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John J Sidtis

Publications and source records attributed to John J Sidtis.

At least 19 recordsLinked to original sources

Some problems for representations of brain organization based on activation in functional imaging.

Functional brain imaging has overshadowed traditional lesion studies in becoming the dominant approach to the study of brain-behavior relationships. The proponents of functional imaging studies frequently argue that this approach provides an advantage over lesion studies by observing normal brain activity in vivo without the disruptive effects of brain damage. However, the enthusiastic onslaught of brain images, frequently presented as veridical representations of mental function, has sometimes overwhelmed some basic facts about brain organization repeatedly observed over more than a century. In particular, the lateralization of speech and language to the left cerebral hemisphere in over 90% of the right-handed population does not appear to have been taken as a serious constraint in the interpretation of imaging results in studies of these functions. This paper reviews a number of areas in which standard activation assumptions yield results that are at odds with clinical experience. The activation approach will be contrasted with a performance-based analysis of functional image data, which, at least in the case of speech production, yields results in better agreement with lesion data. Functional imaging represents enormous opportunities for understanding brain-behavior relationships, but at the present level of understanding of what is being represented in such images, it is premature to adhere to a single approach based on the strong but questionable assumptions inherent in most activation studies.

Animals↗

The effect of mifepristone (RU 486) on plasma cortisol in Alzheimer's disease.

The glucocorticoid receptor (GR) antagonist mifepristone (RU-486) has been reported to increase early morning plasma ACTH/cortisol in diverse non-demented populations. This pilot study examined the cortisol response to RU 486 in patients with Alzheimer's disease (AD), a condition associated with abnormalities in various aspects of the hypothalamic-pituitary-adrenal (HPA) axis. Nine AD subjects were randomized in a placebo-controlled parallel study: 4 in the placebo group and 5 in the RU 486 group. Subjects received oral doses of RU 486 (200 mg) or placebo daily for 6-weeks. Morning plasma cortisol was determined at baseline, at 12 h following the first study drug dose, and weekly thereafter. RU 486 resulted in a significant increase in cortisol levels [F(1,6)=65.32; P<0.001]. The magnitude of this increase grew over the course of the study [F(1,6)=63.17; P<0.001], was not related to cortisol suppression after dexamethasone and appeared greater than that reported in the literature in younger populations in response to the same drug regimen. However, further studies with age-matched controls should be done to determine possible AD related changes in this response.

Aged↗

Elevation in plasma Abeta42 in geriatric depression: a pilot study.

Elevated plasma amyloid beta 1-42 (Abeta42) level has been linked to increased risk for incident AD in cognitively-intact elderly. However, plasma Abeta levels in individuals with late-life depression (LLMD), especially those with a late age of onset of first depressive episode, who are at a particularly increased risk for Alzheimer's disease, have not been studied. We compared plasma Abeta in 47 elderly with LLMD with 35 controls and examined its relationships to age of onset of first depressive episode, antidepressant treatment (paroxetine or nortriptyline), and indices of platelet activation (platelet factor 4 and beta-thromboglobulin) and brain abnormalities. Results indicated that plasma Abeta42 levels and the Abeta42/40 ratio were elevated in the LLMD group relative to controls in the overall group analyses and in the age- and gender-matched groups. MRI data indicated that higher Abeta42/40 ratio was associated with greater severity of total white matter hyperintensity burden in LLMD. Plasma Abeta levels in LLMD were not influenced by age of onset of first depressive episode or antidepressant treatment and were not related to indices of platelet activation. Our preliminary results suggest that increased plasma Abeta42 and Abeta42/40 ratio are present in geriatric depression, and future studies should be done to confirm these findings and to determine their relationship to cognitive decline and brain abnormalities associated with LLMD.

Aged↗

Dose-dependent retrograde facilitation of verbal memory in healthy elderly after acute oral lorazepam administration.

RATIONALE: Retrograde facilitation (RF) refers to a paradoxical phenomenon in which recall of information presented before acute administration of agents generally associated with anterograde amnestic and sedative effects, such as benzodiazepines, is enhanced relative to a placebo condition. However, it is unclear whether this effect occurs in elderly individuals and if it is influenced by plasma drug levels, baseline cognitive function, or genetic factors such as the APOE e-4 allele, that may modulate drug-induced cognitive toxicity. OBJECTIVES: To determine if acute oral doses of lorazepam (0.5 mg, 1 mg) produced RF in elderly individuals exposed to interference tasks, and the variables associated with RF. MATERIALS AND METHODS: Sixty-four cognitively intact and highly educated (>12 years) older adults (mean age, 66.09 years) participated in a placebo-controlled double-blind crossover study. The Buschke Selective Reminding Test was used to assess RF and amnestic effects for verbal memory. Self-ratings of mood states were also obtained. RESULTS: Lorazepam administration resulted in significant dose-dependent RF, i.e., better recall of pre-drug word lists compared to placebo [F(1,63)= 15.358; p<0.001 and F(1,63)= 46.163; p<0.001 for 0.5 and 1 mg lorazepam, respectively]. Also, more of the pre-drug words were recalled in the 1.0-mg-lorazepam condition relative to the 0.5-mg-lorazepam condition [F(1,63)=29.498; p<0.001]. In both the 0.5 and 1 mg lorazepam conditions, participants who exhibited high RF experienced significantly greater lorazepam-induced memory impairments over time [F(3,61)=2.901; p<0.05; F(3,61)=2.698; p<0.05; 0.5 and 1 mg lorazepam, respectively]. Also, in the 1-mg-lorazepam condition, participants who exhibited high RF reported significantly greater drowsiness relative to participants who showed less RF [t(62)=-2.521; p<0.05]. RF was not significantly associated with age, the APOE epsilon4 allele, years of education, global cognitive status, vocabulary scores, or a memory index score. CONCLUSION: In healthy elderly, acute oral lorazepam administration resulted in dose-dependent RF, which was associated with greater anterograde amnestic and sedative effects.

Aged↗

Mapping cerebral blood flow during speech production in hereditary ataxia.

Dysarthria is a significant feature of the dominantly inherited spinocerebellar ataxias (SCA), but little is known about the patterns of brain activity associated with this disorder of motor speech control. Positron emission tomography (PET) was used to study regional cerebral blood flow during speech and rest in a group of 24 subjects with hereditary ataxia with mild-to-moderate dysarthria. These data were compared to the results obtained from a group of 13 age-matched, normal speakers. In the ataxic subjects, speech rates during scanning were significantly slowed compared to normal speakers. Significant reductions in mean regional blood flow were found in the cerebellum but not in supratentorial regions in the ataxic subjects. Multiple linear regression was used to model speech rate from regional blood flow. Four regions were identified as having significant relationships with speech rate in the model: the left inferior frontal and transverse temporal regions, and the right inferior cerebellar region and caudate nucleus. The relationship between flow and rate was positive in the inferior frontal and cerebellar regions and negative in the caudate and the transverse temporal region. The ataxic model represents an elaboration of the relationship previously reported for normal speakers, likely reflecting both the effects of, and compensation for, cerebellar degeneration in motor speech control. Although the mean regional blood flow values presented a pattern of functional organization for motor speech control at odds with lesion data, the performance-based model was in agreement with clinical experience. Incorporating performance data in functional image analysis may be more revealing of system characteristics than simply examining mean blood flow values.

Adult↗

Timed Gait test: normative data for the assessment of the AIDS dementia complex.

The Timed Gait test is a standardized procedure assessing motor dysfunction of lower extremities and gait abnormalities associated with AIDS dementia complex. Heretofore, interpretations of Timed Gait results have been hampered by the lack of normative data. We provide results on this test derived from 1,549 subjects (HIV-seronegatives (HIV-) and seropositives (HIV+) classified according to ADC stage). Timed Gait was found to be a useful screening and assessment tool for evaluating ADC and correlated with clinical ADC staging as well as more extensive structured neurological and neuropsychological evaluations. Analysis of covariance results (with age and education as covariates) revealed symptomatic HIV+(SX) and AIDS groups having significantly slower Timed Gait scores than those in the HIV- and asymptomatic HIV+(ASX) groups. The SX group obtained significantly slower timed gait scores than those in the AIDS group. There was a significant increase in Timed Gait scores with each increase in dementia staging with the HIV- subjects having the fastest mean Timed Gait scores and the HIV+ dementia stage 2+ having the slowest. These normative data should prove useful in both recognition of ADC and treatment response. Given its minimal training requirements, the Timed Gait would have utility in resource limited settings.

AIDS Dementia Complex↗

Dysprosodic speech following basal ganglia insult: toward a conceptual framework for the study of the cerebral representation of prosody.

Progress in understanding brain/behavior relationships in adult-acquired dysprosody has led to models of cortical hemispheric representation of prosodic processing based on functional (linguistic vs affective) or physical (timing vs pitch) parameters. These explanatory perspectives have not been reconciled, and also a number of neurobehavior syndromes that include dysprosody among their neurological signs have not yet been integrated. In addition to expanding the functional perspective on prosody, some of these syndromes have implicated a significant role of subcortical nuclei in prosodic competence. In this article, two patients with acquired dysprosodic speech following damage to basal ganglia nuclei were evaluated using behavioral, acoustic, cognitive, and radiographic approaches. Selective quantitative measures were performed on each individual's performance to provide detailed verification and clarification of clinical observations, and to test hypotheses regarding prosodic function. These studies, combined with a review of related clinical research findings, exemplify the value of a broader perspective on the neurobehavioral dysfunction underlying acquired adult dysprosodic speech, and lead to a new, proposed conceptual framework for the cerebral representation of prosody.

Adult↗

Sex-related elevation in cortisol during chronic treatment with alprazolam associated with enhanced cognitive performance.

OBJECTIVE: There is evidence of more widespread use and abuse of benzodiazepines (BZPs) among elderly women. However, factors underlying this observation are poorly understood but could be related to more intense withdrawal reactions, which are a major risk factor for continued BZP use. We previously reported elevations in interdose morning plasma cortisol levels in healthy elderly individuals after chronic treatment with alprazolam, possibly consistent with increased hypothalamic-pituitary-adrenal (HPA) axis activity and drug withdrawal. In this study, we examined sex-related differences in this population. METHOD: Twenty-five cognitively intact healthy elderly (13 women and 12 men) participated in a parallel, double-blind, placebo-controlled study that included a group that received acute and chronic (3 weeks) treatment with alprazolam (0.5 mg b.i.d.). RESULTS: Elderly women, but not men, experienced significant elevations in interdose morning plasma cortisol levels over 3 weeks of chronic treatment with alprazolam (0.5 mg b.i.d.) compared to placebo. In addition, higher morning plasma cortisol levels were significantly associated with better cognitive performance but not with higher plasma drug levels or greater degree of tolerance development to an acute alprazolam challenge. CONCLUSION: Elderly females experienced a greater interdose activation of the HPA axis during treatment with therapeutic doses of alprazolam than men, which could be related to drug withdrawal.

Aged↗

Abnormal white matter integrity in healthy apolipoprotein E epsilon4 carriers.

Apolipoprotein E epsilon4 is a major genetic risk factor for Alzheimer's disease, but the neurobiological basis for this risk is unknown. We used diffusion tensor imaging to measure diffusion anisotropy in the parahippocampal gyrus white matter in healthy elderly apolipoprotein E epsilon4 carriers and noncarriers. We also measured volumes of the lateral ventricles and temporal horns as proxies of cerebral atrophy. The epsilon4 carriers (n=14) showed significantly lower fractional anisotropy and higher radial diffusivity in the parahippocampal white matter 15 mm below the anterior commissure-posterior commissure plane than noncarriers (n=15). No group differences in ventricular volumes were found, nor were diffusion tensor imaging measures modulated by ventricular volumes. Diffusion tensor imaging may be sufficiently sensitive to detect preclinical brain changes related to Alzheimer's disease.

Aged↗

Apolipoprotein E epsilon4 allele and lorazepam effects on memory in high-functioning older adults.

CONTEXT: The apolipoprotein E (APOE) epsilon4 allele has been implicated as a significant risk factor in the development of late-onset Alzheimer disease, but the evidence of cognitive sequelae in healthy individuals has been mixed. OBJECTIVE: To determine if the APOE epsilon4 allele increases susceptibility to lorazepam-induced verbal learning impairment in nondemented older adults. DESIGN: A placebo-controlled crossover design. SETTING: A community-based sample of subjects. PARTICIPANTS: Sixty-four cognitively intact and highly educated (>12 years) adults. Twenty-four subjects (mean age, 66.3 years) were carriers of an APOE epsilon4 allele (epsilon4 positive) and 40 (mean age, 66.0 years) were not (epsilon4 negative). INTERVENTIONS: All subjects received a single oral dose of placebo and lorazepam (0.5 and 1.0 mg) 1 week apart. MAIN OUTCOME MEASURE: We used the Buschke Selective Reminding Test to assess verbal learning during a 5-hour period after placebo or lorazepam administration. RESULTS: We found a time-related, dose-dependent effect of lorazepam, with long-term recall generally decreasing with higher doses of lorazepam at up to 2.5 hours. At 5 hours, the epsilon4-negative group showed significant improvement in long-term memory, but the epsilon4-positive group demonstrated a persistent deficit. Subsequent analysis revealed that the poor performance at 5 hours was found in an epsilon4-positive subgroup with lower baseline performance. CONCLUSIONS: In cognitively intact, older adults, the effect of the APOE epsilon4 allele is not necessarily seen in the immediate response to benzodiazepine challenge. Rather, the APOE epsilon4 allele appears to affect the carrier's ability to recover from a cognitive challenge in a normal fashion, at least in a subgroup of subjects with relatively low baseline performance. This suggests that although carrying an APOE epsilon4 allele increases the risk for cognitive toxic effects, allele status alone is not a sufficient predictor of such effects. Studying the response to and the recovery from cognitive challenges may provide insights into the role of the APOE epsilon4 allele and its interaction with other factors in the development of Alzheimer disease and other age-related cognitive problems.

Aged↗

Selective reductions in plasma Abeta 1-42 in healthy elderly subjects during longitudinal follow-up: a preliminary report.

OBJECTIVE: Longitudinal changes in plasma beta amyloid protein 1-42 and 1-40 (Abeta42 and Abeta40) levels and possible relationships with cognitive decline and apolipoprotein (APOE) genotype were studied in healthy elderly individuals. METHODS: Authors determined cognitive level and plasma Abeta40 and Abeta42 levels twice, approximately 4 years apart, in 34 elderly subjects. RESULTS: Analyses revealed a selective reduction in Abeta42 levels at follow-up, which were not modulated by the epsilon4 allele. Greater reductions and higher baseline plasma Abeta42 levels were associated with reductions in cognitive scores. CONCLUSIONS: Alterations in plasma Abeta42 levels may be associated with subtle cognitive decline in elderly subjects without dementia.

Aged↗

Cortisol response to diazepam: its relationship to age, dose, duration of treatment, and presence of generalized anxiety disorder.

OBJECTIVE: Acute diazepam administration has been shown to decrease plasma cortisol levels consistent with decreased activity of the hypothalamic-pituitary-adrenal axis, especially in individuals experiencing stress. However, the effects of chronic diazepam treatment on cortisol have been less studied, and the relationship to age, anxiety, duration of treatment, and dose are not well understood. METHOD: This double-blind placebo-controlled study examined acute and chronic effects of diazepam on plasma cortisol levels in young (19-35 years) and elderly (60-79 years) individuals with and without generalized anxiety disorder (GAD). Subjects received single oral challenges of placebo or diazepam (2.5 mg or 10 mg) in a placebo-controlled cross-over design, followed by 3 weeks of chronic daily treatment with 2.5 mg or 10 mg diazepam or placebo taken at 10 p.m., and then by a final acute challenge with a single oral dose of the same study medication received during chronic treatment. RESULTS: The elderly experienced significant reductions in plasma cortisol levels compared to placebo both in the initial challenge and during chronic treatment, but the young did not. However, cortisol response to drug was comparable in both groups. Final challenge did not produce any significant cortisol effects in either group and the cortisol response in the elderly was significantly reduced compared to the initial challenge. GAD status was not a factor in plasma cortisol responses to diazepam. CONCLUSIONS: Diazepam reduced cortisol both acutely and during chronic treatment, but not during final challenge, consistent with some tolerance development. This effect was most apparent in the elderly compared with the young adults and was not modulated by GAD status or dosage, and was not related to drug effects on performance and on self-ratings of sedation and tension.

Adult↗

Baseline plasma GABA: its relationship to the adverse effects of acute lorazepam administration on cognition in the elderly.

The GABA system is an active target for drugs to treat a variety of disorders and the availability of an indirect measure of central GABA activity would not only enhance psychiatric research, but also permit assessment of the pharmacodynamic effects of drugs designed to act on this system. The relationships between plasma baseline pre-drug GABA concentrations and cognitive impairments induced by an acute oral dose of lorazepam (0.5 and 1.0 mg) were investigated in 22 healthy elderly individuals. Partial correlations controlling for plasma lorazepam concentrations revealed no significant relationship between baseline plasma GABA levels and lorazepam-induced impairments on tests of cognitive functioning. Plasma GABA concentration does not appear to be a useful marker of susceptibility to benzodiazepine-induced cognitive toxicity in the elderly. Other approaches to estimating central GABA activity should be pursued.

Affect↗

The effect of set on the resting state in functional imaging: a role for the striatum?

The effects of experimental set on brain activity during the resting state were identified in four positron emission tomography (PET) studies that employed different tasks, identical resting states, and the same subjects. A group of 11, right-handed, normal volunteers participated in four PET studies that shared the same block design in which four resting scans were alternated with four performance scans. The tasks were finger opposition, syllable repetition, sustained phonation, and repetitive lip closure. Each study used only one task and different studies were done on different days. Repeated measures analysis of variance revealed that resting regional cerebral blood flow was significantly affected by the task being studied. This influence varied with task and region. A series of analyses examining left/right regional pairs revealed significant effects of state (rest versus performance) and task and their interaction on most brain regions. The caudate was the only region in which state was not significant either as a main effect or in an interaction with task. Additional analyses revealed that resting and performance blood flow values from a single study were more highly correlated than were resting values across studies. Set may be associated with brain changes that fall into a class of recently described pre- and post-performance effects and may reflect the striatum's role in learning.

Adult↗

Effects of acute lorazepam administration on aminergic activity in normal elderly subjects: relationship to performance effects and apolipoprotein genotype.

The effects of acute lorazepam challenges on plasma (p) HVA, MHPG, and 5-HIAA, and their relationship to drug-induced cognitive and motor deficits and the apolipoprotein (APOE)-epsilon4 allele were examined. Eighteen healthy elderly (8 epsilon4 carriers) received placebo or acute oral lorazepam doses (0.5 mg or 1 mg) in random sequence, 1-week apart. Cognitive assessment and plasma levels of pHVA, pMHPG, and p5-HIAA were determined at baseline and at 1, 2.5, and 5 h postchallenge. There was no drug-to-placebo difference in monoamine levels and no consistent relationship between changes in monoamine levels and cognitive performance, regardless of epsilon4 status. However, the 1.0 mg dose increased p5-HIAA in epsilon4 carriers, whereas it caused a reduction in noncarriers. Higher baseline pMHPG and p5-HIAA levels were associated with better baseline memory. The epsilon4 allele may modulate the effect of lorazepam on p5-HIAA, but further studies are needed to confirm this finding and elucidate its possible significance.

Aged↗

Increased anticholinergic challenge-induced memory impairment associated with the APOE-epsilon4 allele in the elderly: a controlled pilot study.

The degree to which elderly adults experience cognitive impairments from centrally acting anticholinergic drugs is variable, but the cause of this variability is unknown. The present study examined the epsilon4 allele as a possible modulator of the effects of trihexyphenidyl hydrochloride (Artane( trade mark )), an anticholinergic drug, on memory functioning. Of the 24 cognitively intact, elderly participants (age range 62-76), 12 who possessed the epsilon4 allele, participated in a double-blind, randomized, placebo-controlled, crossover, three-way study. All participants were tested after receiving a single oral dose of trihexyphenidyl (1 or 2 mg) or placebo, with a 7-day washout period between sessions. Memory and psychomotor tests were administered at baseline, and at 1, 2.5, and 5 h post-treatment. Results showed that participants with the epsilon4 allele demonstrated significant impairments in delayed recall after both 1 and 2 mg doses of trihexyphenidyl while the non-epsilon4 group did not. Additionally, while acute administration of the 2 mg dose significantly impaired total recall in both epsilon4 and non-epsilon4 carriers, the epsilon4 carriers showed a more persistent impairment. These findings held when participants with the epsilon2 allele were excluded from the analyses. The epsilon4 groups did not differ with respect to psychomotor performance or plasma drug levels. These results provide evidence suggesting that the epsilon4 allele plays a significant role in increasing cognitive sensitivity to trihexyphenidyl and that a temporal component of memory consolidation may be especially vulnerable. A larger study is warranted to confirm these preliminary findings.

Aged↗

Interdose elevation in plasma cortisol during chronic treatment with alprazolam but not lorazepam in the elderly.

Benzodiazepines (BZPs) have been shown to reduce hypothalamic-pituitary-adrenal (HPA) axis activity acutely in normal humans. In contrast, the effects of chronic BZP treatment on the HPA axis have not been well studied, especially in the geriatric population. This study examined the acute and chronic effects (3 weeks) of alprazolam and lorazepam on plasma cortisol in 68 subjects (60-83 years) who received 0.25 or 0.50 mg b.i.d. alprazolam, or 0.50 or 1.0 mg b.i.d. lorazepam, or placebo orally according to a randomized, double-blind, placebo-controlled parallel design. Memory assessment and blood samples for plasma cortisol were obtained prior to the morning dose on days 0, 7, 14, and 21, and at 1, 2.5, and 5 h postdrug on days 0 and 21. Assessments of anxiety and depression were carried out at days 0, 7, 14, and 21 before drug administration. Plasma cortisol was affected compared to placebo only by the 0.5 mg alprazolam dose. During the first and the last day of treatment, there was a significant drop in cortisol at 2.5 h after alprazolam compared to placebo. The predose cortisol levels increased significantly during chronic alprazolam treatment, and correlations were found between these cortisol changes and changes in depression, anxiety, and memory scores. These findings suggest that even a short period of chronic treatment with alprazolam, but not lorazepam, may result in interdose HPA axis activation in the elderly, consistent with drug withdrawal. If confirmed, this effect may contribute to an increased risk for drug escalation and dependence during chronic alprazolam treatment.

Aged↗