Christopher Benjamin

Expression of vascular adhesion molecules in inflammatory bowel disease

The expression of the vascular adhesion molecules ELAM-1 (endothelial leukocyte adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) was evaluated in colonic mucosa of patients with inflammatory bowel disease and normal controls by immunocytochemistry. VCAM-1 was found to be constitutively expressed in lymphoid aggregates in normal colonic mucosa and was not significantly enhanced or altered in distribution in mucosa of patients with inflammatory bowel disease regardless of the activity of the inflammatory process. In contrast, ELAM-1 was not detected by these techniques in normal colonic mucosa (n = 11) or in colonic mucosa of patients with inflammatory bowel disease which was either uninvolved or quiescent (n = 30). However, high levels of ELAM-1 were consistently found on endothelial surfaces in association with active inflammation in affected areas of colonic mucosa in patients with either ulcerative colitis (n = 27) or Crohns colitis (n = 9). In addition, ELAM-1 appeared to be present within neutrophils which had migrated into crypt abscesses in affected mucosa. Similar analysis was carried out in the cotton-top tamarin (CTT), a primate that experiences an idiopathic chronic diffuse colitis resembling human ulcerative colitis. Although anti-human VCAM-1 antibodies did not react with the CTT, anti-human ELAM-1 stained endothelial surfaces in mucosal biopsies from CTT with active colitis. No ELAM-1 was identified in mucosa of CTT in which colitis activity was quiescent. Thus ELAM-1 is expressed on colonic endothelial surfaces in association with inflammation and may play an important role in facilitating leukocyte migration into sites of active IBD involvement.

Behavioral and Neural Correlates of Executive Functioning in Musicians and Non-Musicians

Executive functions (EF) are cognitive capacities that allow for planned, controlled behavior and strongly correlate with academic abilities. Several extracurricular activities have been shown to improve EF, however, the relationship between musical training and EF remains unclear due to methodological limitations in previous studies. To explore this further, two experiments were performed; one with 30 adults with and without musical training and one with 27 musically trained and untrained children (matched for general cognitive abilities and socioeconomic variables) with a standardized EF battery. Furthermore, the neural correlates of EF skills in musically trained and untrained children were investigated using fMRI. Adult musicians compared to non-musicians showed enhanced performance on measures of cognitive flexibility, working memory, and verbal fluency. Musically trained children showed enhanced performance on measures of verbal fluency and processing speed, and significantly greater activation in pre-SMA/SMA and right VLPFC during rule representation and task-switching compared to musically untrained children. Overall, musicians show enhanced performance on several constructs of EF, and musically trained children further show heightened brain activation in traditional EF regions during task-switching. These results support the working hypothesis that musical training may promote the development and maintenance of certain EF skills, which could mediate the previously reported links between musical training and enhanced cognitive skills and academic achievement.

Increased serotonin receptor availability in human sleep: Evidence from an [18F]MPPF PET study in narcolepsy

Data from animal studies suggest that serotonin release promotes wakefulness and suppresses REM sleep, but there are dangers in extrapolating these findings to humans. Binding of the radioligand [18F]MPPF to 5HT1A receptors is sensitive to levels of endogenous serotonin. In this study, we aimed to demonstrate changes in serotonin receptor availability in the human brain in wakefulness and sleep using [18F]MPPF and positron emission tomography. 14 subjects with narcolepsy cataplexy underwent [18F]MPPF PET scans in wakefulness and in sleep. Subjects who used the stimulant methylphenidate took their normal medication for the wake scan but omitted it prior to the sleep scan. The change in binding potential (BP) between the sleep and wake scans was examined using paired t test. Methylphenidate is thought to have little or no effect on serotonergic neurotransmission, and in order to confirm the absence of an effect on [18F]MPPF binding, a concurrent study was performed using a beta-microprobe technique to examine the effect of methylphenidate administration on [18F]MPPF binding in Sprague-Dawley rats. The human study showed a significant increase in [18F]MPPF binding in sleep compared to wakefulness in the whole brain and all regions of interest examined (temporal cortex, mesial temporal region and cingulate cortex). The beta-microprobe study confirmed that methylphenidate administration had no effect on [18F]MPPF binding. These findings indicate that serotonin receptor availability is increased in sleep compared to wakefulness in narcoleptic humans.

The Influence of Rest Period Instructions on the Default Mode Network

The default mode network (DMN) refers to regional brain activity that is greater during rest periods than during attention-demanding tasks; many studies have reported DMN alterations in patient populations. It has also been shown that the DMN is suppressed by scanner background noise (SBN), which is the noise produced by functional magnetic resonance imaging (fMRI). However, it is unclear whether different approaches to “rest” in the noisy MR environment can alter the DMN and constitute a confound in studies investigating the DMN in particular patient populations (e.g., individuals with schizophrenia, Alzheimers disease). We examined 27 healthy adult volunteers who completed an fMRI experiment with three different instructions for rest: (1) relax and be still, (2) attend to SBN, or (3) ignore SBN. Region of interest analyses were performed to determine the influence of rest period instructions on core regions of the DMN and DMN regions previously reported to be altered in patients with or at risk for Alzheimers disease or schizophrenia. The dorsal medial prefrontal cortex (dmPFC) exhibited greater activity when specific resting instructions were given (i.e., attend to or ignore SBN) compared to when non-specific resting instructions were given. Condition-related differences in connectivity were also observed between regions of the dmPFC and inferior parietal/posterior superior temporal cortex. We conclude that rest period instructions and SBN levels should be carefully considered for fMRI studies on the DMN, especially studies on clinical populations and groups that may have different approaches to rest, such as first-time research participants and children.

Optimization of tractography of the optic radiations

Imaging and delineation of the optic radiations (OpRs) remains challenging, despite repeated attempts to achieve reliable validated tractography of this complex structure. Previous studies have used varying methods to generate representations of the OpR which differ markedly from one another and, frequently, from the OpRs known structure. We systematically examined the influence of a key variable that has differed across previous studies, the tractography seed region, in 13 adult participants (nine male; mean age 31 years; SD 8.7 years; range 16–47). First, we compared six seed regions at the lateral geniculate nucleus (LGN) and sagittal stratum based on the literature and known OpR anatomy. Three of the LGN regions seeded streamlines consistent with the OpRs three “bundles,” whereas a fourth seeded streamlines consistent with each of the three bundles. The remaining two generated OpR streamlines unreliably and inconsistently. Two stratum regions seeded the radiations. This analysis identified a set of optimal regions of interest (ROI) for seeding OpR tractography and important inclusion and exclusion ROI. An optimized approach was then used to seed LGN regions to the stratum. The radiations, including streamlines consistent with Meyers Loop, were streamlined in all cases. Streamlines extended 0.2 ± 2.4 mm anterior to the tip of the anterior horn of the lateral ventricle. These data suggest some existing approaches likely seed representations of the OpR that are visually plausible but do not capture all OpR components, and that using an optimized combination of regions seeded previously allows optimal mapping of this complex structure. Hum Brain Mapp 35:683–697, 2014.

Elemental spatial and temporal association formation in left temporal lobe epilepsy

The mesial temporal lobe (MTL) is typically understood as a memory structure in clinical settings, with the sine qua non of MTL damage in epilepsy being memory impairment. Recent models, however, understand memory as one of a number of higher cognitive functions that recruit the MTL through their reliance on more fundamental processes, such as “self-projection” or “association formation”. We examined how damage to the left MTL influences these fundamental processes through the encoding of elemental spatial and temporal associations. We used a novel fMRI task to image the encoding of simple visual stimuli, either rich or impoverished, in spatial or spatial plus temporal information. Participants included 14 typical adults (36.4 years, sd. 10.5 years) and 14 patients with left mesial temporal lobe damage as evidenced by a clinical diagnosis of left temporal lobe epilepsy (TLE) and left MTL impairment on imaging (34.3 years, sd. 6.6 years). In-scanner behavioral performance was equivalent across groups. In the typical group whole-brain analysis revealed highly significant bilateral parahippocampal activation (right > left) during spatial associative processing and left hippocampal/parahippocampal deactivation in joint spatial-temporal associative processing. In the left TLE group identical analyses indicated patients used MTL structures contralateral to the seizure focus differently and relied on extra-MTL regions to a greater extent. These results are consistent with the notion that epileptogenic MTL damage is followed by reorganization of networks underlying elemental associative processes. In addition, they provide further evidence that task-related fMRI deactivation can meaningfully index brain function. The implications of these findings for clinical and cognitive neuropsychological models of MTL function in TLE are discussed.

The Neural Correlates of Reading Fluency Deficits in Children

Multiple studies have shown that individuals with a reading disability (RD) demonstrate deficits in posterior left-hemispheric brain regions during reading-related tasks. These studies mainly focused on reading sub-skills, and it remains debated whether such dysfunction is apparent during more ecologically valid reading skills, such as reading fluency. In this fMRI study, reading fluency was systematically varied to characterize neural correlates of reading fluency in 30 children with (RD) and without (typical developing children, TYP) a RD. Sentences were presented at constrained, comfortable, and accelerated speeds, which were determined based on individual reading speed. Behaviorally, RD children displayed decreased performance in several reading-related tasks. Using fMRI, we demonstrated that both TYP and RD children display increased activation in several components of the reading network during fluent reading. When required to read at an accelerated speed, RD children exhibited less activation in the fusiform gyrus (FG) compared with the TYP children. A region of interest analysis substantiated differences in the FG and demonstrated a relationship to behavioral reading performance. These results suggest that the FG plays a key role in fluent reading and that it can be modulated by speed. These results and their implications for remediation strategies should be considered in educational practice.

Detailed analysis of the public idiotype of anti-hen egg-white lysozyme antibodies.

For several years we have studied the idiotypy of the immune response to hen egg-white lysozyme (HEL). We have shown that almost all anti-HEL antibodies, late in the primary response and after secondary immunization, are characterized by the presence of a predominant idiotype, IdXL. This idiotype dominates the anti-HEL response in all animals so far tested: many strains of inbred mice, outbred mice, rats, deermice, and rabbits.’ IdXL, however, is largely absent on early primary anti-HEL and on monoclonal anti-HEL generated by the hybridoma technique from B cells of mice given a primary immunization nine days previously.* IdXL is also absent on antibody raised against human lysozyme (HUL) except for those rare molecules showing cross-reactivity with hen egg-white lysozyme.’ On the other hand, monoclonal anti-HEL antibodies produced by hybridomas generated from B cells of mice given a secondary immunization 3 to 5 days previously, universally show the presence of IdXL.2 These “late” monoclonal antibodies have allowed us to begin an examination of the relation of epitypic specificity and the presence of IdXL. We were able to show that two monoclonal anti-HEL of clearly different specificity (for different regions of HEL) were each reactive with anti-IdXL rabbit sera. Strikingly, each of these antibodies when immobilized on a column was able to completely absorb all anti-IdXL from rabbit sera.3 In this report, we more extensively examine the range of epitope specificity of a collection of IdXL positive secondary monoclonal anti-hen egg-white lysozyme. Also examined are the heavy chain variable region gene rearrangements present in hybridomas producing these antibodies.

Neuropsychological function in patients with a single gene mutation associated with autosomal dominant nocturnal frontal lobe epilepsy.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the alpha4 nicotinic acetylcholine receptor (nAChR). The nAChR modulates aspects of memory and attention. We examined the neuropsychological phenotype of ADNFLE, with a particular emphasis on understanding the impact on frontal lobe functions. We used standard clinical tests as well as focused measures of frontal lobe function in a well-defined group of patients with ADNFLE. Their performance was compared with that of a group of age-, sex-, and education-matched control participants. Patients with ADNFLE showed impairments on tasks requiring cognitive flexibility against a background of well-preserved intellectual abilities. In accord with existing research, verbal memory impairments were identified in the patient group; the level of impairment on these tasks correlated with disease-related factors. In our study of ADNFLE associated with one mutation, cognitive flexibility appears to be the core cognitive deficit.

Presurgical language fMRI: Mapping of six critical regions

Language mapping is a key goal in neurosurgical planning. fMRI mapping typically proceeds with a focus on Brocas and Wernickes areas, although multiple other language‐critical areas are now well‐known. We evaluated whether clinicians could use a novel approach, including clinician‐driven individualized thresholding, to reliably identify six language regions, including Brocas Area, Wernickes Area (inferior, superior), Exners Area, Supplementary Speech Area, Angular Gyrus, and Basal Temporal Language Area. We studied 22 epilepsy and tumor patients who received Wada and fMRI (age 36.4[12.5]; Wada language left/right/mixed in 18/3/1). fMRI tasks (two × three tasks) were analyzed by two clinical neuropsychologists who flexibly thresholded and combined these to identify the six regions. The resulting maps were compared to fixed threshold maps. Clinicians generated maps that overlapped significantly, and were highly consistent, when at least one task came from the same set. Cases diverged when clinicians prioritized different language regions or addressed noise differently. Language laterality closely mirrored Wada data (85% accuracy). Activation consistent with all six language regions was consistently identified. In blind review, three external, independent clinicians rated the individualized fMRI language maps as superior to fixed threshold maps; identified the majority of regions significantly more frequently; and judged language laterality to mirror Wada lateralization more often. These data provide initial validation of a novel, clinician‐based approach to localizing language cortex. They also demonstrate clinical fMRI is superior when analyzed by an experienced clinician and that when fMRI data is of low quality judgments of laterality are unreliable and should be withheld. Hum Brain Mapp 38:4239–4255, 2017.