Two-Dimensional Temporal Clustering Analysis for Patients with Epilepsy: Detecting Epilepsy-Related Information in EEG-fMRI Concordant, Discordant and Spike-Less Patients.

EEG acquired simultaneously with fMRI (EEG-fMRI) is a multimodal method that has shown promise in mapping the seizure onset zone in patients with focal epilepsy. However, there are many instances when this method is unsuccessful or not applicable, and other data driven fMRI methods may be utilized. One such method is the two-dimensional temporal clustering analysis (2dTCA). In this study we compared the classic EEG-fMRI and 2dTCA performance in mapping regions related to the seizure onset region in 18 focal epilepsy patients (12 presenting interictal epileptiform discharges (IEDs), during EEG-fMRI acquisition) with Engel I or II surgical outcome. Activation maps of both 2dTCA timing outputs (positive and negative histograms) and EEG detected IEDs were computed and compared to the region of epilepsy surgical resection. Patients were evaluated in three categories based on frequency of EEG detected spiking during the MRI. EEG-fMRI maps were concordant to the epilepsy region in 5/12 subjects, four with frequent IEDs on EEG. The 2dTCA was successful in mapping 13/18 patients including 3/6 with no IEDs detected (10/12 with IEDs detected). The epilepsy-related activities were successfully mapped by both methods in only 4/12 patients. This work suggests that the epilepsy-related information detected by each method may be different: while EEG-fMRI is more accurate in patients with high rather than lower numbers of EEG detected IEDs; 2dTCA can be useful in evaluating patients even when no concurrent EEG spikes are detected or EEG-fMRI is not effective. Therefore, our results support that 2dTCA might be an alternative for mapping epilepsy-related BOLD activity in negative EEG-fMRI (6/7 patients) and spike-less patients.

Towards motion insensitive EEG-fMRI: Correcting motion-induced voltages and gradient artefact instability in EEG using an fMRI prospective motion correction (PMC) system.

The simultaneous acquisition of electroencephalography and functional magnetic resonance imaging (EEG-fMRI) is a multimodal technique extensively applied for mapping the human brain. However, the quality of EEG data obtained within the MRI environment is strongly affected by subject motion due to the induction of voltages in addition to artefacts caused by the scanning gradients and the heartbeat. This has limited its application in populations such as paediatric patients or to study epileptic seizure onset. Recent work has used a Moiré-phase grating and a MR-compatible camera to prospectively update image acquisition and improve fMRI quality (prospective motion correction: PMC). In this study, we use this technology to retrospectively reduce the spurious voltages induced by motion in the EEG data acquired inside the MRI scanner, with and without fMRI acquisitions. This was achieved by modelling induced voltages from the tracking system motion parameters; position and angles, their first derivative (velocities) and the velocity squared. This model was used to remove the voltages related to the detected motion via a linear regression. Since EEG quality during fMRI relies on a temporally stable gradient artefact (GA) template (calculated from averaging EEG epochs matched to scan volume or slice acquisition), this was evaluated in sessions both with and without motion contamination, and with and without PMC. We demonstrate that our approach is capable of significantly reducing motion-related artefact with a magnitude of up to 10mm of translation, 6° of rotation and velocities of 50mm/s, while preserving physiological information. We also demonstrate that the EEG-GA variance is not increased by the gradient direction changes associated with PMC. Provided a scan slice-based GA template is used (rather than a scan volume GA template) we demonstrate that EEG variance during motion can be supressed towards levels found when subjects are still. In summary, we show that PMC can be used to dramatically improve EEG quality during large amplitude movements, while benefiting from previously reported improvements in fMRI quality, and does not affect EEG data quality in the absence of large amplitude movements.

Using network dynamic fMRI for detection of epileptogenic foci.

BACKGROUND: Epilepsy is one of the most prevalent neurological disorders. It remains medically intractable for about one-third of patients with focal epilepsy, for whom precise localization of the epileptogenic zone responsible for seizure initiation may be critical for successful surgery. Existing fMRI literature points to widespread network disturbances in functional connectivity. Per previous scalp and intracranial EEG studies and consistent with excessive local synchronization during interictal discharges, we hypothesized that, relative to same regions in healthy controls, epileptogenic foci would exhibit less chaotic dynamics, identifiable via entropic analyses of resting state fMRI time series. METHODS: In order to first validate this hypothesis on a cohort of patients with known ground truth, here we test individuals with well-defined epileptogenic foci (left mesial temporal lobe epilepsy). We analyzed voxel-wise resting-state fMRI time-series using the autocorrelation function (ACF), an entropic measure of regulation and feedback, and performed follow-up seed-to-voxel functional connectivity analysis. Disruptions in connectivity of the region exhibiting abnormal dynamics were examined in relation to duration of epilepsy and patients' cognitive performance using a delayed verbal memory recall task. RESULTS: ACF analysis revealed constrained (less chaotic) functional dynamics in left temporal lobe epilepsy patients, primarily localized to ipsilateral temporal pole, proximal to presumed focal points. Autocorrelation decay rates differentiated, with 100 % accuracy, between patients and healthy controls on a subject-by-subject basis within a leave-one-subject out classification framework. Regions identified via ACF analysis formed a less efficient network in patients, as compared to controls. Constrained dynamics were linked with locally increased and long-range decreased connectivity that, in turn, correlated significantly with impaired memory (local left temporal connectivity) and epilepsy duration (left temporal - posterior cingulate cortex connectivity). CONCLUSIONS: Our current results suggest that data driven functional MRI methods that target network dynamics hold promise in providing clinically valuable tools for identification of epileptic regions.

Prnp gene and cerebellum volume in patients with refractory mesial temporal lobe epilepsy.

The cellular prion protein, encoded by Prnp gene, is involved in neuroprotection, neuroplasticity and neurodevelopment. The variant allele Valine at codon 129 of the Prnp was associated with decreased brain volume in healthy volunteers and schizophrenic patients. We investigate the association between the cerebellum volume and the presence of variant allele Valine at codon 129 of the Prnp gene in patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS). The Prnp coding sequence was determined in 41 refractory MTLE-HS patients. The cerebellum volume corrected by the intracranial volume of patients with the normal Prnp genotypes was compared with that of patients presenting the variant alleles at codon 129. Twenty patients showed the Met129Met genotype, 16 showed Met129Val, and 5 had Val129Val. There were no association among clinical, demographic, electrophysiological, antiepileptic drugs used, and the presence of the Prnp variant alleles. The presence of Prnp variant allele at codon 129 was not associated with the analyzed cerebellum volume. Prnp variant alleles at codon 129 are not associated with cerebellum volume in patients with refractory MTLE-HS.

Atypical neuropsychological profiles and cognitive outcome in mesial temporal lobe epilepsy.

Patients with left mesial temporal lobe epilepsy (MTLE) have deficits in verbal memory processes, while patients with right MTLE have visuospatial memory impairment. However, atypical cognitive phenotypes among patients with MTLE may occur. In this study, we analyzed preoperative memory deficits in a cohort of 426 right-handed patients with unilateral MTLE. We also evaluated the cognitive outcome after anterior temporal lobectomy (ATL) of patients with atypical profiles in comparison with those with typical memory profile. We found that 25% of our patients had a typical cognitive profile, with verbal memory deficits associated with left side hippocampal sclerosis (HS) and visuospatial memory deficits associated with right side HS. However, 75% of our patients had atypical memory profiles. Despite these atypical profiles, patients submitted to right ATL had no significant cognitive deficit after surgery. In patients submitted to left ATL, the higher the presurgical scores on verbal memory and naming tests, the higher the cognitive decline after surgery.

Amygdala gene expression of NMDA and GABA(A) receptors in patients with mesial temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy and affects 40% of the patients. Seizures arising from the mesial temporal lobe structures (i.e., amygdala and hippocampus) are common, whereas neocortical seizures are rare. In recent years, many studies aimed to identify the pattern of gene expression of neurotransmitters involved in molecular mechanisms of epilepsy. We used real-time PCR to quantify the expression of GABA(A) (subunits α1, ß1, ß2) and NMDA (subunits NR1, NR2A, and NR2B) receptor genes in amygdalae of 27 patients with TLE and 14 amygdalae from autopsy controls. The NR1 subunit was increased in patients with epilepsy when compared with controls. No differences were found in expression of NMDA subunits NR2A and NR2B or in α1, ß1, and ß2 subunits of GABA(A) receptors. Our results suggest that the NR1 subunit of NMDA receptors is involved in the amygdala hyperexcitability in some of the patients with TLE.

Psychiatric comorbidity in refractory focal epilepsy: a study of 490 patients.

We studied the prevalence and associated factors of psychiatric comorbidities in 490 patients with refractory focal epilepsy. Of these, 198 (40.4%) patients had psychiatric comorbidity. An Axis I diagnosis was made in 154 patients (31.4%) and an Axis II diagnosis (personality disorder) in another 44 (8.97%) patients. After logistic regression, positive family history of psychiatric comorbidities (O.R.=1.98; 95% CI=1.10-3.58; p=0.023), the presence of Axis II psychiatric comorbidities (O.R.=3.25; 95% CI=1.70-6.22; p<0.0001), and the epileptogenic zone located in mesial temporal lobe structures (O.R.=1.94; 95% CI=1.25-3.03; p=0.003) remained associated with Axis I psychiatric comorbidities. We concluded that a combination of clinical variables and selected structural abnormalities of the central nervous system contributes to the development of psychiatric comorbidities in patients with focal epilepsy.

Validation of the Subjective Handicap of Epilepsy (SHE) in Brazilian patients with epilepsy.

The objectives of the study were to translate and adapt the Subjective Handicap of Epilepsy (SHE) instrument to Brazilian Portuguese and to determine its psychometric properties for the evaluation of quality of life in patients with epilepsy. A sample of 448 adult patients with epilepsy with different clinical profiles (investigation, preoperative period, postoperative period, and drug treatment follow-up) was evaluated with the SHE and the Epilepsy Surgery Inventory (ESI-55). Exploratory factorial analysis demonstrated that four factors explained 60.47% of the variance and were sensitive to discriminate the different clinical groups, with the preoperative group having the poorest quality of life. Internal consistency ranged from 0.92 to 0.96, and concurrent validity with the ESI-55 was moderate/strong (0.32-0.70). Test-retest reliability was confirmed, with an ICC value of 0.54 (2 days), 0.91 (7 days), and 0.97 (30 days). The SHE had satisfactory psychometric qualities for use in the Brazilian population, similar to those of the original version. The instrument seems to be more adequate in psychometric terms for the postoperative and drug treatment follow-up groups, and its use should be encouraged.

Improving surgical outcome with electric source imaging and high field magnetic resonance imaging.

While most patients with focal epilepsy present with clear structural abnormalities on standard, 1.5 or 3 T MRI, some patients are MRI-negative. For those, quantitative MRI techniques, such as volumetry, voxel-based morphometry, and relaxation time measurements can aid in finding the epileptogenic focus. High-field MRI, just recently approved for clinical use by the FDA, increases the resolution and, in several publications, was shown to improve the detection of focal cortical dysplasias and mild cortical malformations. For those cases without any tissue abnormality in neuroimaging, even at 7 T, scalp EEG alone is insufficient to delimitate the epileptogenic zone. They may benefit from the use of high-density EEG, in which the increased number of electrodes helps improve spatial sampling. The spatial resolution of even low-density EEG can benefit from electric source imaging techniques, which map the source of the recorded abnormal activity, such as interictal epileptiform discharges, focal slowing, and ictal rhythm. These EEG techniques help localize the irritative, functional deficit, and seizure-onset zone, to better estimate the epileptogenic zone. Combining those technologies allows several drug-resistant cases to be submitted to surgery, increasing the odds of seizure freedom and providing a must needed hope for patients with epilepsy.

Multidimensional Approach Assessing the Role of Interleukin 1 Beta in Mesial Temporal Lobe Epilepsy.

We aimed to investigate the role of interleukin-1 beta (IL-1ß) in the mechanisms underlying mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS). We assessed a cohort of 194 patients with MTLE+HS and 199 healthy controls. Patients were divided into those with positive and negative antecedent febrile seizures (FS). We used a multidimensional approach, including (i) genetic association with single nucleotide polymorphisms (SNPs) in the IL1B gene; (ii) quantification of the IL1B transcript in the hippocampal tissue of patients with refractory seizures; and (iii) quantification of the IL-1ß protein in the plasma. We found a genetic association signal for two SNPs, rs2708928 and rs3730364*C in the IL1B gene, regardless of the presence of FS (adjusted p = 9.62e-11 and 5.14e-07, respectively). We found no difference between IL1B transcript levels when comparing sclerotic hippocampal tissue from patients with MTLE+HS, without FS, and hippocampi from autopsy controls (p > 0.05). Nevertheless, we found increased IL-1ß in the plasma of patients with MTLE+HS with FS compared with controls (p = 0.0195). Our results support the hypothesis of a genetic association between MTLE+HS and the IL1B gene.

Histological correlates of hippocampal magnetization transfer images in drug-resistant temporal lobe epilepsy patients.

OBJECTIVE: Temporal lobe epilepsy patients (TLE) often present with hippocampal atrophy, increased T2 relaxation, and reduced magnetization transfer ratio (MTR) in magnetic resonance images (MRI). The histological correlates of the reduced hippocampal MTR are so far unknown. Since MTR is dependent on the tissue's macromolecules, our aim was to evaluate the correlations between cellular populations, extracellular matrix molecules and the MTR in TLE patients. METHODS: Patients with TLE (n = 26) and voluntaries (=20) were scanned in a 3 Tesla MRI scanner, and MTR images were calculated from 3DT1 sequences with magnetization pulse on resonance. Immunohistochemistry for neurons, reactive astrocytes, activated microglia, and extracellular matrix chondroitin sulfate were performed in formalin fixed, paraffin embedded tissues of TLE and autopsy controls (n = 10). Results were considered significant with adjusted p < 0.05. RESULTS: Compared to the respective controls, TLE patients had reduced hippocampal MTR, increased reactive astrocytes and activated microglia, increased extracellular chondroitin sulfate, and reduced neuron density, compares to controls. MTR correlated positively with neuron density in CA3 and with chondroitin sulfate in CA3 and CA1. Multiple linear regressions reinforced the correlations between chondroitin sulfate and MTR. SIGNIFICANCE: Our data indicate that extracellular matrix molecules are the most significant histological correlates of magnetization transfer ratio in the hippocampus of TLE patients.

Assessment and surgical outcomes for mild type I and severe type II cortical dysplasia: a critical review and the UCLA experience.

Recent findings on the clinical, electroencephalography (EEG), neuroimaging, and surgical outcomes are reviewed comparing patients with Palmini type I (mild) and type II (severe) cortical dysplasia. Resources include peer-reviewed studies on surgically treated patients and a subanalysis of the 2004 International League Against Epilepsy (ILAE) Survey of Pediatric Epilepsy Surgery. These sources were supplemented with data from University of California, Los Angeles (UCLA). Cortical dysplasia is the most frequent histopathologic substrate in children, and the second most common etiology in adult epilepsy surgery patients. Cortical dysplasia patients present with seizures at an earlier age than other surgically treated etiologies, and 33-50% have nonlocalized scalp EEG and normal magnetic resonance imaging (MRI) scans. 2-((18)F)Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is positive in 75-90% of cases. After complete resection, 80% of patients are seizure free compared with 20% with incomplete resections. Compared with type I, patients with type II cortical dysplasia present at younger ages, have higher seizure frequencies, and are extratemporal. Type I dysplasia is found more often in adult patients in the temporal lobe and is often MRI negative. These findings identify characteristics of patients with mild and severe cortical dysplasia that define surgically treated epilepsy syndromes. The authors discuss future challenges to identifying and treating medically refractory epilepsy patients with cortical dysplasia.

Do psychiatric comorbidities predict postoperative seizure outcome in temporal lobe epilepsy surgery?

Clinical and demographic presurgical variables may be associated with unfavorable postsurgical neurological outcome in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). However, few reports include preoperative psychiatric disorders as a factor predictive of long-term postsurgical MTLE-HS neurological outcome. We used Engel's criteria to follow 186 postsurgical patients with MTLE-HS for an average of 6 years. DSM-IV criteria and psychiatric comorbidity criteria specific to epilepsy (interictal dysphoric disorder, postictal and interictal psychosis) were used to assess presurgical psychiatric disorders. Kaplan-Meier event-free survival and adjusted hazard ratios were estimated with unconditional logistic regression. Seventy-seven (41.4%) patients had a preoperative Axis I psychiatric diagnosis. Thirty-six patients had depression, 11 interictal dysphoric disorder, 14 interictal psychosis, 6 postictal psychosis, and 10 anxiety disorders. Twenty-three (12.4%) patients had Axis II personality disorders. Regarding seizure outcome, preoperative anxiety disorders (P=0.009) and personality disorders (P=0.003) were positively correlated with Engel class 1B (remaining auras) or higher. These findings emphasize the importance of presurgical psychiatric evaluation, counseling, and postsurgical follow-up of patients with epilepsy and psychiatric disorders.

Manual Hippocampal Subfield Segmentation Using High-Field MRI: Impact of Different Subfields in Hippocampal Volume Loss of Temporal Lobe Epilepsy Patients.

In patients with temporal lobe epilepsy (TLE), presurgical magnetic resonance imaging (MRI) often reveals hippocampal atrophy, while neuropathological assessment indicates the different types of hippocampal sclerosis (HS). Different HS types are not discriminated in MRI so far. We aimed to define the volume of each hippocampal subfield on MRI manually and to compare automatic and manual segmentations for the discrimination of HS types. The T2-weighted images from 14 formalin-fixed age-matched control hippocampi were obtained with 4.7T MRI to evaluate the volume of each subfield at the anatomical level of the hippocampal head, body, and tail. Formalin-fixed coronal sections at the level of the body of 14 control cases, as well as tissue samples from 24 TLE patients, were imaged with a similar high-resolution sequence at 3T. Presurgical three-dimensional (3D) T1-weighted images from TLE went through a FreeSurfer 6.0 hippocampal subfield automatic assessment. The manual delineation with the 4.7T MRI was identified using Luxol Fast Blue stained 10-µm-thin microscopy slides, collected at every millimeter. An additional section at the level of the body from controls and TLE cases was submitted to NeuN immunohistochemistry for neuronal density estimation. All TLE cases were classified according to the International League Against Epilepsy's (ILAE's) HS classification. Manual volumetry in controls revealed that the dentate gyrus (DG)+CA4 region, CA1, and subiculum accounted for almost 90% of the hippocampal volume. The manual 3T volumetry showed that all TLE patients with type 1 HS (TLE-HS1) had lower volumes for DG+CA4, CA2, and CA1, whereas those TLE patients with HS type 2 (TLE-HS2) had lower volumes only in CA1 (p ≤ 0.038). Neuronal cell densities always decreased in CA4, CA3, CA2, and CA1 of TLE-HS1 but only in CA1 of TLE-HS2 (p ≤ 0.003). In addition, TLE-HS2 had a higher volume (p = 0.016) and higher neuronal density (p < 0.001) than the TLE-HS1 in DG + CA4. Automatic segmentation failed to match the manual or histological findings and was unable to differentiate TLE-HS1 from TLE-HS2. Total hippocampal volume correlated with DG+CA4 and CA1 volumes and neuronal density. For the first time, we also identified subfield-specific pathology patterns in the manual evaluation of volumetric MRI scans, showing the importance of manual segmentation to assess subfield-specific pathology patterns.

Pontine activation during focal status epilepticus secondary to hamartoma of the floor of the fourth ventricle.

Epileptic seizures associated with hamartoma of the floor of the fourth ventricle (HFFV) are generally resistant to antiepileptic medication, may evolve into status epilepticus, and can respond favorably to surgical therapy. HFFV are rare, and during the neonatal or infantile period may be associated with repetitive and stereotyped attacks of hemifacial spasm, eye blinking, facial movements, head deviation and dysautonomic manifestations. Similarly, to gelastic seizures provoked by hypothalamic hamartomas, it has been suggested that these spells arise from within the HFFV, thus constituting a type of non-cortical seizure. We report an infant female patient that developed continuous left hemifacial attacks since she was 2-month-old, and that underwent presurgical investigation when she was 18-month-old. MRI disclosed a left sided HFFV, Video-EEG showed non-localizing and non-lateralizing findings, and SPECT aligned with MRI showed marked hyperperfusion within the hamartoma, spreading to ipsilateral cerebellar parenchyma and brainstem nuclei. Patient underwent lesionectomy and became seizure-free. We found two evidences on literature supporting the hypothesis of non-cortical seizures related to HFFV. The first, intra-cerebellar recordings surrounding hamartoma showed electrical activity related to seizures. The second, subtracted SPECT co-registered MRI showed hyperemia within hamartoma. The present report provides the third additional evidence. We found the involvement not only of the hamartoma, and pars of cerebellar hemisphere, but also an intense hyperemia involving brainstem nuclei during seizures. We believe that all these findings suggest a short subcortical network responsible for generating seizures in HFFV patients.

Seizure outcome after surgery for epilepsy due to focal cortical dysplastic lesions.

Neocortical development is a highly complex process encompassing cellular proliferation, neuronal migration and cortical organization. At any time this process can be interrupted or modified by genetic or acquired factors causing malformations of cortical development (MCD). Epileptic seizures are the most common type of clinical manifestation, besides developmental delay and focal neurological deficits. Seizures due to MCD are frequently pharmacoresistant, especially those associated to focal cortical dysplasia (FCD). Surgical therapy results have been reported since 1971, however, currently available data from surgical series are still limited, mainly due to small number of patients, distinct selection of candidates and surgical strategies, variable pathological diagnosis and inadequate follow-up. This study addresses the possibilities of seizure relief following resection of focal cortical dysplasia, and the impact of presurgical evaluation, extent of resection and pathological findings on surgical outcome. We included 41 patients, 22 adults and 19 children and adolescents, with medically intractable seizures operated on from 1996 to 2002. All were submitted to standardized presurgical evaluation including high-resolution MRI, Video-EEG monitoring and ictal SPECT. Post-surgical seizure outcome was classified according to Engel's schema. Univariate and multivariate analysis were performed. Fifteen patients had temporal and 26 extratemporal epilepsies. Of the total 26 patients (63.4%) reached seizure-free status post-operatively. There was no correlation between outcome and age at surgery, duration of epilepsy, frequency of seizures, and pathological findings. There was, however, a clear correlation with topography of FCD (temporal versus extratemporal) and regional ictal EEG onset, on univariate as well as multivariate analysis.

Adhesio interthalamica and cavum septum pellucidum in mesial temporal lobe epilepsy.

The absence of the adhesio interthalamica (AI; also called interthalamic adhesion or massa intermedia) and the presence of a large cavum septum pellucidum (CSP) later in life have been related to neurodevelopmental alterations and have not been systematically investigated in epilepsy to date. This study carried out a MRI evaluation of the AI and CSP in a large sample with mesial temporal lobe epilepsy (MTLE). A total of 179 patients, classified according to the side of the epileptogenic focus, and 156 age- and sex-balanced healthy controls were assessed. Between-group comparisons of the prevalence and length of both AI and CSP were conducted. Neuropsychological assessments were also performed in 160 MTLE patients. The patients exhibited reduction in the AI prevalence (P < 0.05; FDR-uncorrected) and length (P < 0.05; FDR-corrected) when compared to controls. Patients without AI showed lower scores in a proportion of neuropsychological tests than patients with AI. No CSP differences were found between MTLE patients and controls. These results support that AI anomalies have clinical significance in MTLE, as well as indicate that neurodevelopmental alterations may be implicated in this disorder.

Interictal SPECT in patients with mesial temporal lobe epilepsy and psychosis: a case-control study.

Psychosis is commonly observed in patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS). Interictal single photon emission computed tomography (SPECT) was performed to compare regional cerebral blood flow (rCBF) pattern of MTLE-HS patients with psychosis of epilepsy (POE) comorbidity and MTLE-HS patients without any psychiatric disorders (Control group). For this, 21 patients with POE and 23 Control patients were matched by educational level, clinical, demographic, electrophysiological, and MRI data. SPECT scans were acquired using (99m)Tc and interpreted with a semiquantitative method. We analyzed brain regions of interest (ROI) of frontal, temporal, and parietal cortex, in addition to subcortical structures. There were no significant statistical differences of ROI between the POE group and the Control group after Bonferroni adjustment. However, we observed a trend for rCBF increase of right posterior cingulate in the POE Group. This increase would be in accordance with recent findings of cingulate abnormalities in schizophrenia, suggesting that abnormal function in this region might be associated with the psychotic phenomena.