Biomedical subjects

Jordan Grafman

Publications and source records attributed to Jordan Grafman.

At least 19 recordsLinked to original sources

PubMed2007

Neural correlates of automatic beliefs about gender and race.

Functional MRI was used to identify the brain areas underlying automatic beliefs about gender and race, and suppression of those attitudes. Participants (n = 20; 7 females) were scanned at 3 tesla while performing the Implicit Association Test (IAT), an indirect measure of race and gender bias. We hypothesized that ventromedial prefrontal cortex areas (PFC) would mediate gender and racial stereotypic attitudes, and suppression of these beliefs would recruit dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC). Performance data on the IAT revealed gender and racial biases. Racial bias was correlated with an explicit measure of racism. Results showed activation of anteromedial PFC and rostral ACC while participants implicitly made associations consistent with gender and racial biases. In contrast, associations incongruent with stereotypes recruited DLPFC. Implicit gender bias was correlated with amygdala activation during stereotypic conditions. Results suggest there are dissociable roles for anteromedial and dorsolateral PFC circuits in the activation and inhibition of stereotypic attitudes.

Adult↗

PubMed2006

Event frequency modulates the processing of daily life activities in human medial prefrontal cortex.

Event sequence knowledge is necessary to learn, plan, and perform activities of daily life. Clinical observations suggest that the prefrontal cortex (PFC) is crucial for goal-directed behavior such as carrying out plans, controlling a course of actions, or organizing everyday life routines. Functional neuroimaging studies provide further evidence that the PFC is involved in processing event sequence knowledge, with the medial PFC (Brodmann area 10) primarily engaged in mediating predictable event sequences. However, the exact role of the medial PFC in processing event sequence knowledge depending on the frequency of corresponding daily life activities remains obscure. We used event-related functional magnetic resonance imaging while healthy volunteers judged whether event sequences from high- (HF), moderate- (MF), and low-frequency (LF) daily life activities were correctly ordered. The results demonstrated that different medial PFC subregions were activated depending on frequency. The anterior medial Area 10 was differentially activated for LF and the posterior medial Area 10 for HF activities. We conclude that subregions of the medial PFC are differentially engaged in processing event sequence knowledge depending on how often the activity was reportedly performed in daily life.

Activities of Daily Living↗

PubMed2006

Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD.

BACKGROUND: A new locus for amyotrophic lateral sclerosis--frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p. METHODS: We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus. RESULTS: Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples. CONCLUSION: Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.

Amyotrophic Lateral Sclerosis↗

PubMed2006

Hemispheric specialization in human prefrontal cortex for resolving certain and uncertain inferences.

Uncertainty is a fact of life that must be accommodated in real-world decision making. Although it has been suggested that the right prefrontal cortex (PFC) has a special role to play in decision making under uncertainty, there is very little hard data to support this hypothesis. To better understand the roles of left and right PFCs in reasoning and decision making in situations with complete and incomplete information, we administered simple inference problems to 18 patients with lateralized focal lesions to PFC (9 right hemisphere, 9 left hemisphere) and 22 age- and education-matched normal controls. The stimuli were systematically manipulated for completeness of information regarding the status of the conclusion. Our results demonstrated a 2-way interaction such that patients with left PFC lesions were selectively impaired in trials with complete information, whereas patients with right PFC lesions were selectively impaired in trials with incomplete information. These results provide compelling evidence for hemispheric specialization for reasoning in PFC and suggest that the right PFC has a critical role to play in reasoning about incompletely specified situations. We postulate this role involves the maintenance of ambiguous mental representations that temper premature overinterpretation by the left hemisphere.

Adult↗

PubMed2006

Effect of prefrontal cortex damage on resolving lexical ambiguity in text.

The function of suppression of context-inappropriate meanings during lexical ambiguity resolution was examined in 25 adults with prefrontal cortex damage (PFCD) localized to the left (N=8), right (N=6), or bilaterally (N=11); and 21 matched Controls. Results revealed unexpected inverse patterns of suppression between PFCD and Control groups, with measures suggesting decreased interference across time in the PFCD group and increased interference in the Control group. The PFCD group, however, had significantly lower accuracy rates for the context-inappropriate condition. Results suggest a loss of the control aspects of inhibitory processes in lexical ambiguity resolution following PFCD. An aging effect on suppression function is also suggested.

Adult↗

PubMed2006

Human fronto-mesolimbic networks guide decisions about charitable donation.

Humans often sacrifice material benefits to endorse or to oppose societal causes based on moral beliefs. Charitable donation behavior, which has been the target of recent experimental economics studies, is an outstanding contemporary manifestation of this ability. Yet the neural bases of this unique aspect of human altruism, which extends beyond interpersonal interactions, remain obscure. In this article, we use functional magnetic resonance imaging while participants anonymously donated to or opposed real charitable organizations related to major societal causes. We show that the mesolimbic reward system is engaged by donations in the same way as when monetary rewards are obtained. Furthermore, medial orbitofrontal-subgenual and lateral orbitofrontal areas, which also play key roles in more primitive mechanisms of social attachment and aversion, specifically mediate decisions to donate or to oppose societal causes. Remarkably, more anterior sectors of the prefrontal cortex are distinctively recruited when altruistic choices prevail over selfish material interests.

Adult↗

PubMed2006

A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia.

OBJECTIVE: To evaluate neurotransmitter deficiencies and neurotransmitter-based treatments for frontotemporal dementia (FTD). METHODS: The authors conducted a systematic review of the literature on the mechanism and treatment of FTD and a meta-analysis of treatment studies of antidepressants for the behavioral symptoms of FTD. RESULTS: Patients with FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, while the acetylcholine system appears relatively intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments appear to improve the behavioral but not cognitive symptoms of FTD. CONCLUSIONS: Studies of neurotransmitter deficiencies in frontotemporal dementia (FTD) can be helpful in developing treatments. Treatment studies on FTD are scarce, given the prevalence and severity of this illness. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy. Multicenter studies are likely the best way to complete treatment studies in a timely manner.

Antidepressive Agents↗

PubMed2006

Characteristics of frontotemporal dementia patients with a Progranulin mutation.

OBJECTIVE: Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined. METHODS: In this study, we examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations. RESULTS: We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination. INTERPRETATION: Known PGRN and MAPT mutations were rare and of similar prevalence in our sample (2 compared with 1/84). The patients with the PGRN R493X mutation had a clinical presentation comparable with other behavior-predominant FTD patients. The neuropathology of an affected family member of a patient with the PGRN R493X mutation appears not to be Alzheimer's disease.

Adolescent↗

PubMed2006

Head of the caudate nucleus is most vulnerable in chorea-acanthocytosis: a voxel-based morphometry study.

Chorea-acanthocytosis (ChAc; OMIM 200150) is a rare autosomal recessive disease with dysfunction of the erythrocyte membrane, presenting with acanthocytes and neurological manifestations characterized by progressive hyperkinesias (chorea, dystonia) and neuropsychological impairment. Damage to the basal ganglia was described previously in neuropathological and neuroimaging investigations. We analyzed high-resolution MRI of six ChAc patients with mutations in the VPS13A gene (median age, 37 years; mean time since clinical onset, 13 years) with respect to regional atrophy by use of the observer-independent technique of voxel-based morphometry in comparison to 15 age-matched healthy controls. Additionally, global brain atrophy was determined using the standardized brain parenchymal fraction (BPF) method. A robust regional reduction of gray matter density was observed in the head of the caudate nucleus bilaterally and was nearly symmetrical (P < 0.001, corrected for small volumes). No additional gray matter changes were found. In the BPF analysis, there was no significant global brain atrophy. The predilection of atrophy in the head of the caudate nucleus, as suggested by our results, argues for a particular vulnerability of this part of the striatum in ChAc and is in agreement with pronounced neuropsychological disturbances that are thought to rely on these regions.

Adult↗

PubMed2006

Alzheimer's disease presenting as corticobasal syndrome.

A 60-year-old man presented with slowly progressive left hemi-Parkinsonism, left hand apraxia, myoclonus, dystonia, visuospatial disturbances, and alien limb phenomenon, resembling corticobasal syndrome. Eight years later, neuropathology revealed features of Alzheimer's disease, with asymmetrical (right more than left) cortical tau burden with image analysis. The videotaped clinical features, neuropsychological aspects, and neuropathological correlates are presented and discussed.

Alzheimer Disease↗

PubMed2006

Cognitive neural plasticity during learning and recovery from brain damage.

The process of neuroplasticity is the ability of the brain to change, either in response to experience or injury. It is a vital process both during normal development and for the recovery after brain injury. Recent research has emphasized that this takes place via both local restitution as well as reorganization and compensatory reassignment. The fact that the brain can undergo such plastic changes has provided evidence for what underlies developmental brain disorders, as well as the variable response to injury at different points in the lifespan. The factors affecting plasticity and its long-term consequences may have increasing importance in exposing the pattern of changes that occur in the normal brain with aging.

Animals↗

PubMed2006

Genetic variability in CHMP2B and frontotemporal dementia.

A nonsense/protein chain-terminating mutation in the CHMP2B gene has recently been reported as a cause of frontotemporal dementia (FTD) in the single large family known to show linkage to chromosome 3. Screening for mutations in this gene in a large series of FTD families and individual patients led to the identification of a protein-truncating mutation in 2 unaffected members of an Afrikaner family with FTD, but not in their affected relatives. The putative pathogenicity of CHMP2B mutations for dementia is discussed.

Adult↗

PubMed2006

Transverse patterning and human amnesia.

The transverse patterning (TP) task (A+ B-, B+ C-, C+ A-) has played a central role in testing the hypothesis that medial-temporal (and, in particular, hippocampal) brain damage selectively impairs learning on at least some classes of configural (i.e., nonlinear) learning tasks. Results in the animal and human literature generally support that hypothesis. Reed and Squire [Impaired transverse patterning in human amnesia is a special case of impaired memory for two-choice discrimination tasks. Behavioral Neuroscience, 113, 3-9, 1999], however, advanced an alternative account in which impaired TP performance in amnesia reflects a generic scaling artifact arising from the greater difficulty of the TP task compared to the elemental (i.e., linear) control task that is typically used. We begin with a critique of Reed and Squire, countering their conceptual arguments and showing that their results, when analyzed appropriately, support the configural deficit hypothesis. We then report results from eight new amnesic patients and controls on an improved version of the TP task. Despite substantial practice, accuracy of patients with bilateral hippocampal damage due to anoxia reached and maintained an asymptote of only 54% correct, well below the maximum accuracy obtainable (67%) in the absence of configural learning. A patient with selective bilateral damage to the anterior thalamic nuclei exhibited a TP accuracy asymptote that was near 67%, a pattern of two out of three correct consecutive trials, and a pattern of nearly always answering correctly for two of the three TP item pairs. These results are consistent with a set of unique and parameter-free predictions of the configural deficit hypothesis.

Aged↗

PubMed2006

Markedly increased vitamin B12 concentrations attributable to IgG-IgM-vitamin B12 immune complexes.

BACKGROUND: High serum vitamin B12 concentrations have been reported in patients with hepatic disease, disseminated neoplasia, myeloproliferative disorders, and hypereosinophilic syndromes. We recently discovered an extraordinarily increased vitamin B12 concentration in a patient without these underlying conditions. METHODS: Affinity and size-exclusion chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and ELISA methods were used to determine the cause of the increased vitamin B12 concentrations in this patient's serum. RESULTS: The protein G column eluates from 2 apparently healthy volunteers and 2 patients with recent vitamin B12 treatment for anemia had vitamin B12 concentrations of <74 pmol/L, whereas the vitamin B12 concentration in the protein G column eluate from the patient was 7380 pmol/L. The elution profile from size-exclusion chromatography of vitamin B12-binding proteins in the patient's serum revealed an abnormal vitamin-B12-binding protein. SDS-PAGE analysis of the concentrated eluates from the protein G column, under reducing conditions, revealed an additional band with an apparent molecular mass of 76 kDa, which was not present in control column eluates. MALDI-TOF MS identified this band as an IgM heavy chain. By use of a modified ELISA, we determined that the IgM present in the patient's eluates was associated with the IgG to form IgG-IgM immune complexes. CONCLUSIONS: This case demonstrates the unusual circumstance of a patient with markedly increased vitamin B12 concentrations attributed to immune complexes composed of IgG, IgM, and vitamin B12 and illustrates techniques that can be used to identify this occurrence.

Amyotrophic Lateral Sclerosis↗

PubMed2005

Recharging cognition with DC brain polarization.

Electrical direct current (DC) has been applied to the human head throughout history for various reasons and with claims of behavioral effects and clinical benefits. This technique has recently been rediscovered and its effects validated with modern quantitative techniques and experimental designs. Despite the very weak current used, DC polarization applied to specific brain areas can alter verbal fluency, motor learning and perceptual thresholds, and can be used in conjunction with transcranial magnetic stimulation. Compact and safe, this old technique seems poised to allow major advances cognitive science and therapy.

Cerebral Cortex↗

PubMed2005

Social contracts and precautions activate different neurological systems: an fMRI investigation of deontic reasoning.

We conducted an event-related, functional MRI investigation of 12 male's and 12 female's reasoning about conditional deontic rules, rules regulating people's behavior. We employed two different types of rules: social contracts and nonsocial, precautionary rules. Although the rules and the demands of the task were matched in terms of their logical structure, reasoning about social contracts and precautions activated a different constellation of neurological structures. The regions differentially activated by social contracts included dorsomedial PFC (BA 6/8), bilateral ventrolateral PFC (BA 47), the left angular gyrus (BA 39), and left orbitofrontal cortex (BA 10). The regions differentially activated by precautions included bilateral insula, the left lentiform nucleus, posterior cingulate (BA 29/31), anterior cingulate (BA 24) and right postcentral gyrus (BA 3). Collectively, reasoning about prescriptive rules activated the dorsomedial PFC (BA 6/8). The results reinforce the view that human reasoning is not a unified phenomenon, but is content-sensitive.

Adult↗

PubMed2005

Only spontaneous counterfactual thinking is impaired in patients with prefrontal cortex lesions.

Counterfactual thoughts (CFT) are mental simulations of what might have been if another behavior had been executed. They are pervasive in everyday life, help people learn from experience, modulate their emotional state, and contribute to decision-making and social functioning. To test the hypothesis that the prefrontal cortex (PFC) is involved in the generation, content, and use of CFT, we studied 18 patients with strictly prefrontal cortex lesions. Our results indicated that the PFC is crucial only for self-generated counterfactual reflections. We did not detect CFT generation differences based on lesion location within the PFC. CFT performance correlated positively with measures of attention, creativity, verbal skills, conscientiousness, and self-esteem and negatively with depression and dysexecutive symptoms. An impairment in counterfactual thinking may contribute to the lack of regret and insight often observed in patients with frontal lobe lesions.

Adult↗

PubMed2005

Representation of attitudinal knowledge: role of prefrontal cortex, amygdala and parahippocampal gyrus.

It has been proposed that behavior is influenced by representations of different types of knowledge: action representations, event knowledge, attitudes and stereotypes. Attitudes (representations of a concept or object and its emotional evaluation) allow us to respond quickly to a given stimulus. In this study, we explored the representation and inhibition of attitudes. We show that right dorsolateral prefrontal cortex mediates negative attitudes whereas left ventrolateral prefrontal cortex mediates positive attitudes. Parahippocampal regions and amygdala mediate evaluative processing. Furthermore, anxiety modulates right dorsolateral prefrontal activation during negative attitude processing. Inhibition of negative attitudes activates left orbitofrontal cortex: a region that when damaged is associated with socially inappropriate behavior in patients. Inhibition of positive attitudes activates a brain system involving right inferior frontal gyrus and bilateral anterior cingulate. Thus, we show that there are dissociable networks for the representation and inhibition of attitudes.

Adult↗