David A. Kareken

Cognitive Deficits in Chronic Heart Failure

Background:Patients with heart failure (HF) have been found to have cognitive deficits, but it remains unclear whether these deficits are associated with HF or with aging or comorbid conditions common in HF. Objectives:The purpose of this study was (a) to determine the types, the frequency, and the severity of cognitive deficits among patients with chronic HF compared with age- and education-matched healthy participants and participants with major medical conditions other than HF, and (b) to evaluate the relationships between HF severity, age, and comorbidities and cognitive deficits. Methods:A sample of 414 participants completed the study (249 HF patients, 63 healthy and 102 medical participants). The HF patients completed measures of HF severity, comorbidity (multiple comorbidity, depressive symptoms), and neuropsychological functioning. Blood pressure and oxygen saturation were assessed at interview; clinical variables were abstracted from records. Participants in the comparison groups completed the same measures as the HF patients except those specific to HF. Results:Compared with the healthy and medical participants, HF patients had poorer memory, psychomotor speed, and executive function. Significantly more HF patients (24%) had deficits in three or more domains. Higher (worse) HF severity was associated with more cognitive deficits; HF severity interacted with age to explain deficits in executive function. Surprisingly, men with HF had poorer memory, psychomotor speed, and visuospatial recall ability than women. Multiple comorbidity, hypertension, depressive symptoms, and medications were not associated with cognitive deficits in this sample. Discussion:HF results in losses in memory, psychomotor speed, and executive function in almost one fourth of patients. Patients with more severe HF are at risk for cognitive deficits. Older patients with more severe HF may have more problems in executive function, and men with HF may be at increased risk for cognitive deficits. Studies are urgently needed to identify the mechanisms for the cognitive deficits in HF and to test innovative interventions to prevent cognitive loss and decline.

Comparison of rhyming and word generation with FMRI

Functional magnetic resonance imaging (FMRI) has been successfully used to non‐invasively map language function, but has several disadvantages. These include severe motion sensitivity, which limits overt verbal responses in behavioral paradigms, such as word generation. The lack of overt responses prevents behavioral validation, making data interpretation difficult. Our objective was to compare the FMRI activation patterns of a novel silent rhyme determination task requiring a non‐verbal response, to covert word generation from visually presented letters. Five strongly right‐handed subjects performed both tasks during multi‐slice coronal echo‐planar T2*–weighted FMRI. Single subject activation maps were generated for each task by correlation analysis of single pixel time series to a boxcar reference function. These maps for the two tasks were separately interpolated to 2563, transformed into Talairach space, summed, and thresholded at t>6. Combined activation maps from both tasks showed similar robust perisylvian language area activation, including inferior frontal gyrus, posterior superior temporal lobe, and fusiform gyrus. Subjects performed well on the rhyming task, which activated left hemisphere cortical regions more selectively than the word generation task. The rhyming task showed less activation than the word generation task in areas typically not considered specifically related to language function, such as the dorsolateral prefrontal cortex and anterior cingulate. The rhyming task is a useful tool for brain mapping and clinical applications, potentially more specific to cortical language areas than verbal fluency. Hum. Brain Mapping 10:99–106, 2000.

Functional Anatomy of Human Odor Sensation, Discrimination, and Identification in Health and Aging

Aging of cerebral olfactory regions was studied in 5 younger and 6 older healthy adults, matched by odor discrimination and identification scores, with positron emission tomography during odor sensory stimulation, discrimination, and identification tasks. Sensory stimulation engaged bilateral piriform and orbitofrontal regions, but neither discrimination nor identification evoked added temporal or orbital activity. Discrimination involved the hippocampus, implicating its role in serial odor comparisons (olfactory working memory). Left inferior frontal activity during identification may reflect semantic associations. Older participants deactivated the left gyrus rectus/medial orbital gyrus (GR/MOG) during sensory stimulation but activated GR/MOG during discrimination and identification. Adjusting for detection threshold eliminated GR/MOG group differences during sensory stimulation. Diminished threshold may lead to reduced engagement of olfactory association areas.

Alcohol‐Related Olfactory Cues Activate the Nucleus Accumbens and Ventral Tegmental Area in High‐Risk Drinkers: Preliminary Findings

BACKGROUND The mesocorticolimbic dopamine system is implicated in motivation and reward and may be involved in the development of alcoholism. METHODS We used functional magnetic resonance imaging to study the blood oxygen level-dependent (BOLD) response to alcohol-related olfactory stimuli (AROS; odors of beer and whiskey) and non-alcohol-related olfactory stimuli (NAROS; odors of grass and leather) in 10 high-risk (HR) drinkers (average drinks per week, 19.99; SD, 6.99; all with > or = 2 first- or second-degree alcoholic relatives) and 5 low-risk (LR) social drinking controls (drinks per week, 2.82; SD, 2.87; 1 subject had 1 second-degree alcoholic relative). Data were analyzed with SPM99 and random effects analysis by using regions of interest and corrected cluster statistics (p < 0.05) to focus on the nucleus accumbens (NAc) and ventral tegmental area (VTA). RESULTS In HR subjects, there was a greater BOLD signal increase in the NAc during AROS than during clean air. BOLD signal increases during AROS were also greater in the NAc than the signal increases induced by NAROS. The AROS signal was significantly greater than the NAROS signal in a small number of voxels in the VTA. Finally, the AROS/NAROS difference signal was larger in HR drinkers in both the NAc and VTA. CONCLUSIONS Alcoholic olfactory cues may invoke the dopaminergic mesocorticolimbic system to a greater degree than nonalcoholic odors and could be effective tools in exploring the role of the dopamine system in susceptibility to alcoholism.

Food-Related Odor Probes of Brain Reward Circuits During Hunger: A Pilot fMRI Study

Food aromas can be powerful appetitive cues in the natural environment. Although several studies have examined the cerebral responses to food images, none have used naturalistic food aromas to study obesity. Ten individuals (five normal‐weight and five obese) were recruited to undergo 24 h of food deprivation. Subjects were then imaged on a 3T Siemens Trio‐Tim scanner (Siemens, Erlangen, Germany) while smelling four food‐related odors (FRO; two sweet odors and two fat‐related) and four “nonappetitive odors” (NApO; e.g., Douglas fir). Before the imaging session, subjects rated their desire to eat each type of food to determine their most preferred (P‐FRO). Across all 10 subjects, P‐FRO elicited a greater blood oxygenation level dependent (BOLD) response than the NApO in limbic and reward‐related areas, including the bilateral insula and opercular (gustatory) cortex, the anterior and posterior cingulate, and ventral striatum. Obese subjects showed greater activation in the bilateral hippocampus/parahippocampal gyrus, but lean controls showed more activation in the posterior insula. Brain areas activated by food odors are similar to those elicited by cues of addictive substances, such as alcohol. Food odors are highly naturalistic stimuli, and may be effective probes of reward‐related networks in the context of hunger and obesity.

Olfactory system activation from sniffing: effects in piriform and orbitofrontal cortex

Neuroimaging studies suggest that piriform cortex is activated at least in part by sniffing. We used H(2)(15)O positron emission tomography (PET) to study 15 healthy volunteers while they participated in four conditions, two of which were sniffing odorants and odorless air. The remaining two conditions involved a constant, very low flow of either odorized or odorless air during velopharyngeal closure (VPC), a technique that prevents subject-induced airflow through the nasal passages. Contrary to expectation, sniffing under odorless conditions did not induce significant piriform and surrounding cortical (PC+) activity when compared to odorless VPC, even at a liberal statistical threshold. However, a small correlation emerged in PC+ between the difference signal of [odorless sniffing - odorless VPC] and peak rate of nasal pressure change. PC+ activity was, however, strongly evoked by odorant exposure during sniffing and VPC, with neither technique showing greater activation. Activity in orbitofrontal (olfactory association) cortex was absent during odorant stimulation (OS) with VPC, but present during odorant sniffing. Sniffing may therefore play an important role in facilitating the higher-order analysis of odors. A right orbitofrontal region was also activated with odorless sniffing, which suggests a possible orbitofrontal role in guided olfactory exploration.

The neurobehavioural rating scale-revised: sensitivity and validity in closed head injury assessment

OBJECTIVES To investigate the factor structure and psychometric properties of the neurobehavioural rating scale-revised (NRS-R) and to determine its usefulness in clinical trials. METHODS A consecutive series of patients sustaining severe closed head injury were evacuated to one of 11 large regional North American trauma centres and entered into a randomised, phase III, multicentre clinical trial investigating the therapeutic use of moderate hypothermia. Acute care personnel were blinded to outcome and outcome personnel were blinded to treatment condition. The Glasgow outcome scale (GOS) was the primary outcome measure. Secondary outcome measures included the disability rating scale (DRS) and the NRS-R. RESULTS Exploratory factor analysis of NRS-R data collected at 6 months after injury (n=210) resulted in a five factor model including: (1) executive/cognition, (2) positive symptoms, (3) negative symptoms, (4) mood/affect, and (5) oral/motor. These factors showed acceptable internal consistency (0.62 to 0.88), low to moderate interfactor correlations (0.19 to 0.61), and discriminated well between GOS defined groups. Factor validity was demonstrated by significant correlations with specific neuropsychological domains. Significant change was measured from 3 to 6 months after injury for the total score (sum of all 29 item ratings) and all factor scores except mood/affect and positive symptoms. The total score and all factor scores correlated significantly with concurrent GOS and DRS scores. CONCLUSIONS The NRS-R is well suited as a secondary outcome measure for clinical trials as its completion rate exceeds that of neuropsychological assessment and it provides important neurobehavioural information complementary to that provided by global outcome and neuropsychological measures.

When What You See Isn’t What You Get: Alcohol Cues, Alcohol Administration, Prediction Error, and Human Striatal Dopamine

BACKGROUND The mesolimbic dopamine (DA) system is implicated in the development and maintenance of alcohol drinking; however, the exact mechanisms by which DA regulates human alcohol consumption are unclear. This study assessed the distinct effects of alcohol-related cues and alcohol administration on striatal DA release in healthy humans. METHODS Subjects underwent 3 PET scans with [(11)C]raclopride (RAC). Subjects were informed that they would receive either an IV Ringers lactate infusion or an alcohol (EtOH) infusion during scanning, with naturalistic visual and olfactory cues indicating which infusion would occur. Scans were acquired in the following sequence: (1) Baseline Scan: Neutral cues predicting a Ringers lactate infusion, (2) CUES Scan: Alcohol-related cues predicting alcohol infusion in a Ringers lactate solution, but with alcohol infusion after scanning to isolate the effects of cues, and (3) EtOH Scan: Neutral cues predicting Ringers, but with alcohol infusion during scanning (to isolate the effects of alcohol without confounding expectation or craving). RESULTS Relative to baseline, striatal DA concentration decreased during CUES, but increased during EtOH. CONCLUSION While the results appear inconsistent with some animal experiments showing dopaminergic responses to alcohols conditioned cues, they can be understood in the context of the hypothesized role of the striatum in reward prediction error, and of animal studies showing that midbrain dopamine neurons decrease and increase firing rates during negative and positive prediction errors, respectively. We believe that our data are the first in humans to demonstrate such changes in striatal DA during reward prediction error.

A Polymorphism in GABRA2 Is Associated With the Medial Frontal Response to Alcohol Cues in an fMRI Study

BACKGROUND Significant evidence has accumulated to suggest an association between single-nucleotide polymorphisms (SNPs) in the GABRA2 gene and alcoholism. However, research has yet to show an association between these polymorphisms and the human brains reward system function. In this study, we stratified subjects who had participated in an fMRI study of alcohol cue responses according to their genotype at a SNP in GABRA2 (rs279871) shown to be associated with alcohol dependence (Edenberg et al., 2004). METHODS Genotyping showed 13 subjects to be homozygous for the high-risk allele (AA), and 23 subjects to be heterozygous (AG). In fMRI, subjects were exposed to the aromas of their preferred alcoholic drink odors (AO), as well as to appetitive control odors (ApCO) under both alcohol intoxication and placebo control conditions. RESULTS Homozygous AA subjects had a larger [AO > ApCO] response than did AG subjects in medial frontal cortical areas thought to code reward value. However, AG subjects had a larger [AO > ApCO] effect in the ventral tegmental area. Alcohol intoxication did not alter these group differences. CONCLUSIONS These are the first data to suggest that GABRA2 genotype could affect the brains responses to cues associated with alcohol.

Neuropsychological test performance in healthy elderly volunteers before and after donepezil administration: A randomized, controlled study

Abstract: Neuropsychological performance was examined in healthy elderly participants administered the cholinesterase inhibitor donepezil. Of principal interest was examination of the sensitivity of a series of neuropsychological measures to detect cognitive changes after drug administration using typical phase I research parameters (eg, a small sample over a short treatment period). In this double-blind parallel study over a period of 6 weeks, 26 healthy elderly participants (aged 55 to 75 years) were randomized into 1 of 2 arms (14 donepezil and 12 placebo) and completed 14 days of donepezil (5 mg, twice a day) or placebo (twice a day). A battery of neuropsychological tests was administered on days 0, 14 (prerandomization), 28 (end of treatment), and 42 (washout). After 2 weeks of donepezil treatment (day 28), subjects in the donepezil group performed slightly but significantly worse on 2 tests of speed, attention, and short-term memory (P < 0.05) compared with the placebo group. No significant improvement in performance was present on any test during treatment with donepezil. These results are consistent with a previous study in healthy young participants in which transient mild worsening on some cognitive tests during donepezil administration was observed, possibly caused by perturbation of an already optimized cholinergic system in healthy participants. These results are important to consider when designing clinical development plans for putative cognitive-enhancing drugs; in addition, these results raise questions about when the optimal point to begin treatment is for patients who have not yet met criteria for dementia.