Disrupted Neural Synchrony Mediates the Relationship between White Matter Integrity and Cognitive Performance in Older Adults.

Our main goal was to determine the influence of white matter integrity on the dynamic coupling between brain regions and the individual variability of cognitive performance in older adults. Electroencephalography was recorded while participants performed a task specifically designed to engage working memory and inhibitory processes, and the associations among functional activity, structural integrity, and cognitive performance were assessed. We found that the association between white matter microstructural integrity and cognitive functioning with aging is mediated by time-varying alpha and gamma phase-locking value. Specifically, better preservation of the inferior fronto-occipital fasciculus in older individuals drives faster task-related modulations of alpha and gamma long-range phase-locking value between the inferior frontal gyrus and occipital lobe and lower local phase-amplitude coupling in occipital lobes, which in turn drives better cognitive control performance. Our results help delineate the role of individual variability of white matter microstructure in dynamic synchrony and cognitive performance during normal aging.

Neural Correlates of Evidence and Urgency During Human Perceptual Decision-Making in Dynamically Changing Conditions.

Current models of decision-making assume that the brain gradually accumulates evidence and drifts toward a threshold that, once crossed, results in a choice selection. These models have been especially successful in primate research; however, transposing them to human fMRI paradigms has proved it to be challenging. Here, we exploit the face-selective visual system and test whether decoded emotional facial features from multivariate fMRI signals during a dynamic perceptual decision-making task are related to the parameters of computational models of decision-making. We show that trial-by-trial variations in the pattern of neural activity in the fusiform gyrus reflect facial emotional information and modulate drift rates during deliberation. We also observed an inverse-urgency signal based in the caudate nucleus that was independent of sensory information but appeared to slow decisions, particularly when information in the task was ambiguous. Taken together, our results characterize how decision parameters from a computational model (i.e., drift rate and urgency signal) are involved in perceptual decision-making and reflected in the activity of the human brain.

Predictive model of spread of Parkinson's pathology using network diffusion.

Growing evidence suggests that a "prion-like" mechanism underlies the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). We extend and tailor previously developed quantitative and predictive network diffusion model (NDM) to PD, by specifically modeling the trans-neuronal spread of alpha-synuclein outward from the substantia nigra (SN). The model demonstrated the spatial and temporal patterns of PD from neuropathological and neuroimaging studies and was statistically validated using MRI deformation of 232 Parkinson's patients. After repeated seeding simulations, the SN was found to be the most likely seed region, supporting its unique lynchpin role in Parkinson's pathology spread. Other alternative spread models were also evaluated for comparison, specifically, random spread and distance-based spread; the latter tests for Braak's original caudorostral transmission theory. We showed that the distance-based spread model is not as well supported as the connectivity-based model. Intriguingly, the temporal sequencing of affected regions predicted by the model was in close agreement with Braak stages III-VI, providing what we consider a "computational Braak" staging system. Finally, we investigated whether the regional expression patterns of implicated genes contribute to regional atrophy. Despite robust evidence for genetic factors in PD pathogenesis, NDM outperformed regional genetic expression predictors, suggesting that network processes are far stronger mediators of regional vulnerability than innate or cell-autonomous factors. This is the first finding yet of the ramification of prion-like pathology propagation in Parkinson's, as gleaned from in vivo human imaging data. The NDM is potentially a promising robust and clinically useful tool for diagnosis, prognosis and staging of PD.

Limbic system mGluR5 availability in cocaine dependent subjects: a high-resolution PET [(11)C]ABP688 study.

Cocaine self-administration decreases type 5 metabotropic glutamate receptor (mGluR5) tissue concentrations in laboratory rats during early abstinence. These changes are thought to influence the drug's reinforcing properties and the ability of drug-related cues to induce relapse. Here, our goal was to measure brain regional mGluR5 availability in recently abstinent cocaine dependent humans. Participants meeting DSM-IV diagnostic criteria for current cocaine dependence (n=9) were recruited from the general population. mGluR5 availability (binding potential, non-displaceable; BPND) was measured with high-resolution positron emission tomography (PET HRRT) and [(11)C]ABP688. Compared to age- and sex-matched healthy controls (n=9), cocaine dependent subjects showed significantly lower BPND values in the ventral (bilateral: -28.2%, p=0.011), associative (right: -21.4%, p=0.043), and sensorimotor striatum (bilateral: -21.7%, p=0.045), amygdala (left: -26%, p=0.046) and insula (right: -23.3%, p=0.041). Among the cocaine users, receptor availabilities were related to abstinence (range: 2 to 14days). The longer the duration of abstinence, the lower the BPND values in the sensorimotor striatum (r=-0.71, p=0.034), left amygdala (r=-0.73, p=0.026) and right insula (r=-0.67, p=0.046). Compared to healthy controls, BPND values were significantly reduced in those who tested negative for cocaine on the PET test session in the ventral (p=0.018) and sensorimotor striatum (p=0.017), left amygdala (p=0.008), and right insula (p=0.029), but not in those who tested positive. Together, these results provide evidence of time-related mGluR5 alterations in striatal and limbic regions in humans during early cocaine abstinence.

Critical involvement of the thalamus and precuneus during restoration of consciousness with physostigmine in humans during propofol anaesthesia: a positron emission tomography study.

BACKGROUND: Functional brain imaging offers a way to investigate how general anaesthetics impair consciousness. However, functional imaging changes may result from drug effects unrelated to hypnosis. Establishing a causal link with loss of consciousness is thus difficult. METHODS: To identify changes of neuronal activity functionally linked to the level of consciousness, physostigmine was used to restore consciousness without changing the anaesthetic concentration in 11 subjects anaesthetized with propofol. Eight subjects (responders) regained consciousness after physostigmine and three did not (non-responders). Positron emission tomography was used to measure regional cerebral blood flow (rCBF); during baseline (awake), after anaesthesia-induced loss of consciousness, after physostigmine administration, and recovery. In addition to subtraction analyses, we used conjunction analysis in the responders to identify changes common to the baseline-anaesthesia and physostigmine-anaesthesia contrasts. RESULTS: Complete data were available for seven subjects (four responders and three non-responders). The analyses revealed that unconsciousness was associated with rCBF decreases in the thalamus and precuneus. Restoration of consciousness by physostigmine was associated with rCBF increases in these same structures, with the strongest effect in the thalamus. CONCLUSIONS: The results provide strong evidence that reductions in rCBF in the thalamus and precuneus are functionally related to propofol-induced unconsciousness independently of any non-specific effects of propofol. These observations confirm that the thalamus and precuneus are key elements to understand how general anaesthetics cause unconsciousness and how patients wake up from anaesthesia. Furthermore, they are consistent with the notion that anaesthetic-induced unconsciousness is associated with reduced cholinergic activation.

The neurobiology of appetite: hunger as addiction.

Obesity is now being recognized as a neurobehavioral disorder. Although the view of appetite as an addiction to food is controversial, there are useful lessons to be learned from the neuroscience of addiction for understanding obesity. The speakers in this symposium all addressed different aspects of the neurobiology of feeding and obesity. In this overview and the associated reviews, the behavioral, genetic and neural factors that promote over-eating in animals and humans are discussed.

Neural substrates of cognitive skill learning in Parkinson's disease.

While cognitive skill learning is normally acquired implicitly through frontostriatal circuitry in healthy individuals, neuroimaging studies suggest that patients with Parkinson's disease (PD) do so by activating alternate, intact brain areas associated with explicit memory processing. To further test this hypothesis, 10 patients with PD and 12 healthy controls were tested on a modified, learning version of the Tower of London task while undergoing positron emission tomography at four different time points over the course of learning. Despite having less accurate problem solving abilities than controls, PD patients were able to acquire the skill learning task. However, as compared to controls, they maintained higher levels of cerebral blood flow activity in the dorsolateral prefrontal cortex and hippocampus and showed an increase in activity in the frontopolar cortex and posterior cingulate over the course of learning. These findings reflect a shift to the explicit memory system in PD patients, enabling them to learn this cognitive skill, which is normally acquired by control subjects using implicit learning strategies and frontostriatal circuitry.

Network connectivity determines cortical thinning in early Parkinson's disease progression.

Here we test the hypothesis that the neurodegenerative process in Parkinson's disease (PD) moves stereotypically along neural networks, possibly reflecting the spread of toxic alpha-synuclein molecules. PD patients (n = 105) and matched controls (n = 57) underwent T1-MRI at entry and 1 year later as part of the Parkinson's Progression Markers Initiative. Over this period, PD patients demonstrate significantly greater cortical thinning than controls in parts of the left occipital and bilateral frontal lobes and right somatomotor-sensory cortex. Cortical thinning is correlated to connectivity (measured functionally or structurally) to a "disease reservoir" evaluated by MRI at baseline. The atrophy pattern in the ventral frontal lobes resembles one described in certain cases of Alzheimer's disease. Our findings suggest that disease propagation to the cortex in PD follows neuronal connectivity and that disease spread to the cortex may herald the onset of cognitive impairment.

Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers.

Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent d-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to d-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean ± s.d. = 22.1 ± 3.4 years) [(11)C]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated d-amphetamine (3 × 0.3 mg kg(-1), by mouth; n = 8) or placebo (3 × lactose, by mouth; n = 9). Mood and physiological measurements were recorded throughout each session. Before the d-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P ⩽ 0.05). Following the d-amphetamine regimen, the stress-induced cortisol responses were augmented (P < 0.04), and voxel-based analyses showed larger stress-induced decreases in [(11)C]raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [(11)C]raclopride binding, primarily in the sensorimotor striatum (P < 0.05). Together, this study provides evidence for drug × stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.

Wisconsin Card Sorting revisited: distinct neural circuits participating in different stages of the task identified by event-related functional magnetic resonance imaging.

The Wisconsin Card Sorting Task (WCST) has been used to assess dysfunction of the prefrontal cortex and basal ganglia. Previous brain imaging studies have focused on identifying activity related to the set-shifting requirement of the WCST. The present study used event-related functional magnetic resonance imaging (fMRI) to study the pattern of activation during four distinct stages in the performance of this task. Eleven subjects were scanned while performing the WCST and a control task involving matching two identical cards. The results demonstrated specific involvement of different prefrontal areas during different stages of task performance. The mid-dorsolateral prefrontal cortex (area 9/46) increased activity while subjects received either positive or negative feedback, that is at the point when the current information must be related to earlier events stored in working memory. This is consistent with the proposed role of the mid-dorsolateral prefrontal cortex in the monitoring of events in working memory. By contrast, a cortical basal ganglia loop involving the mid-ventrolateral prefrontal cortex (area 47/12), caudate nucleus, and mediodorsal thalamus increased activity specifically during the reception of negative feedback, which signals the need for a mental shift to a new response set. The posterior prefrontal cortex response was less specific; increases in activity occurred during both the reception of feedback and the response period, indicating a role in the association of specific actions to stimuli. The putamen exhibited increased activity while matching after negative feedback but not while matching after positive feedback, implying greater involvement during novel than routine actions.

Repetitive transcranial magnetic stimulation of the human prefrontal cortex induces dopamine release in the caudate nucleus.

Dopamine is implicated in movement, learning, and motivation, and in illnesses such as Parkinson's disease, schizophrenia, and drug addiction. Little is known about the control of dopamine release in humans, but research in experimental animals suggests that the prefrontal cortex plays an important role in regulating the release of dopamine in subcortical structures. Here we used [(11)C]raclopride and positron emission tomography to measure changes in extracellular dopamine concentration in vivo after repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in healthy human subjects. Repetitive TMS of the left dorsolateral prefrontal cortex caused a reduction in [(11)C]raclopride binding in the left dorsal caudate nucleus compared with rTMS of the left occipital cortex. There were no changes in binding in the putamen, nucleus accumbens, or right caudate. This shows that rTMS of the prefrontal cortex induces the release of endogenous dopamine in the ipsilateral caudate nucleus. This finding has implications for the therapeutic and research use of rTMS in neurological and psychiatric disorders.

Ghrelin.

BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism.

Effect of vascular activity in the determination of rate constants for the uptake of 18F-labeled 2-fluoro-2-deoxy-D-glucose: error analysis and normal values in older subjects.

Regional cerebral blood volume (CBV) can be calculated using data obtained during the kinetic analysis of 18F-labeled 2-fluoro-2-deoxy-D-glucose (FDG) uptake measured by positron emission tomography (PET). As a result the influence of vascular activity upon the determination of FDG rate constants can be minimized. The method is investigated by simulation experiments and by analysis of PET studies on seven older, healthy human volunteers aged 52-70 years. The accuracy of measured FDG rate constants k1, k2, and k3, obtained either by omitting the early portion of the uptake curve or by explicit inclusion of CBV as a fit parameter, is compared. The root mean square error in measured rate constant for the latter method is equivalent to that obtained by omitting the first 2.5-3 min of tissue data and neglecting the CBV term. Hence, added information about the physiological state of the tissue is obtained without compromising the accuracy of the (FDG) rate constant measurement. In hyperemic tissue the explicit determination of the vascular fraction results in more accurate estimates of the FDG rate constants. The ratio of CBV determined by this method to CBV obtained using C15O in six subjects with CBV in the normal range was 0.92 +/- 0.32. A comparison of the CBV image obtained by this method with that obtained using C15O in an arteriovenous malformation case demonstrates the accuracy of the approach over a wide range of CBV values. The mean value for CBV fraction in gray matter obtained by this method in the older control group was 0.040 +/- 0.014. Average gray matter rate constants obtained were k1 = 0.084 +/- 0.012, k2 = 0.150 +/- 0.071, and k3 = 0.099 +/- 0.045 min-1.

Globus pallidus deep brain stimulation for generalized dystonia: clinical and PET investigation.

Bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) in a patient with severe idiopathic generalized dystonia resulted in immediate improvement of all aspects of dystonia. During joystick movement, GPi DBS reduced PET activation bilaterally in the primary motor, lateral premotor, supplementary motor, anterior cingulate, and prefrontal areas and ipsilaterally in the lentiform nucleus. Altering basal ganglia function with GPi DBS reverses the overactivity of certain motor cortical areas present in dystonia.

Prevalence and anatomic characteristics of infarct-like lesions on MR images of middle-aged adults: the atherosclerosis risk in communities study.

BACKGROUND AND PURPOSE: MR imaging has revealed putative evidence of subclinical cerebrovascular disease (CVD) as reflected by white matter signal changes and infarct-like lesions (ILLs). Nonetheless, the prevalence of this condition in the general population has been defined only to a limited extent. We herein report the prevalence and anatomic characteristics of ILLs seen on cranial MR images obtained as part of a population-based study of cardiovascular disease in middle-aged adults. These results are contrasted to those of previous similar studies, particularly those of an elderly population in the Cardiovascular Health Study (CHS). METHODS: This Atherosclerosis Risk in Communities (ARIC) cohort consists of a probability sample of community-living persons who were 55 to 72 years old at the time of MR examination. MR imaging of 1890 participants was performed at two ARIC field centers, based on a common protocol. MR studies were evaluated by trained readers at the MR Reading Center using original digital data displayed on a high-resolution workstation. The measures of lesion size, anatomic location, and signal intensity were collected. The definition for an ILL was a non-mass, hyperintense region with an arterial vascular distribution on spin-density and T2-weighted images. RESULTS: Two hundred ninety participants had ILLs, for an overall prevalence of 15.3%. Eighty-two percent of participants with ILLs had lesions that were 3 mm or larger in maximal dimension, although 87% of these lesions were 20 mm or smaller in maximal dimension. The prevalence of ILLs increased with age, from 7.9% in the 55- to 59-year-old age group to 22.9% in the 65- to 72-year-old age group (P < .001). Lesion prevalence was greater in black (20.7%) than in white persons (10.2% [P < .0001]), but did not differ significantly between male and female participants. The basal ganglia and thalamic region was the most commonly affected anatomic site, accounting for 78.9% of the lesions. CONCLUSION: Considering that the prevalence of self-reported stroke or transient ischemic attack in ARIC participants is 1.5%, these results suggest that there is significantly more subclinical than clinical CVD in the general population. Furthermore, the prevalence of this subclinical disease increases with age, and is greater in black persons. ILLs are dominated by "lacunae" in the basal ganglia and thalamus. These results are, in general, similar to those of a comparable study of elderly participants in the CHS, except for a 60% lower prevalence of ILLs in this younger population.

Neural transplantation cannula and microinjector system: experimental and clinical experience. Technical note.

The authors present a simple, reliable, and safe system for performing neural transplantation in the human brain. The device consists of a transplantation cannula and microinjector system that has been specifically designed to reduce implantation-related trauma and to maximize the number of graft deposits per injection. The system was evaluated first in an experimental rat model of Parkinson's disease (PD). Animals in which transplantation with this system had been performed showed excellent graft survival with minimal trauma to the brain. Following this experimental stage, the cannula and microinjector system were used in eight patients with PD enrolled in the Halifax Neural Transplantation Program who received bilateral putaminal transplants of fetal ventral mesencephalic tissue. A total of 16 transplantation operations and 64 trajectories were performed in the eight patients, and there were no intraoperative or perioperative complications. Magnetic resonance imaging studies obtained 24 hours after surgery revealed no evidence of tissue damage or hemorrhage. Transplant survival was confirmed by fluorodopa positron emission tomography scans obtained 6 and 12 months after surgery. As neural transplantation procedures for the treatment of neurological conditions evolve, the ability to deliver viable grafts safely will become critically important. The device presented here has proved to be of value in maximizing the number of graft deposits while minimizing implantation-related trauma to the host brain.

Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line--derived neurotrophic factor in patients with Parkinson's disease. Report of two cases and technical considerations.

The authors have studied the ability of glial cell line-derived neurotrophic factor (GDNF) to promote survival of human fetal dopaminergic tissue after a storage period of 6 days and subsequent implantation into the human putamen. The results indicate that GDNF promotes survival of stored dopaminergic cells. Cells stored without GDNF had a 30.1% decrease in survival time compared with those exposed to GDNF. Two patients with Parkinson's disease received bilateral putaminal implants of fetal dopaminergic cells exposed to GDNF for 6 days and showed enhancement of graft survival as assessed by positron emission tomography scanning. A mean increase of 107% in putaminal fluorodopa uptake from baseline values was observed 12 months postgrafting.

Imaging Performance of a Dynamic Positron Emission Tomograph: Positome IIIp.

This paper documents modifications to an older PET system to improve its dead time, scatter fraction, and spatial resolution in high count rate, short duration studies. A new dual-tapered collimator reduces scatter by 33 percent while providing excellent resolution uniformity in all slices. A data encoding scheme produces uniformly sampled parallel projections from the coincidence data in real time while the detector array executes an orbital motion. The image uniformity, scatter compensation and high count-rate performance have been validated up to 40 kBq/cc in a 20 cm flood source. The errors in image quantification due to counting statistics, live time, and random counts are estimated from repeated measurements on a contrast phantom at high count-rates. The effects of two methods of scatter compensation on image contrast are shown in contrast phantoms and a typical glucose utilization study. Blood flow measurements using 0-15 labeled water bolus method, made under different physiological conditions, reflected the changes expected. The true count efficiency of 75 kcps/(uCi/cc) permits these studies to be done with only 500-900 MBq (13-25 mCi) injected activity.

A neural model of working memory processes in normal subjects, Parkinson's disease and schizophrenia for fMRI design and predictions.

A computational model was previously developed to investigate the role of parallel basal ganglia-thalamocortical loops in solving tasks that rely on working memory. Different lesions are applied to the model in order to investigate the working memory deficits observed in Parkinson's disease and schizophrenia. The simulations predict that the working memory deficits observed in Parkinson's disease result from a local dysfunction within the brain due to a problem in the disinhibitory process arising from the basal ganglia. They also predict that the working memory deficits observed in schizophrenia involve many cortical and subcortical areas and result from a problem in selecting items in working memory which are stored in basal ganglia-thalamocortical loops. The simulations predict the temporal unfolding of neuronal activity in different brain regions, both in the normal case and in the two disease states. A specific event-related functional magnetic resonance imaging study was elaborated to test some of those predictions.