Comparison between postcontrast thin-slice T1-weighted 2D spin echo and 3D T1-weighted SPACE sequences in the detection of brain metastases at 1.5 and 3 T.

OBJECTIVES: Accurate detection of metastatic brain lesions (MBL) is critical due to advances in radiosurgery. We compared the results of three readers in detecting MBL using T1-weighted 2D spin echo (SE) and sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) sequences with whole-brain coverage at both 1.5 T and 3 T. METHODS: Fifty-six patients evaluated for MBL were included and underwent a standard protocol (1.5 T, n = 37; 3 T, n = 19), including postcontrast T1-weighted SE and SPACE. The rating was performed by three raters in two sessions > six weeks apart. The true number of MBL was determined using all available imaging including follow-up. Intraclass correlations for intra-rater and inter-rater agreement were calculated. Signal intensity ratios (SIR; enhancing lesion, white matter) were determined on a subset of 46 MBL > 4 mm. A paired t-test was used to evaluate postcontrast sequence order and SIR. Reader accuracy was evaluated by the coefficient of determination. RESULTS: A total of 135 MBL were identified (mean/subject 2.41, SD 6.4). The intra-rater agreement was excellent for all 3 raters (ICC = 0.97-0.992), as was the inter-rater agreement (ICC = 0.995 SE, 0.99 SPACE). Subjective qualitative ratings were lower for SE images; however, signal intensity ratios were higher in SE sequences. Accuracy was high in all readers for both SE (R2 0.95-0.96) and SPACE (R2 0.91-0.96) sequences. CONCLUSIONS: Although SE sequences are superior to gradient echo sequences in the detection of small MBL, they have long acquisition times and frequent artifacts. We show that T1-weighted SPACE is not inferior to standard thin-slice SE sequences in the detection of MBL at both imaging fields. CRITICAL RELEVANCE STATEMENT: Our results show the suitability of 3D T1-weighted turbo spin echo (TSE) sequences (SPACE, CUBE, VISTA) in the detection of brain metastases at both 1.5 T and 3 T. KEY POINTS: • Accurate detection of brain metastases is critical due to advances in radiosurgery. • T1-weighted SE sequences are superior to gradient echo in detecting small metastases. • T1-weighted 3D-TSE sequences may achieve high resolution and relative insensitivity to artifacts. • T1-weighted 3D-TSE sequences have been recommended in imaging brain metastases at 3 T. • We found T1-weighted 3D-TSE equivalent to thin-slice SE at 1.5 T and 3 T.

Association of Tumor Treating Fields (TTFields) therapy with survival in newly diagnosed glioblastoma: a systematic review and meta-analysis.

PURPOSE: Tumor Treating Fields (TTFields) therapy, an electric field-based cancer treatment, became FDA-approved for patients with newly diagnosed glioblastoma (GBM) in 2015 based on the randomized controlled EF-14 study. Subsequent approvals worldwide and increased adoption over time have raised the question of whether a consistent survival benefit has been observed in the real-world setting, and whether device usage has played a role. METHODS: We conducted a literature search to identify clinical studies evaluating overall survival (OS) in TTFields-treated patients. Comparative and single-cohort studies were analyzed. Survival curves were pooled using a distribution-free random-effects method. RESULTS: Among nine studies, seven (N = 1430 patients) compared the addition of TTFields therapy to standard of care (SOC) chemoradiotherapy versus SOC alone and were included in a pooled analysis for OS. Meta-analysis of comparative studies indicated a significant improvement in OS for patients receiving TTFields and SOC versus SOC alone (HR: 0.63; 95% CI 0.53-0.75; p < 0.001). Among real-world post-approval studies, the pooled median OS was 22.6 months (95% CI 17.6-41.2) for TTFields-treated patients, and 17.4 months (95% CI 14.4-21.6) for those not receiving TTFields. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields use. Furthermore, for patients included in studies reporting data on device usage (N = 1015), an average usage rate of ≥ 75% was consistently associated with prolonged survival (p < 0.001). CONCLUSIONS: Meta-analysis of comparative TTFields studies suggests survival may be improved with the addition of TTFields to SOC for patients with newly diagnosed GBM.

Eighteen years' experience with tumor treating fields in the treatment of newly diagnosed glioblastoma.

Introduction: The prognosis of glioblastoma remains unfavorable. TTFields utilize low intensity electric fields (frequency 150-300 kHz) that disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields are delivered via transducer arrays placed on the patients' scalp. Methods: Between the years 2004 and 2022, 55 patients (20 female), aged 21.9-77.8 years (mean age 47.3±11.8 years; median 47.6 years) were treated with TTFields for newly-diagnosed GBM, and compared to 54 control patients (20 females), aged 27.0-76.7 years (mean age 51.4±12.2 years; median 51.7 years) (p=0.08). All patients underwent gross total or partial resection of GBM. One patient had biopsy only. When available, MGMT promoter methylation status and IDH mutation was detected. Results: Patients on TTFields therapy demonstrated improvements in PFS and OS relative to controls (hazard ratio: 0.64, p=0.031; and 0.61, p=0.028 respectively). TTFields average time on therapy was 74.8% (median 82%): median PFS of these patients was 19.75 months. Seven patients with TTFields usage ≤60% (23-60%, mean 46.3%, median 53%) had a median PFS of 7.95 months (p=0.0356). Control patients with no TTFields exposure had a median PFS of 12.45 months. Median OS of TTF patients was 31.67 months compared to 24.80 months for controls. Discussion: This is the most extensive study on newly-diagnosed GBM patients treated with TTFields, covering a period of 18 years at a single center and presenting not only data from clinical trials but also a group of 36 patients treated with TTFields as a part of routine clinical practice.

Long-term cognitive trajectory and activities of daily living in healthy aging.

OBJECTIVE: The purpose of the present study was to investigate if participants in NANOK study (National Normative Study of Cognitive Determinants of Healthy Ageing) who show no cognitive decline throughout five years (successful healthy agers; SHA) will show less age-related differences in instrumental activities of daily living (IADL) based on Functional Activities Questionnaire in comparison to participants who show subtle cognitive decline (Decliners) over time. METHOD: We used two different classifications of SHA: Rogalski (N = 25 SHA and N = 15 Decliners) based on cross-sectional neuropsychology measures and linear mixed model (LMEM; 20 SHA and 20 Decliners) based on the Montreal Cognitive Assessment longitudinal 5-years follow-up. Whole-brain T1- and T2-weighted images were corrected for distortions and segmented using Freesurfer. Whole-brain volumetry was performed using FSL's voxel-based morphometry tool. RESULTS: The cognitive decline after four years follow-up but not age predicts subtle impairment in IADL in healthy ageing participants. We found brain volumetric differences between SHA and Decliners based on Rogalski but not LMEM classification especially in bilateral insular cortices and ventrolateral frontal cortex. The logistic regression model achieved an accuracy of 75% for the Rogalski in comparison to 67.5% for the LMEM classification. CONCLUSIONS: Slight restrictions in IADL seem to be a useful tool for screening healthy ageing participants at risk of developing subtle cognitive decline over a period of five years and the cross-sectional Rogalski criteria based on standardized neuropsychological measures were superior for tapping age-related brain changes to longitudinal LMEM classification based on screening (Montreal Cognitive Assessment).

Formation of gadolinium-ferritin from clinical magnetic resonance contrast agents.

Gadolinium deposition in the brain following administration of gadolinium-based contrast agents (GBCAs) has led to health concerns. We show that some clinical GBCAs form Gd3+-ferritin nanoparticles at (sub)nanomolar concentrations of Gd3+ under physiological conditions. We describe their structure at atomic resolution and discuss potential relevance for clinical MRI.

Whole brain apparent diffusion coefficient measurements correlate with survival in glioblastoma patients.

INTRODUCTION: Glioblastoma (GBM) is the most common malignant primary brain tumor, and methods to improve the early detection of disease progression and evaluate treatment response are highly desirable. We therefore explored changes in whole-brain apparent diffusion coefficient (ADC) values with respect to survival (progression-free [PFS], overall [OS]) in a cohort of GBM patients followed at regular intervals until disease progression. METHODS: A total of 43 subjects met inclusion criteria and were analyzed retrospectively. Histogram data were extracted from standardized whole-brain ADC maps including skewness, kurtosis, entropy, median, mode, 15th percentile (p15) and 85th percentile (p85) values, and linear regression slopes (metrics versus time) were fitted. Regression slope directionality (positive/negative) was subjected to univariate Cox regression. The final model was determined by aLASSO on metrics above threshold. RESULTS: Skewness, kurtosis, median, p15 and p85 were all below threshold for both PFS and OS and were analyzed further. Median regression slope directionality best modeled PFS (p = 0.001; HR 3.3; 95% CI 1.6-6.7), while p85 was selected for OS (p = 0.002; HR 0.29; 95% CI 0.13-0.64). CONCLUSIONS: Our data show tantalizing potential in the use of whole-brain ADC measurements in the follow up of GBM patients, specifically serial median ADC values which correlated with PFS, and serial p85 values which correlated with OS. Whole-brain ADC measurements are fast and easy to perform, and free of ROI-placement bias.

Diffusion tensor imaging in the characterization of multiple system atrophy.

PURPOSE: Multiple system atrophy (MSA) is a rare neurodegenerative disease that remains poorly understood, and the diagnosis of MSA continues to be challenging. We endeavored to improve the diagnostic process and understanding of in vivo characteristics of MSA by diffusion tensor imaging (DTI). MATERIALS AND METHODS: Twenty MSA subjects, ten parkinsonian dominant (MSA-P), ten cerebellar dominant (MSA-C), and 20 healthy volunteer subjects were recruited. Fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity maps were processed using tract-based spatial statistics. Diffusion data were additionally evaluated in the basal ganglia. A support vector machine was used to assess diagnostic utility, leave-one-out cross-validation in the evaluation of classification schemes, and receiver operating characteristic analyses to determine cutoff values. RESULTS: We detected widespread changes in the brain white matter of MSA subjects; however, no group-wise differences were found between MSA-C and MSA-P subgroups. Altered DTI metrics in the putamen and middle cerebellar peduncles were associated with a positive parkinsonian and cerebellar phenotype, respectively. Concerning clinical applicability, we achieved high classification performance on mean diffusivity data in the combined bilateral putamen and middle cerebellar peduncle (accuracy 90.3%±9%, sensitivity 86.5%±11%, and specificity 99.3%±4%). CONCLUSION: DTI in the middle cerebellar peduncle and putamen may be used in the diagnosis of MSA with a high degree of accuracy.

Late morphological changes after radiosurgery of brain arteriovenous malformations: an MRI study.

BACKGROUND: Radiosurgery by Gamma Knife (GK) is an effective treatment for brain arteriovenous malformations (AVM). The aim of the present study was to evaluate late, radiation-induced changes detectable by MRI after AVM radiosurgery in patients treated minimally 10 years prior, with AVM obliteration proven by angiography. METHODS: Thirty-five patients with 37 AVMs were included. AVMs were irradiated 16.6 ± 3.5 years prior with AVM obliteration proven 13 ± 4 years prior. All patients underwent recent MRI examinations, including application of gadolinium-based contrast. RESULTS: In one case, post-irradiative cystic formation with mass effect and signs of hemorrhage requiring surgery was found. Post-gadolinium enhancement at the site of obliterated nidi was apparent in 28 of 37 cases (76 %). In all cases except one, the mean volume of enhancement at the time of review was clearly lower than the volume of the originally irradiated AVM (88 ± 20 %; median 92 %); in one case the extent was 142 % greater than the irradiated AVM. When we compared enhancing and non-enhancing nidi, we found that enhancing nidi were significantly larger than non-enhancing nidi at the time of radiosurgery (4.39 ± 3.35 cc vs. 0.89 ± 0.79 cc, p = 0.004). Enhancement was not influenced by total radiation dose, patient age at the time of irradiation, duration since radiosurgery, or the number of irradiations. Wallerian degeneration was found in nine of 37 cases (24 %); in six cases the optical tracts were affected and visual field defects were proven. In five of nine cases (55.6 %) with Wallerian degeneration previous hemorrhage was present. Dual vascular pathology was found in eight of 35 patients (23 %). CONCLUSIONS: GK radiosurgery for AVM is a safe treatment method although delayed complications may occur. Post-gadolinium enhancement of obliterated nidi may indicate an active post-irradiative process.

Correlation between relaxometry and diffusion tensor imaging in the globus pallidus of Huntington's disease patients.

Huntington's disease (HD) is an inherited neurodegenerative disorder with progressive impairment of motor, behavioral and cognitive functions. The clinical features of HD are closely related to the degeneration of the basal ganglia, predominantly the striatum. The main striatal output structure, the globus pallidus, strongly accumulates metalloprotein-bound iron, which was recently shown to influence the diffusion tensor scalar values. To test the hypothesis that this effect dominates in the iron-rich basal ganglia of HD patients, we examined the globus pallidus using DTI and T2 relaxometry sequences. Quantitative magnetic resonance (MR), clinical and genetic data (number of CAG repeats) were obtained from 14 HD patients. MR parameters such as the T2 relaxation rate (RR), fractional anisotropy (FA) and mean diffusivity (MD) were analysed. A positive correlation was found between RR and FA (R2=0.84), between CAG and RR (R2=0.59) and between CAG and FA (R2=0.44). A negative correlation was observed between RR and MD (R2=0.66). A trend towards correlation between CAG and MD was noted. No correlation between MR and clinical parameters was found. Our results indicate that especially magnetic resonance FA measurements in the globus pallidus of HD patients may be strongly affected by metalloprotein-bound iron accumulation.

Speech disorders reflect differing pathophysiology in Parkinson's disease, progressive supranuclear palsy and multiple system atrophy.

Although speech disorder is frequently an early and prominent clinical feature of Parkinson's disease (PD) as well as atypical parkinsonian syndromes (APS) such as progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), there is a lack of objective and quantitative evidence to verify whether any specific speech characteristics allow differentiation between PD, PSP and MSA. Speech samples were acquired from 77 subjects including 15 PD, 12 PSP, 13 MSA and 37 healthy controls. The accurate differential diagnosis of dysarthria subtypes was based on the quantitative acoustic analysis of 16 speech dimensions. Dysarthria was uniformly present in all parkinsonian patients but was more severe in PSP and MSA than in PD. Whilst PD speakers manifested pure hypokinetic dysarthria, ataxic components were more affected in MSA whilst PSP subjects demonstrated severe deficits in hypokinetic and spastic elements of dysarthria. Dysarthria in PSP was dominated by increased dysfluency, decreased slow rate, inappropriate silences, deficits in vowel articulation and harsh voice quality whereas MSA by pitch fluctuations, excess intensity variations, prolonged phonemes, vocal tremor and strained-strangled voice quality. Objective speech measurements were able to discriminate between APS and PD with 95% accuracy and between PSP and MSA with 75% accuracy. Dysarthria severity in APS was related to overall disease severity (r = 0.54, p = 0.006). Dysarthria with various combinations of hypokinetic, spastic and ataxic components reflects differing pathophysiology in PD, PSP and MSA. Thus, motor speech examination may provide useful information in the evaluation of these diseases with similar manifestations.

Hippocampal but not amygdalar volume loss in narcolepsy with cataplexy.

OBJECTIVE: Narcolepsy with cataplexy (NC) and narcolepsy without cataplexy (NwoC) are lifelong neurological disorders characterized primarily by excessive daytime sleepiness. Emotional events such as laughter are a trigger of cataplexy in NC. METHODS: We compared the volumes of key limbic structures, the amygdala and hippocampus, in 53 NC, 23 NwoC and 37 control subjects. MRI volumetry was performed in FreeSurfer (FS) and by manual delineation. RESULTS: We found no differences in amygdalar volume in the three groups, however, hippocampal volume was significantly smaller in the NC group than in other groups. Amygdalar and hippocampal volumes assessed by FS were significantly greater, but strong positive correlation between manual and FS results were observed. Thus, both methods are suitable for amygdalar and hippocampal volumetry.

New non-linear color look-up table for visualization of brain fractional anisotropy based on normative measurements - principals and first clinical use.

Fractional anisotropy (FA) is the most commonly used quantitative measure of diffusion in the brain. Changes in FA have been reported in many neurological disorders, but the implementation of diffusion tensor imaging (DTI) in daily clinical practice remains challenging. We propose a novel color look-up table (LUT) based on normative data as a tool for screening FA changes. FA was calculated for 76 healthy volunteers using 12 motion-probing gradient directions (MPG), a subset of 59 subjects was additionally scanned using 30 MPG. Population means and 95% prediction intervals for FA in the corpus callosum, frontal gray matter, thalamus and basal ganglia were used to create the LUT. Unique colors were assigned to inflection points with continuous ramps between them. Clinical use was demonstrated on 17 multiple system atrophy (MSA) patients compared to 13 patients with Parkinson disease (PD) and 17 healthy subjects. Four blinded radiologists classified subjects as MSA/non-MSA. Using only the LUT, high sensitivity (80%) and specificity (84%) were achieved in differentiating MSA subjects from PD subjects and controls. The LUTs generated from 12 and 30 MPG were comparable and accentuate FA abnormalities.

Chasing shadows: what determines DTI metrics in gray matter regions? An in vitro and in vivo study.

PURPOSE: To characterize the relationship between superparamagnetic ferritin-bound iron and diffusion tensor scalars in vitro, and validate the results in vivo. MATERIALS AND METHODS: The in vitro model consisted of a series of 40-mL 1.1% agarose gels doped with ferritin covering and exceeding those concentrations normally found within healthy human gray matter. Additionally, regions of interest were placed in the caudate, putamen, and globus pallidus of 29 healthy volunteer subjects 19-80 years of age. Carr-Purcell-Meiboom-Gill sequence (CPMG) and diffusion tensor imaging (DTI) data were collected at 1.5 Tesla (T) and 3T in vitro, and at 1.5T in vivo. RESULTS: In vitro, linear relationships were observed between ferritin-bound iron concentration, R2 (1/T2 ) and 1/SNR. Eigenvalue repulsion with increasing R2 (decreasing SNR) was reflected in an artifactual increase of fractional anisotropy. In vivo, similar relationships were observed, with mean diffusivity also decreasing linearly with increasing R2 . Lambda 3 showed the strongest correlation with R2 both in vitro and in vivo. CONCLUSION: The observation that DTI metrics correlate with ferritin-bound iron is an important consideration in the design and interpretation of studies exploring the diffusion characteristics of gray matter regions, especially in studies focused on adolescence as well as diseases associated with altered brain-iron load such as pantothenate kinase-associated neurodegeneration, Huntington disease and multiple system atrophy.

Diffusion tensor imaging in Alzheimer disease and mild cognitive impairment.

A wide range of imaging studies provides growing support for the potential role of diffusion tensor imaging (DTI) in evaluating microstructural white matter integrity in Alzheimer disease (AD) and mild cognitive impairment (MCI). Our review aims to present DTI principles, post-processing and analysis frameworks and to report the results of particular studies. The distribution of AD-related white matter abnormalities is widely discussed in the light of deteriorated connectivity within certain tracts due to secondary white matter degeneration; primary alterations are also assumed to contribute to the pattern. The question whether it is more effective to assess the whole-brain diffusion or to directly concentrate on specific regions remains an interesting issue. Assessing white matter microstructure alterations, as evaluated by group-level differences of tensor-derived parameters, may be a promising neuroimaging tool for differential diagnosis between AD, MCI and other cognitive disorders, as well as being particularly helpful in the interpretation of underlying pathological processes.

Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields.

Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor, and has a median survival of only 10 to 14 months with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only five to seven months with optimal therapy. Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types. Our center was the first to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals in 2004 and 2005, and four of those original 20 patients are still alive today. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence.

Comparison of CT and MR imaging in ischemic stroke.

BACKGROUND: Cerebrovascular disease represents a major source of global mortality and morbidity. Imaging examinations play a critical role in the management of stroke patients, from establishing the initial diagnosis to determining and guiding further treatment. METHODS: In this article, current CT and MRI methods employed in the management of stroke patients are reviewed, with an emphasis on ischemic stroke. RESULTS: The advantages and disadvantages of these techniques are discussed, a number of cases emphasizing key points are presented, and a comparison between modern CT and MRI techniques is outlined. CONCLUSION: The major drawback of CT is the high radiation dose, while in MRI it is the more complicated and time-consuming aspect of the examination. MAIN MESSAGES: • Cerebrovascular disease represents a major source of global mortality and morbidity • Imaging examinations play a critical role in the management of stroke patients • The penumbra may be seen with both CT and MRI; however, this concept may be overly simplistic • The major drawback of CT is the high radiation dose, while MRI is a more complicated examination.

Volume of the amygdala is reduced in patients with narcolepsy - a structural MRI study.

OBJECTIVE: Based on the clinical observation that patients suffering from narcolepsy with cataplexy (NC) have cataplectic attacks when they experience positive emotions, it is therefore hypothesised that the abnormal processing of external emotional input through the limbic system, or motor dysregulation induced by emotions, takes place during these episodes. To date, imaging studies have failed to reveal consistent brain abnormalities in NC patients. METHODS: Considering the discrepancies in reported structural or functional abnormalities of the hypothalamus, amygdala, and nucleus accumbens, we used the MRI volumetry to determine the volumes of the amygdala and nucleus accumbens in a group of eleven patients with NC (5 males and 6 females, mean age 41.7 years ± 17.7). This data was compared to an equal number of examinations in healthy volunteers matched for age and gender. RESULTS: We found a decrease in the amygdalar volume of NC patients in both raw (p<0.001) and relative (p<0.01) data sets. The difference in amygdalar volume between healthy volunteers and NC patients was about 17%. In contrast to the amygdala, we did not find any differences in the volumes of nucleus accumbens. CONCLUSION: In the present MRI volumetric study, we found bilateral gray matter loss in the amygdala only.

Quantitative brain MR imaging in amyotrophic lateral sclerosis.

OBJECT: To evaluate the potential of quantitative MR techniques [voxel-based morphometry (VBM), T2-relaxometry, mean diffusivity (MD), fractional anisotropy (FA)] in the diagnostics of amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: Thirty-three ALS patients and thirty age- and sex-matched healthy volunteers were included in the cross-sectional study. T1WI, T2WI and T2 relaxometry sequences were performed at 1.5T. DWI was performed in a subgroup of 12 patients. Disease severity was estimated with the ALS Functional Rating Scale (ALS-FRS). RESULTS: We detected decreased T2 relaxation rate (R2) in the frontal white matter (FWM) (left and right P < 0.005) and caudate nucleus (left P < 0.005) in ALS patients. R2 in the FWM correlated with age in patients and controls. A correlation (P < 0.01, cluster-level corrected) between atrophy in the corona radiata and the limb ALS-FRS subset was found, as well as a difference between patients and controls in this area. No correlation between FA/MD and ALS-FRS was observed in the T2 hyperintense region of the posterior limb of the internal capsule (PLIC), or in the site of atrophy detected by VBM. No R2 or PD changes in the PLIC were detected. TBSS revealed decreased FA in the corona radiata and callosal body. CONCLUSIONS: Decreased R2 in the left caudate and bilateral FWM may help in the diagnostic process and disqualifies these regions as internal controls in ALS studies. The PLIC is not a reliable diagnostic marker of ALS.

Volumetry of the human amygdala - an anatomical study.

A striking feature of the studies that have addressed the measurement of the amygdala is the wide range of volumes encountered, with reports of volumes ranging from 1 to almost 4 cm(3). Another striking feature is the number of discrepancies in the landmarks adopted for manual tracing in magnetic resonance imaging (MRI). The goal of our study was to assess the anatomical volume of the amygdala on the basis of its cytoarchitecture while comparing the differences in age and sex. This study was performed on 21 normal male brains (mean age of 56.8 years) and 9 normal female brains (mean age of 61.2 years). The volume of the amygdala was measured by planimetry of Nissl-stained serial sections using ImageJ software. To address the complexity of the amygdala, we elected to use two types of amygdalar measurement that differ mainly in the definition of anterior pole boundaries. The average size of the classic amygdala was 1.24 cm(3) (S.D.=0.14), while the average size of the amygdala with wider borders was 1.63 cm(3) (S.D.=0.2). No interhemispheric or intersexual differences were observed for either type of amygdalar measurement. Neither sex revealed any statistically important relationship between volume of the amygdala and age. Our study was concerned exclusively with the anatomical volume of the amygdala rather than the MRI volume. Nevertheless, our results may have important implications for MRI studies because as of yet there is no gold standard for manual volumetry of the amygdala.