Gerard M. Perera

Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer's disease.

The hippocampal formation is composed of separate anatomical regions interconnected to form a circuit, and investigating abnormal hippocampal function is most revealing at the level of these regions. Until recently, regional analysis of the hippocampal formation could be performed only in animals or in human postmortem tissue. Here, we report a method using functional magnetic resonance imaging that evaluates the hippocampal regions in vivo, and we use this method to study elderly with normal memory, with isolated memory decline, and with probable Alzheimers disease (AD). Although age‐related memory decline occurs commonly, the cause of this decline remains unknown, with disagreement as to whether this decline represents one or more etiologies. Analysis revealed two distinct patterns of regional dysfunction among elderly with isolated memory decline—one pattern similar to that found in elders with AD, involving all hippocampal regions, and a second pattern with dysfunction restricted to only one hippocampal region, the subiculum. These results offer direct evidence of hippocampal dysfunction associated with memory decline in the elderly, and implicate both predementia AD and non‐AD processes as possible underlying causes. Ann Neurol 1999;45:466–472

Circuit mechanisms underlying memory encoding and retrieval in the long axis of the hippocampal formation

Circuits within the hippocampal formation are active during memory processing. Here we used functional magnetic resonance imaging (fMRI) to examine multiple sites across the long axis of the hippocampal formation while subjects performed different phases of an associative memory task, learning to associate faces with names. Viewing faces and hearing names in isolation resulted in separate hippocampal activation patterns. Pairing faces with names resulted a spatially redistributed activation pattern, rather than a simple summation of the activation patterns resulting from viewing faces and hearing names in isolation. Recalling names when cued with faces reactivated a pattern similar to that found during paired training. Finally, the activation patterns representing faces and names were found to be experience dependent, emerging with repeated exposure. Interpreted in the context of hippocampal anatomy and physiology, these findings reveal hippocampal circuit mechanisms that underlie memory encoding and retrieval.

Imaging Physiologic Dysfunction of Individual Hippocampal Subregions in Humans and Genetically Modified Mice

We have developed a variant of functional magnetic resonance imaging (fMRI) designed to be sensitive to static neuronal function. This method is based on resting instead of dynamic changes in oxygen-dependent signal and therefore allows for a spatial resolution that can detect signal from different hippocampal subregions in human subjects as well as in mice. We found that hippocampal signal was significantly diminished in elderly subjects with memory decline compared to age-matched controls, and different subjects showed dysfunction in different subregions. Among healthy elders, signal intensity from the subiculum was correlated selectively with memory performance. This method does not require an activation task; it can be used in anesthetized normal and in genetically modified and cognitively impaired mice. In mice the signal was found to be sufficiently sensitive to detect functional changes in the absence of underlying anatomical changes.

Evaluating the function of hippocampal subregions with high-resolution MRI in Alzheimer's disease and aging

Memory ability declines in older age groups. There is a growing list of physiological processes that target the hippocampal formation in an age‐related fashion, and some might underlie the hippocampal component of memory decline. The hippocampal formation is comprised of separate subregions, and physiological processes differentially target these subregions. The ability to evaluate the functional integrity of individual subregions—performing subregional analysis—is a major clinical goal since it can aid in the diagnosis of memory decline, as well as in elucidating mechanisms of disease and testing potential interventions. Because of its superior spatial resolution, magnetic resonance imaging (MRI) is best suited to accomplish this goal. Despite limited success, most functional MRI (fMRI) protocols have difficulty in performing complete subregional analysis of the hippocampal formation. Here we address sources of difficulty by (1) generating T2* ‐weighted maps of the hippocampal formation with sub‐millimeter resolution; and (2) by adapting an approach used by animal investigators to identify the hippocampal subregions using anatomical landmarks. The protocol is tested in patients with Alzheimers disease and in healthy controls, in an effort to determine whether it can detect neuronal dysfunction. Results showed diminished signal in the hippocampal formation of patients with Alzheimers disease (AD) compared to controls, and multivariate analysis showed that this difference was most prominent in the entorhinal cortex. The protocol can be used to perform subregional analysis of the hippocampal formation. Testing the protocol in other clinical populations is needed to demonstrate its efficacy in evaluating the neuronal integrity of all hippocampal subregions. Microsc. Res. Tech. 51:101–108, 2000.

SPECT imaging of odor identification in schizophrenia

Deficits in olfactory identification, despite normal odor perception, are found in some neuropsychiatric disorders, including schizophrenia. We examined if regional cerebral blood flow (rCBF) differed between schizophrenia patients and controls during odor identification, hypothesizing that these brain regions could be relevant to odor identification impairments. Eight schizophrenia and eight comparison subjects provided a baseline (picture identity matching) and activation (odor identification) SPECT scan, obtained using 99mTc-HMPAO in a low dose/high dose design. Six patients and seven controls had analyzable data. MEDX data saved in ANALYZE format for SPM 95 generated paired t-test statistical data for display in Talairach space, with rCBF changes given as Z-scores. There was no schizophrenia vs. control group difference in rCBF for the baseline picture-matching test. For odor identification, schizophrenia patients had a hypometabolic right-sided cortical region that included the frontal lobe Brocas area, superior temporal lobe, and supramarginal and angular gyri. Post hoc within-group contrasts of picture-matching vs. odor identification showed that the controls significantly increased rCBF in the right-sided inferior temporal fusiform gyrus, and bilateral hippocampi and visual association areas for the odor test. The schizophrenia group showed no rCBF differences for picture-matching compared to odor identification. Patients showed significant hypometabolism in right-sided cortical areas for odor identification. They also failed to show increased rCBF in the hippocampus and visual association area, as seen in controls for odor identification compared to picture-matching. These regions may be unique to schizophrenia or have broader implications for olfactory memory retrieval.

Image distortion in MRI-based polymer gel dosimetry of Gamma Knife stereotactic radiosurgery systems

We have studied effects of MR (magnetic resonance) image distortion on polymer gel dosimetry of Gamma Knife stereotactic radiosurgery systems. MR images of BANG polymer gel phantoms were acquired by using a Hahn spin-echo sequence and a fast 3D imaging GRASS sequence. Image artifacts were studied by varying the directions of frequency encoding and the receiver bandwidth. The phantoms were also CT (computed tomography) scanned. The studies showed that the measured dose distributions are shifted by 1.8+/-0.5 mm (2 pixels) in the frequency encoding direction. The magnitude of the shift is inversely proportional to the receiver bandwidth in agreement with theory. Comparison of MRI with CT showed the same image shift. We concluded that the discrepancy is caused by MR image distortion due to a difference in susceptibility effects between the phantom and the fiducial markers of the Leksell localization box.

Functional magnetic resonance imaging study of word recognition in normal elders

Four healthy, cognitively intact elders participated. Subjects underwent fMRI scanning while performing a word recognition task with an easy condition (low demand) and a difficult condition titrated to each subjects ability (titrated demand). Relative to low, titrated demand was associated with increased activation of the left medial frontal (cluster level P <.002), right superior temporal (P <.007) and right superior parietal cortices (P<.001). Increased activation of bilateral cortical areas by elders during the more challenging titrated demand compared with low demand may indicate recruitment of additional brain regions, enabling subjects to maintain performance despite increasing difficulty. Alternatively, the bilateral activation on this word recognition task may reflect compensatory use of right hemisphere networks.

Activation detection in fMRI data via multiscale singularity detection

Detection of active areas in the brain by functional magnetic resonance imaging (fMRI) is a challenging problem in medical imaging. Moreover, determining the onset and end of activation signal at specific locations in 3-space can determined networks of temporal relationships required for brain mapping. We introduce a method for activation detection in fMRI data via wavelet analysis of singular features. We pose the problem of determining activated areas as singularity detection in the temporal domain. Overcomplete wavelet expansion at integer scales are used to trace wavelet modulus maxima across scales to construct maxima lines. Form these maxima lines, singularities in the signal are located corresponding to the onset and end of an activation signal. We present result for simulated phantom waveforms and clinical fMRI dat from human finger tapping experiments. Different levels of noise were added to two waveforms of phantom data. No assumptions about specific frequency and amplitude of an activation signal were made prior to analysis. Detection was reliable for modest levels of random noise, but less precise at higher levels. For clinical fMRI data, activation maps were comparable to those of existing standard techniques.

Verification of beam placement accuracy in gamma knife radiosurgery by a BANG3 polymer gel dosimeter

Polymer gel dosimeter BANG3(R) was used to measure beam placement accuracy of a Leksell Gamma Knife radiosurgery unit. The authors did two experiments over a five-month period. Both show a 1.8-mm (corresponding to the size of two pixels) shift of measured dose distributions relative to the isodose lines calculated by the treatment planning software in the left-right direction. There is no observable error in the anterior-posterior direction. The authors have considered several sources for the observed shift, which include phantom setup error, MRI image distortion due to field inhomogeneity and non-linearity, treatment planning software error, and design/manufacturing error of the radiosurgery unit. The observed error has not been identified using the quality assurance procedure recommended by the manufacturer. The authors have demonstrated, therefore, that the polymer gel dosimeter is useful to verify the beam placement accuracy of a Leksell Gamma Knife unit as a part of acceptance test of hardware and treatment planning software. They recommend that the treatment prescription should be made considering the accuracy limit presented in this study.