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Biomedical subjects

J Grafman

Publications and source records attributed to J Grafman.

At least 19 recordsLinked to original sources
PubMed2007

Clinicopathologic features of frontotemporal dementia with progranulin sequence variation.

BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). OBJECTIVE: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). METHODS: Patients underwent a single clinical assessment, MRI, and [(18)F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. RESULTS: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A-->G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A-->G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. CONCLUSIONS: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.

Adult↗
PubMed2006

Driving abilities in frontotemporal dementia patients.

OBJECTIVE: To evaluate driving competency and the relationship between neuropsychiatric symptoms and driving behavior in frontotemporal dementia (FTD) patients. METHODS: Fifteen patients with a diagnosis of FTD and 15 healthy controls were administered a driving simulation task. Measures of driving performance and neuropsychiatric symptoms were assessed. RESULTS: The FTD patients received more speeding tickets, ran more stop signs and were involved in more off-road crashes and collisions than the controls. The patients' overall average speed was significantly higher. Driving performance was correlated with agitated behavior. CONCLUSIONS: Behavioral changes characteristic of FTD patients have an impact on their driving skills leading to inappropriate driving behavior.

Adult↗
PubMed2005

Safety and cognitive effect of frontal DC brain polarization in healthy individuals.

BACKGROUND: Data from the human motor cortex suggest that, depending on polarity, direct current (DC) brain polarization can depress or activate cortical neurons. Activating effects on the frontal lobe might be beneficial for patients with frontal lobe disorders. This phase 1 study tested the safety of frontal DC, including its effects on frontal and other brain functions. METHODS: The authors applied 20 minutes of anodal, cathodal, or sham DC to the left prefrontal cortex in three groups of right-handed subjects and looked for effects on global measures of processing and psychomotor speed, emotion, and verbal fluency, a measure of local cortical function. In one experiment (n = 30), the authors tested before and after 1 mA DC and monitored EEG in 9 subjects. In two other experiments using 1 mA (n = 43) and 2 mA (n = 30), the authors tested before and then starting 5 minutes after the onset of DC. RESULTS: All subjects tolerated DC well. There were no significant effects on performance with 1 mA DC. At 2 mA, verbal fluency improved significantly with anodal and decreased mildly with cathodal DC. There were no clinically significant effects on the other measures. CONCLUSIONS: Limited exposure to direct current polarization of the prefrontal cortex is safe and can enhance verbal fluency selectively in healthy subjects. As such, it deserves consideration as a procedure to improve frontal lobe function in patients.

Adult↗
PubMed2003

Category-specific representations of social and nonsocial knowledge in the human prefrontal cortex.

Complex social behavior and the relatively large size of the prefrontal cortex are arguably two of the characteristics that distinguish humans from other animals. Grafman presented a framework concerning how the prefrontal cortex (PFC) controls complex behavior using stored structured event complexes (SECs). We report behavioral and imaging data from a modified go/no-go paradigm in which subjects had to classify words (semantic) and phrases (SEC) according to category. In experimental trials, subjects classified items according to social or nonsocial activity; in control trials, they classified items according to font. Subjects were faster to classify social than nonsocial semantic items, with the reverse pattern evident for the social and nonsocial SEC items. In addition, the conditions were associated with different patterns of PFC activation. These results suggest that there are different psychological and neural substrates for social and nonsocial semantic and SEC representations.

Activities of Daily Living↗
PubMed2003

Yes/no reversals as neurobehavioral sequela: a disorder of language, praxis, or inhibitory control?

This study identifies a linguistic phenomenon suggestive of damage to fronto-subcortical circuitry. Our objective was to determine the occurrence and neuroradiological/neurobehavioral correlates of yes/no reversals in corticobasal degeneration (CBD), and document occurrence of reversals in other neurological conditions. In a prospective study, we evaluated 34 CBD patients using a neuropsychologic battery and magnetic resonance imaging. Patients were subdivided into two groups: those with (n = 11) and without (n = 23) yes/no reversals. In a retrospective study conducted during the period of 1991-2001, we identified 33 patients for whom yes/no reversals occurred to compare correlates with prospective study findings. In the prospective study, 11 patients (32.3%) had yes/no reversals. Significant between-group differences were found in scores of lexical fluency (P = 0.02) and prehension (P = 0.03). Prehension scores correlated with facial praxis (P < 0.0001) and upper limb praxis scores (P < 0.0001) in the yes/no reversal group only. In the retrospective study, nine CBD patients and 24 non-CBD patients had yes/no reversals, with damage to fronto-subcortical areas present in all patients. Results suggest an association with deficits in mental flexibility and inhibitory control. High within-group correlations of lexical fluency and prehension with praxis scores suggest a relationship of yes/no reversals with multiple factors.

Aged↗
PubMed2003

An examination of daily activities and their scripts across the adult lifespan.

In two normative studies, we examined daily scripted activities from the perspective that scripts are frequency-based knowledge structures. In Study 1 individuals recorded their daily activities for 7 consecutive days. Fifteen activities that were reported with low, moderate, and high frequency were selected for Study 2, in which individuals generated a script for each activity. The 18 most frequently generated events from each script are reported, along with their centrality and distinctiveness rankings and the number of individuals reporting each event. Overall, the mean number of events generated increased with increasing script frequency, suggesting that script representations are subject to frequency effects. Also, we found a high level of consistency across the three age groups in the events generated in each script and in their corresponding rankings of centrality and distinctiveness. Finally, we found no evidence of age or gender bias in the frequency or recency of engaging in each of the scripted activities.

Activities of Daily Living↗
PubMed2002

Using an interleukin-6 challenge to evaluate neuropsychological performance in chronic fatigue syndrome.

BACKGROUND: Individuals with acute infections experience a range of symptoms including fatigue, malaise, muscle aches, and difficulties with concentration and memory that are usually self-limited. This cluster of symptoms is otherwise, similar to those that characterize chronic fatigue syndrome (CFS). The goal of the present study was to evaluate the cognitive and psychological functioning of CFS patients and normal controls (NCs) when they both were experiencing acute influenza-like symptoms. To induce influenza-like symptoms, we administered interleukin-6 (IL-6), a cytokine that temporarily activates the acute phase immunological and endocrine responses. METHODS: Nineteen patients who met the 1994 International CFS Study Group Criteria and ten normal controls (NCs) completed routine clinical evaluations, neuropsychological tests of short-term memory, selective attention, and executive control, and self-ratings of somatic symptoms and psychological mood before, shortly following, and 1 day after IL-6 administration. RESULTS: CFS patients consistently reported more somatic symptoms, even when both groups perceived that they were ill. Both groups somatic symptoms increased during the IL-6 challenge, but the CFS patients symptoms increased more rapidly than controls. In general, the CFS patients performed similarly to NCs on the cognitive measures before, during, and after the IL-6. In contrast to predictions, IL-6 provocation did not impair the cognitive performance of either CFS patients or NCs. CONCLUSIONS: The IL-6 provocation exacerbated the patients self-reported symptoms but did not reveal notable cognitive impairments between patients and controls during cytokine-induced acute influenza-like symptoms.

Adult↗
PubMed2002

Obsessive-compulsive disorder (OCD) patients are impaired in remembering temporal order and in judging their own performance.

Obsessive-compulsive disorder (OCD) has been related to frontostriatal dysfunction, but some inconsistencies between studies and a relative paucity of neuropsychological research still characterizes the study of OCD. We compared 28 patients with OCD and matched healthy controls on two neuropsychological tests sensitive to frontal dysfunction: temporal ordering and a "feeling-of-doing" (FOD) judgment about ordering. The OCD group performed significantly worse than controls in the temporal ordering task despite showing normal recognition memory. Patients were also impaired in "feeling-of-doing" judgments suggesting they have a lack of self-awareness of their performance. Thus, the results of the current study reinforces previous research that indicates that OCD patients fail on tasks that require adequate functioning of the frontal-striatal pathways.

Adolescent↗
PubMed2002

Investigating cognitive neuroplasticity in single cases: lessons learned from applying functional neuroimaging techniques to the traditional neuropsychological case study framework.

We summarize two case studies as a context for discussing the use of neuroimaging as a convergent methodology in the study of neuroplasticity in single subjects. Throughout this paper we argue for a different approach for including neuroimaging in these types of study. Previous case studies of neuroplasticity in patients (ours as well as others reported elsewhere) have added neuroimaging to the traditional neuropsychological framework of comparing patient results with matched control groups, and synthesized results through descriptions of anatomical and behavioral dissociations. This type of approach is referred to as the comparison approach. We advocate a different approach that builds on findings from previous behavioral skill learning research. Specifically, we propose adding neuroimaging throughout learning or recovery of the ability of interest and making inferences from systematic changes in activation topography and intensity that occur within the context of predicted behavioral changes. We dub this approach the online approach. This approach should allow future investigators to circumvent many of the interpretation pitfalls that are common in comparison studies.

Adult↗
PubMed2001

FLAIR and magnetization transfer imaging of patients with post-treatment Lyme disease syndrome.

OBJECTIVE: To determine patterns of abnormalities on cerebral MRI that may characterize subgroups of patients with post-treatment Lyme disease syndrome (PTLDS) and to help identify pathomechanisms of disease. METHODS: The authors analyzed the distribution of cerebral lesions in a cohort of 27 patients with PTLDS. A subgroup of eight patients with PTLDS was further studied using whole-brain magnetization transfer ratio measures to identify abnormalities not seen on T2-weighted images. RESULTS: Four patients had focal neurologic deficits, relapsing-remitting disease, and lesions in a distribution typical of MS. Twenty-three patients presented with nonfocal symptoms such as fatigue, subjective memory deficits, and mood disturbance. Twelve of these patients had normal MRI, including the more sensitive fluid-attenuated inversion recovery sequence, 10 had primarily punctate and subcortical lesions, and one patient had multiple periventricular lesions. CONCLUSIONS: In a portion of patients with post-treatment Lyme disease syndrome, white-matter hyperintensities tend to occur in subcortical arteriolar watershed areas and are not specific. Magnetization transfer ratio analysis did not provide evidence for structural abnormalities of the brain parenchyma in patients with nonfocal disease.

Adult↗
PubMed2001

The effects of frontal lobe lesions on goal achievement in the water jug task.

Patients with prefrontal cortex lesions are impaired on a variety of planning and problem-solving tasks. We examined the problem-solving performance of 27 patients with focal frontal lobe damage on the Water Jug task. The Water Jug task has never been used to assess problem-solving ability in neurologically impaired patients nor in functional neuroimaging studies, despite sharing structural similarities with other tasks sensitive to prefrontal cortex function, including the Tower of Hanoi, Tower of London, and Wisconsin Card Sorting Task (WCST). Our results demonstrate that the Water Jug task invokes a unique combination of problem-solving and planning strategies, allowing a more precise identification of frontal lobe lesion patients' cognitive deficits. All participants (patients and matched controls) appear to be utilizing a hill-climbing strategy that does not require sophisticated planning; however, frontal lobe lesion patients (FLLs) struggled to make required "counterintuitive moves" not predicted by this strategy and found within both solution paths. Left and bilateral FLLs were more impaired than right FLLs. Analysis of the left hemisphere brain regions encompassed by the lesions of these patients found that poor performance was linked to left dorsolateral prefrontal cortex damage. We propose that patients with left dorsolateral prefrontal cortex lesions have difficulty making a decision requiring the conceptual comparison of nonverbal stimuli, manipulation of select representations of potential solutions, and are unable to appropriately inhibit a response in keeping with the final goal.

Brain Diseases↗
PubMed2001

Randomized placebo-controlled trial of donepezil in patients with progressive supranuclear palsy.

OBJECTIVE: There is no effective treatment for progressive supranuclear palsy (PSP). Because results of immunochemical and pharmacologic studies suggest that the cholinergic system may play a role in the cognitive and motor features of PSP, the authors investigated the effects of donepezil (10 mg/day), an acetylcholinesterase inhibitor, in 21 patients with PSP (mean age +/- SD; 65.7 +/- 4.7 years) by a randomized, double-blind, placebo-controlled crossover trial. METHODS: Donepezil and placebo were administered for 6 weeks each with a 1-month washout period. Patients were evaluated before and at the end of each treatment phase. Outcome measures evaluated neuropsychiatric, global cognitive, frontal, memory, motor, and activities of daily living (ADL) status. RESULTS: Two patients withdrew during the washout phase because of unrelated medical problems. Donepezil-induced systemic side effects were transient and generally mild. Because of worsening of motor function, three patients received 5 mg/day of donepezil. All patients achieved blood and CSF therapeutic levels of donepezil. While the patients were taking donepezil, their Double Memory Test scores improved, whereas their ADL/mobility scores significantly worsened. CONCLUSION: The findings suggest that acetylcholinesterase inhibitors such as donepezil have at best selective, modest effects on cognition in patients with PSP. In light of its deleterious effects on ADL/mobility, donepezil is not recommended for this patient population.

Aged↗
PubMed2001

Ventromedial prefrontal cortex lesions in humans eliminate implicit gender stereotyping.

Patients with prefrontal cortex lesions and controls were administered an implicit association task (IAT) that measured the degree of association between male and female names and their stereotypical attributes of strength and weakness. They also completed three questionnaires measuring their explicit judgment regarding gender-related stereotypical attributes. There were no between-group differences on the explicit measures. On the IAT, patients with dorsolateral lesions and controls showed a strong association, whereas patients with ventromedial prefrontal cortex lesions had a significantly lower association, between the stereotypical attributes of men and women and their concepts of gender. This finding provides support for the hypothesis that patients with ventromedial prefrontal lesions have a deficit in automatically accessing certain aspects of overlearned associated social knowledge.

Analysis of Variance↗
PubMed2001

Comparison of apraxia in corticobasal degeneration and progressive supranuclear palsy.

OBJECTIVE: To describe ideomotor apraxia in patients with corticobasal degeneration and those with progressive supranuclear palsy, two parkinsonian disorders that are often misdiagnosed due to the overlap in their clinical features, and to determine whether systematic apraxia testing is useful for differential diagnosis. METHODS: Fourteen patients fulfilling National Institute of Neurological Disorders and Stroke-Society for Progressive Supranuclear Palsy clinical criteria for progressive supranuclear palsy, 13 patients fulfilling modified Lang criteria for corticobasal degeneration, and 12 normal healthy control subjects were given the Test of Oral and Limb Apraxia, which was scored according to the Florida Apraxia Battery for occurrence of various types of apraxic errors. RESULTS: Both patients with progressive supranuclear palsy and corticobasal degeneration committed a greater number of apraxic errors than normal healthy control subjects on both transitive and intransitive tasks (p < 0.001 in both cases), but apraxia was much more severe in patients with corticobasal degeneration than progressive supranuclear palsy (p < 0.001). The index of apraxia severity, in combination with the assessment of the two key features of progressive supranuclear palsy (falls and vertical gaze palsy), correctly classified all patients. CONCLUSIONS: Patients with corticobasal degeneration show more severe ideomotor apraxia than patients with progressive supranuclear palsy, and systematic assessment of ideomotor apraxia facilitates the differential diagnosis between patients with progressive supranuclear palsy and those with corticobasal degeneration.

Aged↗
PubMed2001

Enhancing analogic reasoning with rTMS over the left prefrontal cortex.

The authors utilized repetitive transcranial magnetic stimulation (rTMS) in 16 normal volunteers to investigate the role of the left dorsolateral prefrontal cortex (PFC) in analogic reasoning. rTMS over the left and right PFC, over the left motor cortex, and sham stimulation over the left PFC were administered during memory and analogic reasoning conditions. rTMS over the left PFC led to a significant reduction in response times only in the analogy condition without affecting accuracy. These results indicate that the left PFC is relevant for analogic reasoning and that rTMS applied to the PFC can speed up solution time.

Adult↗
PubMed2001

Neural correlates of auditory-visual stimulus onset asynchrony detection.

Intersensory temporal synchrony is an ubiquitous sensory attribute that has proven to be critical for binding multisensory inputs, sometimes erroneously leading to dramatic perceptual illusions. However, little is known about how the brain detects temporal synchrony between multimodal sensory inputs. We used positron emission tomography to demonstrate that detecting auditory-visual stimulus onset asynchrony activates a large-scale neural network of insular, posterior parietal, prefrontal, and cerebellar areas with the highest and task-specific activity localized to the right insula. Interregional covariance analysis further showed significant task-related functional interactions between the insula, the posterior thalamus, and superior colliculus. Based on these results and the available electrophysiological and anatomical connectivity data in animals, we propose that the insula, via its known short-latency connections with the tectal system, mediates temporally defined auditory-visual interaction at an early stage of cortical processing permitting phenomena such as the ventriloquist and the McGurk illusions.

Acoustic Stimulation↗
PubMed2001

Impairment of eyeblink classical conditioning in progressive supranuclear palsy.

In a previous study we showed that learning in eyeblink classical conditioning (EBCC) is normal in Parkinson's disease (PD) and that the serial reaction time task (SRTT) is only marginally impaired. Since pathological lesions are more widespread in the atypical parkinsonian disorder of progressive supranuclear palsy (PSP) than in PD, we hypothesized that PSP patients may show more profound deficits in the EBCC and SRTT learning tasks. We therefore investigated EBCC with a delay and two trace paradigms, an SRTT and the California Verbal Learning Test (CVLT) in eight patients with PSP and an age-matched control group. In all EBCC paradigms, we found a significant difference between groups with no significant learning in PSP patients. In the SRTT, implicit learning may have been impaired, but verbal and manual sequence recall were only marginally impaired. Verbal memory was significantly worse in PSP patients than in the control group. Our study shows a dissociated pattern of learning abilities in PSP, where the EBCC as a measure of implicit learning is impaired, the explicit sequence detection in the SRTT is relatively preserved, and the verbal memory impaired. We hypothesize that the PSP patients' deficits in EBCC learning may be due to lesions of deep cerebellar nuclei. There may be a clinical role for EBCC in distinguishing PD and PSP patients.

Aged↗