Joel T. Lee

Where the brain grows old: decline in anterior cingulate and medial prefrontal function with normal aging.

Even healthy adults worry about declines in mental efficiency with aging. Subjective changes in mental flexibility, self-regulation, processing speed, and memory are often cited. We show here that focal decreases in brain activity occur with normal aging as measured with fluorodeoxyglucose and positron emission tomography. The largest declines localize to a medial network including the anterior cingulate/medial prefrontal cortex, dorsomedial thalamus, and sugenual cingulate/basal forebrain. Declining metabolism in this network correlates with declining cognitive function. The medial prefrontal metabolic changes with aging are similar in magnitude to the hypometabolism found in Mild Cognitive Impairment or Alzheimers disease. These results converge with data from healthy elderly indicating dysfunction in the anterior attention system. The interaction of attention in the anterior cingulate cortex with memory in the medial temporal lobe may explain the global impairment that defines dementia. Despite the implications for an aging population, the neurophysiologic mechanisms of these metabolic decreases remain unknown.

Weight loss during chronic, cervical vagus nerve stimulation in depressed patients with obesity: an observation.

Fourteen patients were treated over 2 years with cervical vagus nerve stimulation (VNS) for adjunctive therapy of severe, treatment-resistant depression. Here, we report the serendipitous observation that this treatment was associated with highly significant, gradual weight loss despite the patients’ report of not dieting or exercising. The weight loss was proportional to the initial BMI, that is, the more severe the obesity, the greater the weight loss. Weight loss did not correlate with changes in mood symptoms. The vagus nerve carries visceral information to and from the brain; modulation of its activity may alter eating behavior. Chronic cervical VNS may merit controlled study for the treatment of severe obesity.

PET study of the localization and laterality of lingual somatosensory processing in humans

Regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) during four tasks in right-handed volunteers with eyes closed: resting, protruding the tongue, stroking the left side of the protruding tongue, and stroking the right side of the protruding tongue. The primary somatosensory tongue representation (S1) mapped to the contralateral central sulcus (Brodmann (BA) 3/4) at approximately 28 mm above the intercommissural plane. Of note, stimulation of the left side of the tongue produced also an ipsilateral S1 response. Analysis of variance (ANOVA) of rCBF at S1 across all four conditions yielded only a significant effect for tongue stimulation, with no effect of laterality; the usually large asymmetries (contralateral >> ipsilateral) in S1 did not surface. We hypothesize that this atypical activation pattern arises from the tongues specialization for language.

Chronic vagus nerve stimulation for treatment-resistant depression decreases resting ventromedial prefrontal glucose metabolism

Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treatment-resistant depression (TRD). Its mechanism of action is not fully understood. Longitudinal measurement of changes in brain metabolism associated with VNS can provide insights into this new treatment modality. Eight severely depressed outpatients who were highly treatment-resistant underwent electrical stimulation of the left vagus nerve for approximately one year. The main outcome measures were resting regional brain glucose uptake measured with positron emission tomography (PET) and the 24-item Hamilton Depression Scale. The most significant and extensive change over one year of chronic VNS localized to the ventromedial prefrontal cortex extending from the subgenual cingulate to the frontal pole. This region continued to decline in metabolism even toward the end of the study. Clinically, this cohort showed a trend for improvement. No correlations surfaced between change in glucose uptake and depression scores. However, the sample size was small; none remitted; and the range of depression scores was limited. Chronic VNS as adjunctive therapy in patients with severe TRD produces protracted and robust declines in resting brain activity within the ventromedial prefrontal cortex, a network with dense connectivity to the amygdala and structures monitoring the internal milieu.

Object and spatial alternation tasks with minimal delays activate the right anterior hippocampus proper in humans

Substantial evidence indicates that the hippocampus plays a critical role in long-term declarative memory. In contrast, the role of the human hippocampus in working memory, particularly when information needs to be maintained only for a few seconds, remains controversial. Using PET, we show robust activation of the right anterior hippocampus proper during the performance of both object and spatial alternation tasks. Hippocampal activation emerged even though subjects only had to remember a single, simple stimulus over a minimum delay of 1 s. No hippocampal activation occurred when the delay was increased to 5 s. This suggests that the role of the hippocampus in working memory is not to maintain information across a delay interval. Instead, its activity reflects a more transient function during encoding and/or retrieval. These data are among the first observations to demonstrate human hippocampal involvement in working memory.

Functional neuroanatomy of the human near/far response to blur cues: eye‐lens accommodation/vergence to point targets varying in depth

The purpose of this study was to identify the networks involved in the regulation of visual accommodation/vergence by contrasting the cortical functions subservient to eye‐lens accommodation with those evoked by foveal fixation. Neural activity was assessed in normal volunteers by changes in rCBF measured with PET. Thirteen right‐handed subjects participated in three monocular tasks: (i) resting with eyes closed; (ii) sustained foveal fixation upon a LED at 1.2 m (0.83 D); and (iii) accommodating alternately on a near (24 cm, 4.16 D) vs. a far (3.0 m, 0.33 D) LED alternately illuminated in sequential 2 s epochs. The contrast between the conditions of near/far accommodation and of constant foveal fixation revealed activation in cerebellar hemispheres and vermis; middle and inferior temporal cortex (BA 20, 21, 37); striate cortex and associative visual areas (BA 17/18). Comparison of the condition of constant fixation with the condition of resting with closed eyes indicated activation of cerebellar hemispheres and vermis; visual cortices (BA 17/18); a right hemisphere dominant network encompassing prefrontal (BA 6, 9, 47), superior parietal (BA 7), and superior temporal (BA 40) cortices; and bilateral thalamus. The contrast between the conditions of near/far accommodation with closed‐eye rest reflected an incremental summation of the activations found in the previous comparisons (i.e. activations associated with constant fixation). Neural circuits activated selectively during the near/far response to blur cues over those during constant visual fixation, occupy posterior structures that include occipital visual regions, cerebellar hemispheres and vermis, and temporal cortex.

Neuroanatomical correlates of the near response: voluntary modulation of accommodation/vergence in the human visual system

This study identifies brain regions participating in the execution of eye movements for voluntary positive accommodation (VPA) during open‐loop vergence conditions. Neuronal activity was estimated by measurement of changes in regional cerebral blood flow (rCBF) with positron emission tomography and 15O‐water. Thirteen naive volunteers viewed a checkerboard pattern with their dominant right eye, while a lens interrupted the line of gaze during alternate 1.5 s intervals. Three counterbalanced tasks required central fixation and viewing of a stationary checkerboard pattern: (i) through a 0.0 diopter (D) lens; (ii) through a −5.0‐D lens while avoiding volitional accommodation and permitting blur; and (iii) through a −5.0‐D lens while maintaining maximal focus. The latter required large‐amplitude, high‐frequency VPA. As an additional control, seven of the subjects viewed passively a digitally blurred checkerboard through a 0.0‐D lens as above. Optometric measurements confirmed normal visual acuity and ability to perform the focusing task (VPA). Large‐amplitude saccadic eye movements, verified absent by electro‐oculography, were inhibited by central fixation. Image averaging across subjects demonstrated multifocal changes in rCBF during VPA: striate and extrastriate visual cortices; superior temporal cortices; and cerebellar cortex and vermis. Decreases in rCBF occurred in the lateral intraparietal area, prefrontal and frontal and/or supplementary eye fields. Analysis of regions of interest in the visual cortex showed systematic and appropriate task dependence of rCBF. Activations may reflect sensorimotor processing along the reflex arc of the accommodation system, while deactivations may indicate inhibition of systems participating in visual search.

Fluorodeoxyglucose positron emission tomography of mild cognitive impairment with clinical follow-up at 3 years

Alzheimers disease (AD) is the most common dementing illness. Development of effective treatments directed at AD requires an early diagnosis. Mild cognitive impairment (MCI) often heralds AD. Thus, characterizing MCI is fundamental to the early diagnosis of AD.

Internet Image Viewer (iiV)

BackgroundVisualizing 3-dimensional (3-D) datasets is an important part of modern neuroimaging research. Many tools address this problem; however, they often fail to address specific needs and flexibility, such as the ability to work with different data formats, to control how and what data are displayed, to interact with values, and to undo mistakes.ResultsiiV, an interactive software program for displaying 3-D brain images, is described. This tool was programmed to solve basic problems in 3-D data visualization. It is written in Java so it is extensible, is platform independent, and can display images within web pages.iiV displays 3-D images as 2-dimensional (2-D) slices with each slice being an independent object with independent features such as location, zoom, colors, labels, etc. Feature manipulation becomes easier by having a full set of editing capabilities including the following: undo or redo changes; drag, copy, delete and paste objects; and save objects with their features to a file for future editing. It can read multiple standard positron emission tomography (PET) and magnetic resonance imaging (MRI) file formats like ECAT, ECAT7, ANALYZE, NIfTI-1 and DICOM. We present sample applications to illustrate some of the features and capabilities.ConclusioniiV is an image display tool with many useful features. It is highly extensible, platform independent, and web-compatible. This report summarizes its features and applications, while illustrating iiVs usefulness to the biomedical imaging community.

Novel DBMS extensions for functional brain image analysis

Using computerized analysis of neuroimages can potentially enhance sensitivity and specificity in the diagnosis of psychiatric diseases, such as Alzheimers disease (AD). However, quantitative analysis of functional brain images remains a manual, tedious task. To address this problem, we are building an extended neuropsychiatric image database system to advance the study of brain images of psychiatric disease toward more comprehensive analyses. We report on our progress so far, and show the design and implementation of a suite of DBMS extensions, as well as the interface used by clinicians to compare metabolism results for single and multiple patients in specific brain regions, a task that was previously insurmountable. We are working toward a first in clinical applications of neuroimaging that bear directly upon patient assessment, diagnosis, and treatment.