Biomedical subjects

Leslie K Jacobsen

Publications and source records attributed to Leslie K Jacobsen.

12 recordsLinked to original sources

PubMed2007

Abnormal hippocampal neurochemistry in smokers: evidence from proton magnetic resonance spectroscopy at 3 T.

OBJECTIVE: In animals, nicotine, the primary psychoactive constituent of tobacco smoke, reduces neurogenesis and increases cell loss in both hippocampus and cortex. Accordingly, tobacco smoking has been linked to reduced performance on cognitive paradigms requiring attention and working memory in humans. However, few prior studies have tested for evidence of structural brain alterations in human tobacco smokers. In this study, proton magnetic resonance spectroscopy was used to assess the effects of chronic smoking on neuronal integrity of the hippocampus and anterior cingulate cortex (ACC). METHODS: Absolute concentrations of N-acetylaspartate, total choline (tCho), and total creatine were measured in the left hippocampus and ACC in 13 chronic tobacco smokers and 13 nonsmokers matched for age, sex, and education. RESULTS: The N-acetylaspartate concentration was significantly reduced in smokers relative to nonsmokers in the left hippocampus but not in the ACC. There were no group differences in the tCho and total creatine concentrations in either voxel. However, ACC tCho concentration was positively correlated with magnitude of lifetime exposure to tobacco smoke (pack-years). CONCLUSION: The results are consistent with prior observations of hippocampal neuronal damage in rodents receiving nicotine and working memory deficits in human tobacco smokers. The positive relationship between tCho and lifetime tobacco exposure suggests that a component of tobacco smoke, presumably nicotine, may increase cortical membrane turnover or modify cell density. Together, these results add to growing evidence that nicotine exerts neurotoxic effects in human brain, although an a priori nature of the findings cannot be ruled out.

Adult↗

PubMed2006

C957T polymorphism of the dopamine D2 receptor gene modulates the effect of nicotine on working memory performance and cortical processing efficiency.

RATIONALE: In both animals and humans, nicotine produces behavioral effects that vary across individuals. Studies examining the role of genetic variability in modulating individual response to nicotine in humans have increased, with recent work showing that genetic variation at the dopamine D2 receptor (DRD2) predicts response to pharmacotherapy for tobacco dependence. OBJECTIVES: To determine whether a polymorphism of the DRD2 gene, C957T, that alters DRD2 binding availability in humans modifies the effects of nicotine on verbal working memory performance and on processing efficiency of brain regions that support verbal working memory. MATERIALS AND METHODS: Working memory and brain function were assessed in 36 adult subjects (15,957T allele carriers and 21,957C homozygotes), each of whom was studied twice, once after placement of a placebo patch and once after placement of a nicotine patch. Brain function was assessed using functional magnetic resonance imaging while the subjects performed a verbal working memory task. RESULTS: During performance of a task with high verbal working memory load, nicotine administration worsened performance accuracy and reduced the processing efficiency of brain regions that support phonological rehearsal during verbal working memory in carriers of the 957T allele. CONCLUSIONS: These findings are consistent with the notion that genetic variation in DRD2 contributes to individual variation in a range of behavioral and brain responses to nicotine in humans.

Adult↗

PubMed2006

Functional correlates of verbal memory deficits emerging during nicotine withdrawal in abstinent adolescent cannabis users.

BACKGROUND: Cannabis remains the most widely used illicit substance by adolescents and is typically consumed by this population in the context of ongoing tobacco use. Human studies have shown that both cannabis and tobacco exert effects on cognitive function; however, little is known about possible interacting effects of these drugs on brain function and cognition during adolescent development. METHODS: Verbal learning and memory were assessed in 20 adolescent users of tobacco and cannabis and 25 adolescent tobacco users with minimal history of cannabis use. Functional magnetic resonance imaging was used to examine brain function and functional connectivity while a subset of these subjects performed a verbal working memory task. RESULTS: Delayed recall of verbal stimuli deteriorated during nicotine withdrawal among cannabis users but not among comparison subjects. During high verbal working memory load, nicotine withdrawal selectively increased task-related activation of posterior cortical regions and was associated with disruption of frontoparietal connectivity in adolescent cannabis users relative to comparison subjects. CONCLUSIONS: These observations suggest that cannabis use during adolescent development may disrupt neurocircuitry supporting verbal memory formation and that deficits associated with disruption of these neurocircuits are unmasked during nicotine withdrawal.

Adolescent↗

PubMed2006

Smoking and structural brain deficits: a volumetric MR investigation.

Growing evidence from animal studies indicates brain-damaging properties of nicotine exposure. Investigations in humans found a wide range of functional cerebral effects of nicotine and cigarette smoking, but studies focusing on brain damage are sparse. In 22 smokers and 23 never-smokers possible differences of the cerebral structures were investigated using magnetic resonance imaging and voxel-based morphometry. Significantly smaller grey matter volume and lower grey matter density (P = 0.05, corrected) were observed in the frontal regions (anterior cingulate, prefrontal and orbitofrontal cortex), the occipital lobe and the temporal lobe including parahippocampal gyrus, in smokers than in never-smokers. Group differences of either grey matter volume or grey matter density were also found in the thalamus, cerebellum and substantia nigra, among other regions. Smokers did not show greater volumes than never-smokers in any cerebral region. Magnitude of lifetime exposure to tobacco smoke (pack-years) was inversely correlated with volume of frontal and temporal lobes and cerebellum (P = 0.001, uncorrected). The data indicate structural deficits of several cortical and subcortical regions in smokers relative to never-smokers. The topographic profile of the group differences show some similarities to brain networks known to mediate drug reinforcement, attention and working memory processing. The present findings may explain in part the frequently reported cognitive dysfunctions in chronic cigarette consumers.

Adult↗

PubMed2005

Visuospatial memory deficits emerging during nicotine withdrawal in adolescents with prenatal exposure to active maternal smoking.

Active maternal smoking during pregnancy elevates the risk of cognitive deficits and tobacco smoking among offspring. Preclinical work has shown that combined prenatal and adolescent exposure to nicotine produces more pronounced hippocampal changes and greater deficits in cholinergic activity upon nicotine withdrawal than does prenatal or adolescent exposure to nicotine alone. Few prior studies have examined the potential modifying effects of gestational exposure to active maternal smoking on cognitive or brain functional response to tobacco smoking or nicotine withdrawal in adolescents. We examined visuospatial and verbal memory in 35 adolescent tobacco smokers with prenatal exposure to active maternal smoking and 26 adolescent tobacco smokers with no prenatal exposure to maternal smoking who were similar in age, educational attainment, general intelligence, and baseline plasma cotinine. Subjects were studied during ad libitum smoking and after 24 h of abstinence from smoking. A subset of subjects from each group also underwent functional magnetic resonance imaging while performing a visuospatial encoding and recognition task. Adolescent tobacco smokers with prenatal exposure experienced greater nicotine withdrawal-related deficits in immediate and delayed visuospatial memory relative to adolescent smokers with no prenatal exposure. Among adolescent smokers with prenatal exposure, nicotine withdrawal was associated with increased activation of left parahippocampal gyrus during early recognition testing of visuospatial stimuli and increased activation of bilateral hippocampus during delayed recognition testing of visuospatial stimuli. These findings extend prior preclinical work and suggest that, in human adolescent tobacco smokers, prenatal exposure to active maternal smoking is associated with alterations in medial temporal lobe function and concomitant deficits in visuospatial memory.

Adolescent↗

PubMed2005

Effects of smoking and smoking abstinence on cognition in adolescent tobacco smokers.

BACKGROUND: In adult animals and humans, nicotine can produce short-term cognitive enhancement and, in some cases, neuroprotection. Recent work in animals, however, suggests that exposure to nicotine during adolescence might be neurotoxic. We tested for evidence of acute and chronic effects of tobacco smoking on cognition in adolescents who smoked tobacco daily and were compared with adolescent nonsmokers. METHODS: Verbal working memory, verbal learning and memory, selective, divided, sustained attention, mood, symptoms of nicotine withdrawal, and tobacco craving were examined in 41 adolescent daily smokers and 32 nonsmokers who were similar in age, gender, and education. Analyses were controlled for general intelligence, reading achievement, parental educational attainment, baseline affective symptoms, and lifetime exposure to alcohol and cannabis. RESULTS: In adolescent smokers, cessation of tobacco use increased tobacco craving, symptoms of nicotine withdrawal, and depressed mood. Adolescent smokers were found to have impairments in accuracy of working memory performance irrespective of recency of smoking. Performance decrements were more severe with earlier age of onset of smoking. Adolescent smokers experienced further disruption of working memory and verbal memory during smoking cessation. As a group, male smokers initiated smoking at an earlier age than female smokers and were significantly more impaired during tests of selective and divided attention than female smokers and nonsmokers. CONCLUSIONS: Adolescent daily tobacco smokers experience acute impairments of verbal memory and working memory after smoking cessation, along with chronic decrements in cognitive performance that are consistent with preclinical evidence that neurotoxic effects of nicotine are more severe when exposure to nicotine occurs at earlier periods in development.

Adolescent↗

PubMed2005

Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene.

UNLABELLED: A polymorphism involving a variable number of tandem repeats (VNTR) has been described in the 3' untranslated region of the gene (SLC6A3) coding for the dopamine transporter (DAT). This polymorphism has 2 common alleles, designated as 10-repeat (*10R) and 9-repeat (*9R), that have been linked with several human clinical phenotypes. Previous investigations of the effects of the SLC6A3 polymorphism on DAT availability in smaller samples of humans have yielded divergent results. METHODS: We assessed genotype at the SLC6A3 promoter VNTR polymorphism in 96 healthy European Americans (age range, 18-88 y) who also underwent SPECT with (123)I-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane (beta-CIT) for measurement of striatal DAT protein availability. A ratio of specific to nondisplaceable brain uptake (i.e., V(3)'' = [striatal -occipital]/occipital), a measure proportional to the binding potential, was derived. For this analysis, 9-9 homozygotes and 9-10 heterozygotes were grouped as SLC6A3 *9R carriers and contrasted with SLC6A3 *10R homozygotes. RESULTS: The SLC6A3 *9R carriers had significantly higher striatal DAT availability (V(3)'') than did the SLC6A3 *10R homozygotes, controlling for age (F(1,93) = 6.25, P = 0.014, analysis of covariance). The *9R carriers (n = 41, 49.8 +/- 19.5 y) had a mean increase in striatal DAT availability of 8.9% relative to the *10R homozygotes (n = 53, 49.9 +/- 19.2 y). Striatal subregion analysis revealed that the effect of DAT genotype was significant for both the caudate and the putamen. CONCLUSION: These results support the interpretation of higher DAT levels in association with the *9R allele in European Americans and may relate to previously observed associations between DAT genotype and neuropsychiatric diseases.

Adolescent↗

PubMed2004

Nicotine effects on brain function and functional connectivity in schizophrenia.

BACKGROUND: Nicotine in tobacco smoke can improve functioning in multiple cognitive domains. High rates of smoking among schizophrenic patients may reflect an effort to remediate cognitive dysfunction. Our primary aim was to determine whether nicotine improves cognitive function by facilitating activation of brain regions mediating task performance or by facilitating functional connectivity. METHODS: Thirteen smokers with schizophrenia and 13 smokers with no mental illness were withdrawn from tobacco and underwent functional magnetic resonance imaging (fMRI) scanning twice, once after placement of a placebo patch and once after placement of a nicotine patch. During scanning, subjects performed an n-back task with two levels of working memory load and of selective attention load. RESULTS: During the most difficult (dichotic 2-back) task condition, nicotine improved performance of schizophrenic subjects and worsened performance of control subjects. Nicotine also enhanced activation of a network of regions, including anterior cingulate cortex and bilateral thalamus, and modulated thalamocortical functional connectivity to a greater degree in schizophrenic than in control subjects during dichotic 2-back task performance. CONCLUSIONS: In tasks that tax working memory and selective attention, nicotine may improve performance in schizophrenia patients by enhancing activation of and functional connectivity between brain regions that mediate task performance.

Adult↗

PubMed2004

Central serotonin transporter availability measured with [123I]beta-CIT SPECT in relation to serotonin transporter genotype.

OBJECTIVE: A functional polymorphism has been described in the promoter region of the gene (SLC6A4) coding for the serotonin transporter protein (SERT). This polymorphism has two common alleles, designated as long and short. Each allele has been linked with a number of human clinical phenotypes, including neuropsychiatric diseases associated with dysregulation of serotonin transmission. In vitro studies of nonneural cells have suggested that the long allele may have higher transcriptional activity than the short allele. However, the relevance of these findings for SERT levels in the brain remains unclear. METHOD: The authors assessed genotypes at the SLC6A4 promoter polymorphism in 96 healthy European American subjects who underwent single photon emission computed tomography scanning with [123I]2beta-carbomethoxy-3beta-(4-iodophenyl) tropane ([123I]beta-CIT) for measurement of central SERT availability. A ratio of specific to nondisplaceable brain uptake (i.e., V3"=[brainstem-diencephalon-occipital]/occipital), a measure proportional to the binding potential (Bmax/KD), was derived. RESULTS: The results showed that the main effect of genotype was significant. Post hoc Tukey pairwise comparisons revealed that the short-short homozygotes had significantly greater SERT availability than the long-short heterozygotes. There was a nonsignificant tendency for the long-long homozygotes to have greater SERT availability than the heterozygotes, but no difference was observed between the long-long homozygotes and the short-short homozygotes. The effect of age was significant in the analysis of covariance model. CONCLUSIONS: These results do not suggest higher central SERT levels in association with the long allele in European American subjects but point to a more complex relationship between SLC6A4 genotype and protein availability.

Adolescent↗

PubMed2004

Impact of cannabis use on brain function in adolescents.

Cannabis is the most common illicit substance used by adolescents. This paper reports results of a pilot study using fMRI and a working memory task to compare brain function of adolescent cannabis users to that of two control groups, one matched for tobacco use and the other for nonsmokers.

Adolescent↗

PubMed2003

Preliminary evidence of hippocampal dysfunction in adolescent MDMA ("ecstasy") users: possible relationship to neurotoxic effects.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is a potent and selective serotonin neurotoxin whose use is growing among adolescents. Although cognitive deficits among adult MDMA users are well documented, little is known of the cognitive and brain functional sequelae of MDMA use during adolescence. OBJECTIVE: We tested for evidence of cognitive deficits and changes in brain function in a pilot sample of adolescent MDMA users, who were compared with adolescent non-users of MDMA. METHODS: Selective and divided attention and verbal working memory were examined in six adolescent MDMA users and six non-users of MDMA who were similar in age, gender, IQ, and other substance use. Brain function was assessed during performance of the working memory task using functional magnetic resonance imaging (fMRI). RESULTS: MDMA users had significantly prolonged reaction times during tests of selective and divided attention, and failed to deactivate the left hippocampus normally during high verbal working memory load. CONCLUSIONS: MDMA use in adolescence may be associated with cognitive impairments and dysfunction of inhibitory circuits within the hippocampus. Further work is urgently needed to delineate the developmental impact and long-term functional and clinical significance of MDMA use during adolescence.

Adolescent↗

PubMed2002

Impact of intravenous nicotine on BOLD signal response to photic stimulation.

Functional magnetic resonance imaging (fMRI) is increasingly being applied in the study of brain effects of nicotine. In addition, because tobacco smoking is common, many subjects studied with fMRI for other reasons may have appreciable levels of nicotine in plasma and brain during scanning. However, there is concern that the vascular effects of nicotine may alter the coupling between blood oxygen level dependent (BOLD) signal and neuronal activity. The objective of this study was to test for evidence of alteration of BOLD signal response of occipital cortex, a region with a relatively low concentration of neuronal nicotine receptors, to photic stimulation during intravenous infusion of nicotine. Nine nicotine dependent healthy smokers were withdrawn from nicotine under controlled conditions and then scanned while receiving photic stimulation and successive intravenous infusions of saline and nicotine. No evidence for an effect of nicotine on BOLD signal response to photic stimulation was detected at the doses studied. This observation suggests that nicotine does not alter the coupling between BOLD signal and neuronal activity in the visual cortex.

Humans↗