal areas (i.e. FAT) and those between the hand-knob motor region and post-central gyrus (PoCG) were found left lateralized in a group of twelve healthy right-handed subjects. The existence of these short frontal connections was confirmed using post-mortem blunt dissections. The functional role of these tracts in motor learning, verbal fluency, prospective behaviour, episodic and working memory is discussed. Our study provides a general model for the local connectivity of the frontal lobes that could be used as an anatomical framework for studies on lateralization and future clinical research in neurological and psychiatric disorders.

Traumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated whether alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion in both male and female mice that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch-clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast-spiking and somatostatin-expressing (SOM+) subtypes of inhibitory neurons in layer V of the orbitofrontal cortex 2 months after injury. These subtypes exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons, respectively. By contrast, the fast-spiking and parvalbumin-expressing interneurons did not show changes in intrinsic excitability or synaptic output, respectively. Impairments in non-fast-spiking/SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI.SIGNIFICANCE STATEMENT TBI frequently leads to chronic deficits in cognitive and behavioral functions that involve the prefrontal cortex, yet the maladaptive changes that occur in these cortical microcircuits are unknown. Our data indicate that alterations in subtype-specific inhibitory circuits, specifically vulnerability in the non-fast-spiking/somatostatin-expressing interneurons, occurs in the orbitofrontal cortex in the context of chronic deficits in reversal learning. These neurons exhibit reduced excitability and synaptic output, whereas the other prominent inhibitory population in layer V, the fast-spiking/parvalbumin-expressing interneurons as well as pyramidal neurons are not affected. Our work offers mechanistic insight into the subtype-specific function of neurons that may contribute to mental inflexibility after TBI.

Albeit the few resting-state fMRI neuroimaging studies in frontal lobe epilepsy (FLE) patients, these studies focused on functional connectivity. The aim of this current study was to examine the effective connectivity based on voxel-based morphometry in FLE patients.

Excessive yawning was described in some neurological conditions as part of periictal or ictal manifestations of epilepsy, most commonly temporal lobe. We present the first case of controllable yawning as a primary seizure semiology with dominant frontal lobe involvement in a 20-year-old man. Video electroencephalography recorded 8 yawning episodes accompanied with right arm movement correlating with rhythmic diffuse theta range activity with left hemispheric predominance. Magnetoencephalography coherence source imaging was consistent with persistent neuronal networks with areas of high coherence reliably present over the left lateral orbitofrontal region. Epileptogenic areas may have widespread networks involving the dominant frontal lobe in unique symptomatogenic areas.

In temporal lobe epilepsy (TLE), frontal-temporal connections are integral parts of the epileptogenic network. Although frontal-temporal gray matter abnormalities have been consistently demonstrated in TLE, white matter connections between these two lobes require further study in this disease setting. We therefore investigated the integrity of two major frontal-temporal white matter association tracts, uncinate fasciculus (UF) and arcuate fasciculus (AF), and their clinical correlates.

This study investigated whether frontal lobe cortical morphology differs for boys and girls with ADHD (ages 8-12 years) in comparison to typically developing (TD) peers.

Language in its highest complexity is a unique human faculty with simultaneous translation being among the most demanding language task involving both linguistic and executive functions. In this context, bilingually grown up individuals as well as simultaneous interpreters (SIs) represent appropriate groups for studying expertise-related neural adaptations in the human brain. The present study was performed to examine if a domain-specific neural network activation pattern, constituted by brain regions involved in speech processing as well as cognitive control mechanisms can be detected during a task-free resting state condition. To investigate this, electroencephalographic (EEG) data were recorded from 16 SIs and 16 age and gender-matched multilingual control subjects. Graph-theoretical network analyses revealed interhemispheric hyperconnectivity between the ventral part of the prefrontal cortex (pars opercularis and pars triangularis) and the dorsolateral prefrontal cortex (DLPFC) in language experts compared to multilingual controls in the alpha frequency range. This finding suggests that the high cognitive demands placed on simultaneous interpreting lead to an increased neural communication between prefrontal brain regions essentially engaged in supporting executive control-a neural fingerprint that is even detectable during rest.

Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene.

In childhood frontal lobe epilepsy (FLE), cognitive impairment and educational underachievement are serious, well-known co-morbidities. The broad scale of affected cognitive domains suggests wide-spread network disturbances that not only involves, but also extends beyond the frontal lobe. In this study we have investigated whole brain connectional properties of children with FLE in relation to their cognitive impairment and compared them with healthy controls. Functional connectivity (FC) of the networks was derived from dynamic fluctuations of resting state fMRI and structural connectivity (SC) was obtained from fiber tractograms of diffusion weighted MRI. The whole brain network was characterized with graph theoretical metrics and decomposed into modules. Subsequently, the graph metrics and the connectivity within and between modules were related to cognitive performance. Functional network disturbances in FLE were related to increased clustering, increased path length, and stronger modularity compared to healthy controls, which was accompanied by stronger within- and weaker between-module functional connectivity. Although structural path length and clustering appeared normal in children with FLE, structural modularity increased with stronger cognitive impairment. It is concluded that decreased coupling between large-scale functional network modules is a hallmark for impaired cognition in childhood FLE.

Traumatic brain injury (TBI) is a major cause of chronic disability in the world. Moderate to severe TBI often results in damage to the frontal lobe region and leads to cognitive, emotional, and social behavioral sequelae that negatively affect quality of life. More specifically, TBI patients often develop persistent deficits in social behavior, anxiety, and executive functions such as attention, mental flexibility, and task switching. These deficits are intrinsically associated with prefrontal cortex (PFC) functionality. Currently, there is a lack of analogous, behaviorally characterized TBI models for investigating frontal lobe injuries despite the prevalence of focal contusions to the frontal lobe in TBI patients. We used the controlled cortical impact (CCI) model in mice to generate a frontal lobe contusion and studied behavioral changes associated with PFC function. We found that unilateral frontal lobe contusion in mice produced long-term impairments to social recognition and reversal learning while having only a minor effect on anxiety and completely sparing rule shifting and hippocampal-dependent behavior.

Self- disgust is an adverse self-conscious emotion that plays an important role in psychopathology and well-being. However, self-disgust has received little attention in the emotion literature, therefore our understanding of the processes underlying the experience of self-disgust is relatively scarce, although neuropsychological and neuroimaging studies support the idea that this emotion may heavily rely on frontal lobe-related cognition. To test this hypothesis, in two studies we investigated the relationship between state and trait levels of self-disgust, cognition and emotion regulation in healthy adults. Specifically, in Study 1 we tested the hypothesis that emotion regulation strategies (avoidance, suppression, and cognitive reappraisal) mediate the relationship between inhibition ability and state and trait levels of self-disgust. In Study 2, we followed a more comprehensive approach to test the hypothesis that frontal lobe-related cognitive processes (updating, Theory of Mind-ToM-, and self-attention) are closely related to the experience of self-disgust in healthy adults. Overall, across these studies, we found evidence to support the idea that inhibition ability and ToM may play a role in the experience of state and trait self-disgust, respectively. However, we did not find consistent evidence across the two studies to support the notion held in the literature that the experience of self- conscious emotions, in this case self-disgust, is heavily dependent on frontal lobe-related cognition.

We aimed to delineate the distribution of periventricular nodular heterotopia (PNH) in patients with 22q11.2 microdeletion syndrome (22q11.2DS) and place this in the context of other genetic forms of PNH.

The purpose of this study was to investigate the cortical electrical activity and electroencephalography (EEG) features of the frontal lobe evoked by dynamic random dot stereogram (DRDS) and to probe the functional connectivity (FC) between the frontal lobe and occipital lobe when processing 3D perception based on the binocular disparity.

The Left Lateral cortex is known to have a role in inductive reasoning tasks. A more specific hypothesis on its role is that it is crucial in the generation of new abstract rules, rather than in the selection and implementation of a specific rule among a set of previously learned ones. Two new tests - the Generation of Hypotheses test and the Recognition of the Rule test - were administered to 46 patients with focal damage to the frontal cortex. Patients were divided in three frontal subgroups: Left Lateral, Right Lateral and Medial. On the basis of the new hypothesis, it was predicted that (i) the Left Lateral subgroup would fail in the Generation of Hypotheses test but would show spared performance on the Recognition of the Rule test and that (ii) the other frontal subgroups would perform normally on both tests. The findings on the Left Lateral and Right Lateral frontal subgroup were consistent with the predictions. This suggests that the Left Lateral frontal cortex is critical specifically for the generation of hypotheses in inductive reasoning. The Medial frontal subgroup, in contrast with our expectations, was impaired on Generation test; two hypotheses have been raised to explain this finding.

To explore the characteristics and mechanisms of working memory impairment in patients with frontal lobe epilepsy (FLE) through a memory game paradigm combined with eye tracking technology.