Faculty Bibliography

BACKGROUND: Stimulation of the subthalamic nuclei (STN) is an effective treatment for Parkinson's disease, but complaints of speech difficulties after surgery have been difficult to quantify. Speech measures do not convincingly account for such reports. OBJECTIVE: This study examined STN stimulation effects on vowel production, in order to probe whether DBS affects articulatory posturing. The objective was to compare positioning during the initiation phase with the steady prolongation phase by measuring vowel spaces for three "corner" vowels at these two time frames. METHODS: Vowel space was measured over the initial 0.25 sec of sustained productions of high front (/i/), high back (/u/) and low vowels (/a/), and again during a 2 sec segment at the midpoint. Eight right-handed male subjects with bilateral STN stimulation and seven age-matched male controls were studied based on their participation in a larger study that included functional imaging. Mean values: age = 57+/-4.6 yrs; PD duration = 12.3+/-2.7 yrs; duration of DBS = 25.6+/-21.2 mos, and UPDRS III speech score = 1.6+/-0.7. STN subjects were studied off medication at their therapeutic DBS settings and again with their stimulators off, counter-balanced order. RESULTS: Vowel space was larger in the initiation phase compared to the midpoint for both the control and the STN subjects off stimulation. With stimulation on, however, the initial vowel space was significantly reduced to the area measured at the mid-point. For the three vowels, the acoustics were differentially affected, in accordance with expected effects of front versus back position in the vocal tract. CONCLUSIONS: STN stimulation appears to constrain initial articulatory gestures for vowel production, raising the possibility that articulatory positions normally used in speech are similarly constrained.

Adapted from the work of Kahana and colleagues (e.g., Kahana, 1996), we present two measures of order of recall in neuropsychological free recall tests. These are the position on the study list of the first recalled item, and the degree of variability in the order in which items are reported at test (i.e., the temporal distance across the first four recalled items). We tested two hypotheses in separate experiments: (1) whether these measures predicted generalized cognitive ability, and (2) whether they predicted gray matter hippocampal volume. To test hypothesis 1, we conducted ordinal regression analyses on data from a group of 452 participants, aged 60 or above. Memory performance was measured with Rey's AVLT and generalized cognitive ability was measured with the MMSE test. To test hypothesis 2, we conducted a linear regression analysis on data from a sample of 79 cognitively intact individuals aged 60 or over. Memory was measured with the BSRT and hippocampal volume was extracted from MRI images. Results of Experiment 1 showed that the position of the first item recalled and the degree of output order variability correlated with MMSE scores only in the delayed test, but not in the immediate test. In Experiment 2, the degree of variability in the recall sequence of the delayed trial correlated (negatively) with hippocampal size. These findings confirm the importance of delayed primacy as a marker of cognitive ability, and are consistent with the idea that the hippocampus is involved in coding the temporal context of learned episodes.

Purpose: Production of formulaic expressions (conversational speech formulas, pause fillers, idioms, and other fixed expressions) is excessive in left hemisphere and deficient in right hemisphere and subcortical stroke. Alzheimer's (AD) speakers, having functional basal ganglia, reveal abnormally high proportions. Persons with Parkinson's disease (PD), having dysfunctional basal ganglia, were predicted to show impoverished formulaic expressions in contrast to AD speakers. This study compared PD, AD, and healthy control (HC) participants on protocols probing production and comprehension of formulaic expressions. Method: Spontaneous speech samples were recorded from 16 individuals diagnosed with Parkinson's disease (PD), 12 with Alzheimer's disease (AD), and 18 healthy control speakers (HC) followed by structured tests as probes of comprehension. Results: The PD group had lower proportions of formulaic expressions than AD or HC speakers. Comprehension testing yielded opposite contrasts: PD participants showed significantly higher performance than AD and did not differ from HC. Discussion: The finding that PD produced lower proportions of formulaic expressions than AD or HC participants supports the view that subcortical nuclei modulate production of formulaic expressions. Contrasting results on formal testing of comprehension, whereby AD performed significantly worse than PD and HC, indicate differential effects on procedural and declarative knowledge associated with these neurological conditions.

Background: Volumetric analyses of MRI data have been employed to predict conversion to Alzheimer's disease (AD), and individuals with preclinical AD tend to show atrophy in the right medial temporal lobe, which includes the hippocampus. In this study, we set out to compare a volumetric measurement of the hippocampus to a newly developed measure of hippocampal integrity in their respective potential for prediction of generalized cognitive performance (MMSE) over time. Methods: Ninety participants, who were cognitively intact at baseline and aged 60 or older, were recruited for a study on major depressive disorder (MDD) and tested twice, over three years. Linear regression models were applied to the data with the change in MMSE score as outcome, and hippocampal integrity (HI), hippocampal volume (HV), age and MDD status among the predictors. HI was measured for the left and right hippocampi as the ratio of the parenchymal voxels to the total number of voxels in an automatically determined hippocampus ROI. The ROI was determined by local affine registration of 65 previously delineated hippocampus atlases to the test subject. HVs were extracted from MRI images using an automated volumetric approach. Results: Change in MMSE performance was significantly predicted by both integrity and volume: greater HI and HV values were associated with less decline. However, when comparing predictors' contributions to the models, HI was slightly better than HV for the right side, and explained more of the variance in MMSE performance; HI and HV contributions were largely comparable for the left side. Conclusions: More research is needed to evaluate whether hippocampal integrity or hippocampal volume is a more accurate predictor of cognitive decline, but tentative results from this study appear to suggest that right side HI measures have the potential to be sensitive to future changes in general cognitive ability

Background: A common method of evaluating memory involves list learning in which the items to be remembered are presented in a temporal sequence. Studies of serial position have highlighted the importance of the order of presentation, but little attention has been paid so far to the order of recall. Following from the work of Kahana and colleagues (e.g., Kahana, 1996; Howard & Kahana, 1999), we have developed two memory indices for neuropsychological tests of memory to examine order of recall and use of temporal context. These are output order (i.e., the first item recalled) and output order variability (i.e., the temporal distance between the first four recalled items). We tested two hypotheses in separate cohorts: 1) whether these indices were correlated with generalized cognitive ability, and 2) whether they were associated with gray matter hippocampal volumes. Methods: To test hypothesis 1, we conducted ordinal and linear regression analyses on data from the Memory Evaluation Research Initiative (MERI), which comprised 680 participants, aged 60 or above. Memory performance was measured with the Rey's AVLT and we included only participants who recalled at least one item; generalized cognitive ability was measured with the MMSE. To test hypothesis 2, we analysed data from a sample of 81 cognitively intact individuals aged 60 or over. Memory was measured with the BSRT and hippocampal volume was extracted from MRI images using an automated volumetric approach. Results: Output order and variability correlated with MMSE scores only in the delayed trial, but not in the immediate trial: higher MMSE scores were associated with starting recall nearer the primacy position, and with less variability. Similarly, variability in the delayed trial correlated (negatively) with hippocampal size. Conclusions: These findings suggest that the hippocampus may be involved in coding the temporal context of the learning episode, and that measuring the ability to employ temporal information can be useful to predict future cognitive performance

Background: The APOE e4 allele, an established risk factor for AD, may act synergistically with depression to increase the risk for progressive cognitive decline and conversion to MCI/AD. However, these findings have been reported inconsistently. Methodological differences across studies, including in the definition of depression, failure to properly diagnose depression or AD, short duration of follow up, and possible inclusion of individuals with preexisting cognitive decline or MCI. These considerations prompted us to conduct a 3-year longitudinal prospective study in cognitively intact elderly individuals, who either had a diagnosis of MDD or were healthy controls, to determine if e4 and depression interacted with respect to progressive cognitive decline. We focused primarily on neurobehavioral tests sensitive to early AD and also examined the CSF total tau/Abeta42 ratio, which has been linked to incident MCI/AD-related decline. Methods: 91 participants were included in this study, age 60 and older, with an MMSE 28 at the beginning of the 3- year longitudinal investigation. 45 participants had a diagnosis of MDD. Participants underwent a comprehensive neuropsychological test battery that included the Buschke Selective Reminding Test and Boston Naming Task at baseline and annually thereafter. APOE status on all and CSFAD biomarkers on a subset of subjects were determined at baseline. Regression analyses examining neuropsych change scores (baseline to follow-up) as functions of baseline characteristics. Results: Adjusting for age and MMSE score, participants with depression and carrying. Conclusions: Our results indicate that cognitively intact depressive e4 carriers have greater decline in selective cognitive tests especially in a confrontation naming task even during a relatively short three year longitudinal period compared to controls. Additionally, increased brain AD pathology as reflected by the CSF tau/Abeta42 ratio appeared to be associated with greater decline in memory performance in all depressives, regardless of APOE e4 status

Vowels provide the acoustic foundation of communication through speech and song, but little is known about how the brain orchestrates their production. Positron emission tomography was used to study regional cerebral blood flow during sustained production of the vowel /a/. Acoustic and blood flow data from 13, normal, right-handed, native speakers of American English were analyzed to identify cerebral blood flow patterns that predicted the stability of the first and second formants of this vowel. Formants are bands of resonance frequencies that provide vowel identity and contribute to voice quality. The results indicated that formant stability was directly associated with blood flow increases and decreases in both left and right-sided brain regions. Secondary brain regions (those associated with the regions predicting formant stability) were more likely to have an indirect negative relationship with first formant variability, but an indirect positive relationship with second formant variability. These results are not definitive maps of vowel production, but they do suggest that the level of motor control necessary to produce stable vowels is reflected in the complexity of an underlying neural system. These results also extend a systems approach to functional image analysis, previously applied to normal and ataxic speech rate that is solely based on identifying patterns of brain activity associated with specific performance measures. Understanding the complex relationships between multiple brain regions and the acoustic characteristics of vocal stability may provide insight into the pathophysiology of the dysarthrias, vocal disorders, and other speech changes in neurologic and psychiatric disorders.

BACKGROUND: The benzodiazepine lorazepam is widely utilized in the treatment of elderly individuals with anxiety disorders and related conditions. Negative effects of acute lorazepam administration on cognitive performance, especially memory, have been reported in both previously untreated elderly and in individuals who have received short term (up to three weeks) treatment with therapeutic doses. However, it remains unclear if these adverse cognitive effects also persist after long-term use, which is frequently found in clinical practice. METHODS: Cognitively intact elderly individuals (n=37) on long-term (at least three months) daily treatment with lorazepam were studied using a double-blind placebo-controlled cross-over study design. Subjects were administered their highest daily unit dose of lorazepam (0.25 - 3.00mg) or placebo on different days, approximately 1week apart in a random order, and were assessed on memory, psychomotor speed, and subjective mood states. RESULTS: Subjects had significantly poorer recall and slowed psychomotor performance following acute lorazepam administration. There were no significant effects on self-ratings of mood, sedation, or anxiety in the whole group, but secondary analyses suggested a differential response in subjects with Generalized Anxiety Disorder. CONCLUSIONS: The reduced recall and psychomotor slowing that we observed, along with an absence of significant therapeutic benefits, following acute lorazepam administration in elderly long-term users reinforces the importance of cognitive toxicity as a clinical factor in benzodiazepine use, especially in this population.

Background: Corpus callosum (CC) size and shape have been previously studied in Alzheimer's disease (AD) with the majority of studies having been cross-sectional. Due to the large variance in normal CC morphology, cross-sectional studies are limited in statistical power. Determining individual rates of change requires longitudinal data. Physiological changes are particularly relevant in mild cognitive impairment (MCI), in which CC morphology has not been previously studied longitudinally. Objective: To study temporal rates of change in CC morphology in MCI patients over a one-year period, and to determine whether these rates differ between MCI subjects who converted to AD (MCI-C) and those who did not (MCI-NC) over an average (+/-SD) observation period of 5.4 (+/-1.6) years. Methods: We used a novel multi-atlas based algorithm to segment the mid-sagittal cross-sectional area of the CC in longitudinal MRI scans. Rates of change of CC circularity, total area, and five sub-areas were compared between 57 MCI-NC and 81 MCI-C subjects. Results: The CC became less circular (-0.89% per year in MCI-NC, -1.85% per year in MCI-C) with time, with faster decline in MCI-C (p = 0.0002). In females, atrophy rates were higher in MCI-C relative to MCI-NC in total CC area (p = 0.0006), genu/rostrum (p = 0.005), and splenium (0.002). In males, these rates did not differ between groups. Conclusion: A greater than normal decline in CC circularity was shown to be an indicator of prodromal AD in MCI subjects. This measure is potentially useful as an imaging biomarker of disease and a therapeutic target in clinical trials.

Schemata are expressions that are fixed except for slots available for novel words (I'm not a ______ person). Our goals were to quantify speakers' knowledge, examine semantic flexibility in open slots, and compare performance data in two generations of speakers using cloze procedures in formulaic expressions, schemata open slots, fixed portions of schemata, and novel sentences. Fewer unique words appeared for the schemata-fixed and formulaic exemplars, reflecting speakers' knowledge of these utterances; the most semantic categories appeared for schemata-open responses. Age groups did not differ. Schemata exemplify creative interplay between novel lexical retrieval and fixed formulaic expression.