Mark P. Richardson

Distant influences of amygdala lesion on visual cortical activation during emotional face processing

Emotional visual stimuli evoke enhanced responses in the visual cortex. To test whether this reflects modulatory influences from the amygdala on sensory processing, we used event-related functional magnetic resonance imaging (fMRI) in human patients with medial temporal lobe sclerosis. Twenty-six patients with lesions in the amygdala, the hippocampus or both, plus 13 matched healthy controls, were shown pictures of fearful or neutral faces in task-releant or task-irrelevant positions on the display. All subjects showed increased fusiform cortex activation when the faces were in task-relevant positions. Both healthy individuals and those with hippocampal damage showed increased activation in the fusiform and occipital cortex when they were shown fearful faces, but this was not the case for individuals with damage to the amygdala, even though visual areas were structurally intact. The distant influence of the amygdala was also evidenced by the parametric relationship between amygdala damage and the level of emotional activation in the fusiform cortex. Our data show that combining the fMRI and lesion approaches can help reveal the source of functional modulatory influences between distant but interconnected brain regions.

Encoding of emotional memories depends on amygdala and hippocampus and their interactions

We have studied patients with variable degrees of left hippocampal and amygdala pathology who performed a verbal encoding task during functional magnetic resonance imaging (fMRI) to assess the impact of pathology on emotional-memory performance and encoding-evoked activity. The severity of left hippocampal pathology predicted memory performance for neutral and emotional items alike, whereas the severity of amygdala pathology predicted memory performance for emotional items alone. Encoding-related hippocampal activity for successfully remembered emotional items correlated with the degree of left amygdala pathology. Conversely, amygdala-evoked activity with respect to subsequently remembered emotional items correlated with the degree of left hippocampal pathology. Our data indicate a reciprocal dependence between amygdala and hippocampus during the encoding of emotional memories.

Large scale brain models of epilepsy: dynamics meets connectomics

The brain is in a constant state of dynamic change, for example switching between cognitive and behavioural tasks, and between wakefulness and sleep. The brains of people with epilepsy have additional features to their dynamic repertoire, particularly the paroxysmal occurrence of seizures. Substantial effort over decades has produced a detailed description of many human epilepsies and of specific seizure types; in some instances there are known causes, sometimes highly specific such as single gene mutations, but the mechanisms of seizure onset and termination are not known. A large number of in vivo animal models and in vitro models based on animal tissues can generate seizures and seizure-like phenomena. Although in some instances there is much known about the mechanism of seizure onset and termination, across the range of models there is a bewildering range of mechanisms. There is a pressing need to bridge the gap between microscale mechanisms in experimental models and mechanisms of human epilepsies. Computational models of epilepsy have advanced rapidly, allowing dynamic mechanisms to be revealed in a computer model that can then be tested in biological systems. These models are typically simplified, leaving a need to scale up these models to the large scale brain networks in which seizures become manifest. The emerging science of connectomics provides an approach to understanding the large scale brain networks in which normal and abnormal brain functions operate. The stage is now set to couple dynamics with connectomics, to reveal the abnormal dynamics of brain networks which allow seizures to occur.

Identical, but not the same: Intra-site and inter-site reproducibility of fractional anisotropy measures on two 3.0 T scanners

Diffusion Tensor Imaging (DTI) is being increasingly used to assess white matter integrity and it is therefore paramount to address the test–retest reliability of DTI measures. In this study we assessed inter- and intra-site reproducibility of two nominally identical 3 T scanners at different sites in nine healthy controls using a DTI protocol representative of typical current “best practice” including cardiac gating, a multichannel head coil, parallel imaging and optimized diffusion gradient parameters. We calculated coefficients of variation (CV) and intraclass correlation coefficients (ICC) of fractional anisotropy (FA) measures for the whole brain, for three regions of interest (ROI) and for three tracts derived from these ROI by probabilistic tracking. We assessed the impact of affine, nonlinear and template based methods for spatially aligning FA maps on the reproducibility. The intra-site CV for FA ranged from 0.8% to 3.0% with ICC from 0.90 to 0.99, while the inter-site CV ranged from 1.0% to 4.1% with ICC of 0.82 to 0.99. Nonlinear image coregistration improved reproducibility compared to affine coregistration. Normalization to template space reduced the between-subject variation, resulting in lower ICC values and indicating a possibly reduced sensitivity. CV from probabilistic tractography were about 50% higher than for the corresponding seed ROI. Reproducibility maps of the whole scan volume showed a low variation of less than 5% in the major white matter tracts but higher variations of 10–15% in gray matter regions. One of the two scanners showed better intra-site reproducibility, while the intra-site CV for both scanners was significantly better than inter-site CV. However, when using nonlinear coregistration of FA maps, the average inter-site CV was below 2%. There was a consistent inter-site bias, FA values on site 2 were 1.0–1.5% lower than on site 1. Correction for this bias with a global scaling factor reduced the inter-site CV to the range of intra-site CV. Our results are encouraging for multi-centre DTI studies in larger populations, but also illustrate the importance of the image processing pipeline for reproducibility.

Motor system hyperconnectivity in juvenile myoclonic epilepsy: a cognitive functional magnetic resonance imaging study

Juvenile myoclonic epilepsy is the most frequent idiopathic generalized epilepsy syndrome. It is characterized by predominant myoclonic jerks of upper limbs, often provoked by cognitive activities, and typically responsive to treatment with sodium valproate. Neurophysiological, neuropsychological and imaging studies in juvenile myoclonic epilepsy have consistently pointed towards subtle abnormalities in the medial frontal lobes. Using functional magnetic resonance imaging with an executive frontal lobe paradigm, we investigated cortical activation patterns and interaction between cortical regions in 30 patients with juvenile myoclonic epilepsy and 26 healthy controls. With increasing cognitive demand, patients showed increasing coactivation of the primary motor cortex and supplementary motor area. This effect was stronger in patients still suffering from seizures, and was not seen in healthy controls. Patients with juvenile myoclonic epilepsy showed increased functional connectivity between the motor system and frontoparietal cognitive networks. Furthermore, we found impaired deactivation of the default mode network during cognitive tasks with persistent activation in medial frontal and central regions in patients. Coactivation in the motor cortex and supplementary motor area with increasing cognitive load and increased functional coupling between the motor system and cognitive networks provide an explanation how cognitive effort can cause myoclonic jerks in juvenile myoclonic epilepsy. The supplementary motor area represents the anatomical link between these two functional systems, and our findings may be the functional correlate of previously described structural abnormalities in the medial frontal lobe in juvenile myoclonic epilepsy.

Reorganization of verbal and nonverbal memory in temporal lobe epilepsy due to unilateral hippocampal sclerosis

Summary:  Purpose: Patients with temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) often suffer from material‐specific memory impairments. The purpose of this study was to use functional magnetic resonance imaging (fMRI) to study the organization of specific memory functions in these patients.

Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy

Objective: The aim of this study was to determine if there were focal cortical abnormalities in juvenile myoclonic epilepsy (JME) using neuropsychological investigations and MRI. Methods: Twenty-eight patients with JME and a large sample of healthy controls were assessed using a series of neuropsychological tests as well as structural and diffusion tensor MRI (DTI). DTI measures assessed fractional anisotropy (FA) within a white matter skeleton. Results: Neuropsychological testing indicated subtle dysfunctions in verbal fluency, comprehension, and expression, as well as nonverbal memory and mental flexibility. Utilizing whole-brain voxel-based morphometry for gray matter MRI data and tract-based spatial statistics for white matter diffusion MRI data, we found reductions in gray matter volume (GMV) in the supplementary motor area and posterior cingulate cortex and reductions in FA in underlying white matter of the corpus callosum. Supplementary motor area FA predicted scores in word naming tasks and expression scores. Posterior cingulate cortex GMV and FA predicted cognitive inhibition scores on the mental flexibility task. Conclusions: The neuropsychological, structural, and tractography results implicate mesial frontal cortex, especially the supplementary motor area, and posterior cingulate cortex in JME.

Preoperative fMRI predicts memory decline following anterior temporal lobe resection

Background: Anterior temporal lobe resection (ATLR) benefits many patients with refractory temporal lobe epilepsy (TLE) but may be complicated by material specific memory impairments, typically of verbal memory following left ATLR, and non-verbal memory following right ATLR. Preoperative memory functional MRI (fMRI) may help in the prediction of these deficits. Objective: To assess the value of preoperative fMRI in the prediction of material specific memory deficits following both left- and right-sided ATLR. Methods: We report 15 patients with unilateral TLE undergoing ATLR; eight underwent dominant hemisphere ATLR and seven non-dominant ATLR. Patients performed an fMRI memory paradigm which examined the encoding of words, pictures and faces. Results: Individual patients with relatively greater ipsilateral compared with contralateral medial temporal lobe activation had greater memory decline following ATLR. This was the case for both verbal memory decline following dominant ATLR and for non-verbal memory decline following non-dominant ATLR. For verbal memory decline, activation within the dominant hippocampus was predictive of postoperative memory change whereas activation in the non-dominant hippocampus was not. Conclusion: These findings suggest that preoperative memory fMRI may be a useful non-invasive predictor of postoperative memory change following ATLR and provide support for the functional adequacy theory of hippocampal function. They also suggest that fMRI may provide additional information, over that provided by neuropsychology, for use in the prediction of postoperative memory decline.

Material-specific lateralization of memory encoding in the medial temporal lobe: Blocked versus event-related design

Lesion-deficit studies have provided evidence for a functional dissociation between the left medial temporal lobe (MTL) mediating verbal memory encoding and right MTL mediating non-verbal memory encoding. While a small number of functional MRI studies have demonstrated similar findings, none has looked specifically for material-specific lateralization using subsequent memory effects. In addition, in many fMRI studies, encoding activity has been located in posterior MTL structures, at odds with lesion-deficit and positron emission tomography (PET) evidence. In this study, we used an event-related fMRI memory encoding paradigm to demonstrate a material-specific lateralization of encoding in the medial temporal lobes of ten healthy control subjects. Activation was left-lateralized for word encoding, bilateral for picture encoding, and right-lateralized for face encoding. Secondly, we demonstrated the locations of activations revealed using an event-related analysis to be more anterior than those revealed using a blocked analysis of the same data. This suggests that anterior MTL structures underlie memory encoding as judged by subsequent memory effects, and that more posterior activity detected in other fMRI studies is related to deficiencies of blocked designs in the analysis of memory encoding.

Memory fMRI in left hippocampal sclerosis: optimizing the approach to predicting postsurgical memory.

Background: An optimal technique for clinical memory fMRI is not established. Previous studies suggest activity in right parahippocampal gyrus and right hippocampus shows the strongest difference between left hippocampal sclerosis (HS) patients and normal control subjects and that the difference in activity between left and right hippocampus predicts postoperative memory change. Methods: The authors studied 30 patients with mesial temporal lobe epilepsy (mTLE) and left HS, 12 of whom subsequently underwent surgery, and 13 normal control subjects. The patients who had surgery underwent neuropsychometric evaluation pre- and postoperatively. All subjects underwent a verbal memory encoding event-related fMRI study. Activation maps were assessed visually. Subsequently, the brain regions involved in the memory task were revealed by group averaging; these regions were used to determine regions of interest (ROIs) for subsequent analysis. By use of stepwise discriminant function and stepwise multiple regression, the ROIs that optimally discriminated between patients and normal control subjects and that optimally predicted postoperative verbal memory outcome were determined. Results: Visual inspection of individual patient activation statistic maps revealed noisy data that did not afford visual interpretation. Stepwise discriminant function revealed the difference between left and right hippocampal activity best discriminated between patients and normal control subjects. Stepwise multiple regression revealed left hippocampal activity was the strongest predictor of postoperative verbal memory outcome; greater left hippocampal activity predicted a greater postoperative decline in memory. Conclusions: Patients with left hippocampal sclerosis (HS) differ from normal control subjects in the distribution of memory-encoding activity between left and right hippocampus. Functional adequacy of left hippocampus best predicts postoperative memory outcome in left HS.