Sex-difference in the association between social drinking, structural brain aging and cognitive function in older individuals free of cognitive impairment.

Background: We investigated a potential sex difference in the relationship between alcohol consumption, brain age gap and cognitive function in older adults without cognitive impairment from the population-based Mayo Clinic Study of Aging. Methods: Self-reported alcohol consumption was collected using the food-frequency questionnaire. A battery of cognitive testing assessed performance in four different domains: attention, memory, language, and visuospatial. Brain magnetic resonance imaging (MRI) was conducted using 3-T scanners (Signa; GE Healthcare). Brain age was estimated using the Brain-Age Regression Analysis and Computational Utility Software (BARACUS). We calculated the brain age gap as the difference between predicted brain age and chronological age. Results: The sample consisted of 269 participants [55% men (n=148) and 45% women (n=121) with a mean age of 79.2 ± 4.6 and 79.5 ± 4.7 years respectively]. Women had significantly better performance compared to men in memory, (1.12 ± 0.87 vs 0.57 ± 0.89, P<0.0001) language (0.66 ± 0.8 vs 0.33 ± 0.72, P=0.0006) and attention (0.79 ± 0.87 vs 0.39 ± 0.83, P=0.0002) z-scores. Men scored higher in visuospatial skills (0.71 ± 0.91 vs 0.44 ± 0.90, P=0.016). Compared to participants who reported zero alcohol drinking (n=121), those who reported alcohol consumption over the year prior to study enrollment (n=148) scored significantly higher in all four cognitive domains [memory: F3,268 = 5.257, P=0.002, Language: F3,258 = 12.047, P<0.001, Attention: F3,260 = 22.036, P<0.001, and Visuospatial: F3,261 = 9.326, P<0.001] after correcting for age and years of education. In addition, we found a significant positive correlation between alcohol consumption and the brain age gap (P=0.03). Post hoc regression analysis for each sex with language z-score revealed a significant negative correlation between brain age gap and language z-scores in women only (P=0.008). Conclusion: Among older adults who report alcohol drinking, there is a positive association between higher average daily alcohol consumption and accelerated brain aging despite the fact that drinkers had better cognitive performance compared to zero drinkers. In women only, accelerated brain aging is associated with worse performance in language cognitive domain. Older adult women seem to be vulnerable to the negative effects of alcohol on brain structure and on certain cognitive functions.

Low frequency repetitive transcranial magnetic stimulation to the right dorsolateral prefrontal cortex engages thalamus, striatum, and the default mode network.

The positive treatment outcomes of low frequency (LF) repetitive transcranial magnetic stimulation (rTMS) when applied over the right dorsolateral prefrontal cortex (DLPFC) in treatment-refractory depression has been verified. However, the mechanism of action behind these results have not been well-explored. In this work we used simultaneous functional magnetic resonance imaging (fMRI) during TMS to explore the effect of LF rTMS on brain activity when applied to the right [RDLPFC1 (MNI: 50, 30, 36)] and left DLPFC sites [LDLPFC1 (MNI: -50, 30, 36), LDLPFC2 (MNI: -41, 16, 54)]. Seventeen healthy adult volunteers participated in this study. To identify brain areas affected by rTMS, an independent component analysis and a general linear model were used. Our results showed an important laterality effect when contrasting rTMS over the left and right sites. Specifically, LF rTMS increased brain activity at the striatum, thalamus, and areas of the default mode network when applied to the right, but not to the contralateral left DLPFC. In contrast, no site differences were observed when evaluating the effect of LF rTMS over the two left sites. These findings demonstrate that LF rTMS to the right DLPFC was able to stimulate the cortico-striato-thalamo-cortical pathway, which is dysregulated in patients with major depressive disorder; therefore, possibly providing some neurobiological justification for the successful outcomes found thus far for LF rTMS in the treatment of depression.

High-Frequency Transcranial Magnetic Stimulation Combined With Functional Magnetic Resonance Imaging Reveals Distinct Activation Patterns Associated With Different Dorsolateral Prefrontal Cortex Stimulation Sites.

OBJECTIVES: Transcranial magnetic stimulation (TMS) has been extensively used for the treatment of depression, obsessive-compulsive disorder, and certain neurologic disorders. Despite having promising treatment efficacy, the fundamental neural mechanisms of TMS remain understudied. MATERIALS AND METHODS: In this study, 15 healthy adult participants received simultaneous TMS and functional magnetic resonance imaging to map the modulatory effect of TMS when it was applied over three different sites in the dorsolateral prefrontal cortex. Independent component analysis (ICA) was used to identify the networks affected by TMS when applied over the different sites. The standard general linear model (GLM) analysis was used for comparison. RESULTS: ICA showed that TMS affected the stimulation sites as well as remote brain areas, some areas/networks common across all TMS sites, and other areas/networks specific to each TMS site. In particular, TMS site and laterality differences were observed at the left executive control network. In addition, laterality differences also were observed at the dorsal anterior cingulate cortex and dorsolateral/dorsomedial prefrontal cortex. In contrast with the ICA findings, the GLM-based results mainly showed activation of auditory cortices regardless of the TMS sites. CONCLUSIONS: Our findings support the notion that TMS could act through a top-down mechanism, indirectly modulating deep subcortical nodes by directly stimulating cortical regions. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03394066.

Simultaneous Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging: Aspects of Technical Implementation.

The simultaneous transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) offers a unique opportunity to non-invasively stimulate brain circuits while simultaneously monitoring changes in brain activity. However, to take advantage of this multimodal technique, some technical issues need to be considered/addressed. In this work, we evaluated technical issues associated with the setup and utilization of this multimodal tool, such as the use of a large single-channel radio frequency (rf) coil, and the artifacts induced by TMS when interleaved with the echo-planar imaging (EPI) sequence. We demonstrated that good image quality can be achieved with this rf coil and that the adoption of axial imaging orientation in conjunction with a safe interval of 100 ms, between the TMS pulse and imaging acquisition, is a suitable combination to eliminate potential image artifacts when using the combined TMS-fMRI technique in 3-T MRI scanners.

Short-term nicotine deprivation alters dorsal anterior cingulate glutamate concentration and concomitant cingulate-cortical functional connectivity.

Most cigarette smokers who wish to quit too often relapse within the first few days of abstinence, primarily due to the aversive aspects of the nicotine withdrawal syndrome (NWS), which remains poorly understood. Considerable research has suggested that the dorsal anterior cingulate cortex (dACC) plays a key role in nicotine dependence, with its functional connections between other brain regions altered as a function of trait addiction and state withdrawal. The flow of information between dACC and fronto-striatal regions is secured through different pathways, the vast majority of which are glutamatergic. As such, we investigated dACC activity using resting state functional connectivity (rsFC) with functional magnetic resonance imaging (fMRI) and glutamate (Glu) concentration with magnetic resonance spectroscopy (MRS). We also investigated the changes in adenosine levels in plasma during withdrawal as a surrogate for brain adenosine, which plays a role in fine-tuning synaptic glutamate transmission. Using a double-blind, placebo-controlled, randomized crossover design, nontreatment seeking smoking participants (N = 30) completed two imaging sessions, one while nicotine sated and another after 36 h nicotine abstinence. We observed reduced dACC Glu (P = 0.029) along with a significant reduction in plasma adenosine (P = 0.03) and adenosine monophosphate (AMP; P < 0.0001) concentrations during nicotine withdrawal in comparison with nicotine sated state. This withdrawal state manipulation also led to an increase in rsFC strength (P < 0.05) between dACC and several frontal cortical regions, including left superior frontal gyrus (LSFG), and right middle frontal gyrus (RMFG). Moreover, the state-trait changes in dACC Glu and rsFC strength between the dACC and both SFG and MFG were positively correlated (P = 0.012, and P = 0.007, respectively). Finally, the change in circuit strength between dACC and LSFG was negatively correlated with the change in withdrawal symptom manifestations as measured by the Wisconsin Smoking Withdrawal Scale (P = 0.04) and Tobacco Craving Questionnaire (P = 0.014). These multimodal imaging-behavioral findings reveal the complex cascade of changes induced by acute nicotine deprivation and call for further investigation into the potential utility of adenosine- and glutamate-signaling as novel therapeutic targets to treat the NWS.

Repetitive Transcranial Magnetic Stimulation Delivered With an H-Coil to the Right Insula Reduces Functional Connectivity Between Insula and Medial Prefrontal Cortex.

OBJECTIVE: Insula neurocircuitry alterations are reported in a range of neuropsychiatric disorders holding promise for clinical interventions. We measured, in a pilot study, acute neuroplastic modulations resulting from high- and low-frequency stimulation with repetitive transcranial magnetic stimulation (rTMS) delivered via an H-coil that targeted the right insula and overlying prefrontal cortex. METHODS: Healthy, nonsmoking, adult participants (N = 28), in a within-participant, sham-controlled experiment, received a single rTMS session on four separate days. Participants received one session each of low- (1 Hz) and high (10 Hz)-frequency stimulation and two sessions of sham stimulation matched to each rTMS frequency. After each rTMS session, participants completed a functional magnetic resonance imaging (fMRI) scan while performing two cognitive tasks and a resting-state scan. The effect of rTMS was examined on task behavior as well as blood oxygenated level-dependent (BOLD) response during task performance and resting state. We expected low- and high-frequency stimulation to decrease and increase, respectively, insula and overlying cortical BOLD signal and network connectivity. RESULTS/CONCLUSIONS: There was no effect of rTMS, regardless of frequency, on task behavior or task-based BOLD response. There was an effect of rTMS compared to sham on rsFC between insula and medial prefrontal cortex, with connectivity reduced after rTMS compared to sham, regardless of frequency. Implications for using rTMS to the insula as a treatment for neuropsychiatric disorders are discussed in light of insula-medial prefrontal cortex connectivity.

Subcortical surface morphometry in substance dependence: An ENIGMA addiction working group study.

While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

Factors Affecting Detection Power of Blood Oxygen-Level Dependent Signal in Resting-State Functional Magnetic Resonance Imaging Using High-Resolution Echo-Planar Imaging.

Latest developments in magnetic resonance imaging (MRI) hardware and software have significantly improved image acquisition for functional MRI (fMRI) techniques, including resting-state fMRI (rsfMRI). Specifically, with improvements in gradient and radiofrequency coils and advances in pulse sequence designs, functional images with higher spatiotemporal resolution can be achieved. However, while smaller voxel size has the benefit of resolving finer brain structures, it also decreases voxel-wise signal-to-noise ratio (SNR) and, subsequently, temporal SNR (tSNR), which is critical for the sensitivity of fMRI. Although the improved temporal resolution allows more image frames to be collected per unit time, the ability to detect brain activity by using the high spatiotemporal fMRI has not been fully characterized. Here, we aimed to evaluate the effects of spatial smoothing, scan length, sample size, seed size, and location on resting-state functional connectivity (rsFC) and tSNR by using data from the human connectome project. Results from this analysis show an important effect of smoothing on the rsFC strength (correlation values between the seed and the target) as well as on the tSNR. In contrast, while rsFC strength is not affected by sample size, the standard error decreases with the increasing number of participants, therefore improving the detection power for larger samples. Scan length and seed size seem to have a moderate effect on rsFC strength. Finally, seed location has an important impact on rsFC maps, as rsFC strength from cortical seeds seems higher than from sub-cortical seeds. In summary, our findings show that the choice of parameters can be critical for an rsfMRI study.

Mega-Analysis of Gray Matter Volume in Substance Dependence: General and Substance-Specific Regional Effects.

OBJECTIVE: Although lower brain volume has been routinely observed in individuals with substance dependence compared with nondependent control subjects, the brain regions exhibiting lower volume have not been consistent across studies. In addition, it is not clear whether a common set of regions are involved in substance dependence regardless of the substance used or whether some brain volume effects are substance specific. Resolution of these issues may contribute to the identification of clinically relevant imaging biomarkers. Using pooled data from 14 countries, the authors sought to identify general and substance-specific associations between dependence and regional brain volumes. METHOD: Brain structure was examined in a mega-analysis of previously published data pooled from 23 laboratories, including 3,240 individuals, 2,140 of whom had substance dependence on one of five substances: alcohol, nicotine, cocaine, methamphetamine, or cannabis. Subcortical volume and cortical thickness in regions defined by FreeSurfer were compared with nondependent control subjects when all sampled substance categories were combined, as well as separately, while controlling for age, sex, imaging site, and total intracranial volume. Because of extensive associations with alcohol dependence, a secondary contrast was also performed for dependence on all substances except alcohol. An optimized split-half strategy was used to assess the reliability of the findings. RESULTS: Lower volume or thickness was observed in many brain regions in individuals with substance dependence. The greatest effects were associated with alcohol use disorder. A set of affected regions related to dependence in general, regardless of the substance, included the insula and the medial orbitofrontal cortex. Furthermore, a support vector machine multivariate classification of regional brain volumes successfully classified individuals with substance dependence on alcohol or nicotine relative to nondependent control subjects. CONCLUSIONS: The results indicate that dependence on a range of different substances shares a common neural substrate and that differential patterns of regional volume could serve as useful biomarkers of dependence on alcohol and nicotine.

Effect of combined naltrexone and bupropion therapy on the brain's functional connectivity.

BACKGROUND: The control of food intake in environments with easy access to highly rewarding foods is challenging to most modern societies. The combination of sustained release (SR) naltrexone and SR bupropion (NB32) has been used in weight-loss and obesity management. However, the effects of NB32 on the brain circuits implicated in the regulation of food intake are unknown. Here we used functional connectivity density (FCD) mapping to evaluate the effects of NB32 on resting brain FC. METHODS: Thirty-six healthy women underwent magnetic resonance imaging (MRI) before and after 4-week treatment with NB32 (n = 16) or with placebo (n = 20). In each imaging visit, a 5-min resting-state functional MRI scan was conducted after 15 h of fasting. The FC of brain regions showing significant group effects on FCD were subsequently assessed using seed-voxel correlation analyses. We characterized the associations between FCD measures and craving control scores in the Control of Eating Questionnaire. RESULTS: After NB32 treatment, the group showed lower local and global FCD than the placebo group in the right superior parietal cortex and lower local FCD in the left middle frontal gyrus. Seed-voxel correlation analysis for the right superior parietal cortex seed demonstrated higher positive FC with the dorsal anterior cingulate gyrus (ACC), bilateral insula, and left superior parietal gyrus and stronger negative FC with right inferior frontal gyrus and right superior parietal cortices for the NB32 than the placebo group. Further, the NB32 group showed a significant correlation between local FCD change after treatment in left middle frontal gyrus and craving control scores (r = 0.519, p = 0.039). CONCLUSIONS: NB32 treatment decreased local and global FCD in superior parietal cortex and increased its connectivity with ACC (involved with saliency attribution), insula (interoception), and decreased local FCD in the medial prefrontal cortex (craving), which might underlie NB32 improved control over eating behaviors. ClinicalTrails.gov: NCT00711.

Graph theory reveals amygdala modules consistent with its anatomical subdivisions.

Similarities on the cellular and neurochemical composition of the amygdaloid subnuclei suggests their clustering into subunits that exhibit unique functional organization. The topological principle of community structure has been used to identify functional subnetworks in neuroimaging data that reflect the brain effective organization. Here we used modularity to investigate the organization of the amygdala using resting state functional magnetic resonance imaging (rsfMRI) data. Our goal was to determine whether such topological organization would reliably reflect the known neurobiology of individual amygdaloid nuclei, allowing for human imaging studies to accurately reflect the underlying neurobiology. Modularity analysis identified amygdaloid elements consistent with the main anatomical subdivisions of the amygdala that embody distinct functional and structural properties. Additionally, functional connectivity pathways of these subunits and their correlation with task-induced amygdala activation revealed distinct functional profiles consistent with the neurobiology of the amygdala nuclei. These modularity findings corroborate the structure-function relationship between amygdala anatomical substructures, supporting the use of network analysis techniques to generate biologically meaningful partitions of brain structures.

Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: association to striatal D2/D3 receptors.

Cocaine, through its activation of dopamine (DA) signaling, usurps pathways that process natural rewards. However, the extent to which there is overlap between the networks that process natural and drug rewards and whether DA signaling associated with cocaine abuse influences these networks have not been investigated in humans. We measured brain activation responses to food and cocaine cues with fMRI, and D2/D3 receptors in the striatum with [11C]raclopride and Positron emission tomography in 20 active cocaine abusers. Compared to neutral cues, food and cocaine cues increasingly engaged cerebellum, orbitofrontal, inferior frontal, and premotor cortices and insula and disengaged cuneus and default mode network (DMN). These fMRI signals were proportional to striatal D2/D3 receptors. Surprisingly cocaine and food cues also deactivated ventral striatum and hypothalamus. Compared to food cues, cocaine cues produced lower activation in insula and postcentral gyrus, and less deactivation in hypothalamus and DMN regions. Activation in cortical regions and cerebellum increased in proportion to the valence of the cues, and activation to food cues in somatosensory and orbitofrontal cortices also increased in proportion to body mass. Longer exposure to cocaine was associated with lower activation to both cues in occipital cortex and cerebellum, which could reflect the decreases in D2/D3 receptors associated with chronicity. These findings show that cocaine cues activate similar, though not identical, pathways to those activated by food cues and that striatal D2/D3 receptors modulate these responses, suggesting that chronic cocaine exposure might influence brain sensitivity not just to drugs but also to food cues.

Computerized MRS voxel registration and partial volume effects in single voxel 1H-MRS.

Partial volume effects in proton magnetic resonance spectroscopy in the brain have been studied previously in terms of proper water concentration calculations, but there is a lack of disclosure in terms of voxel placement techniques that would affect the calculations. The purpose of this study is to facilitate a fully automated MRS voxel registration method which is time efficient, accurate, and can be extended to all imaging modalities. A total of thirteen healthy adults underwent single voxel 1H-MRS scans in 3.0T MRI scanners. Transposition of a MRS voxel onto an anatomical scan is derived along with a full calculation of water concentration with a correction term to account for the partial volume effects. Five metabolites (tNAA, Glx, tCr, mI, and tCho) known to yield high reliability are studied. Pearson's correlation analyses between tissue volume fractions and metabolite concentrations were statistically significant in parietal (tCr, Glx, and tNAA) lobe and occipital lobe (tNAA). MRS voxel overlaps quantified by dice metric over repeated visits yielded 60%~70% and coefficients of variance in metabolites concentration were 4%~10%. These findings reiterate an importance of considering the partial volume effects when tissue water is used as an internal concentration reference so as to avoid misinterpreting a morphometric difference as a metabolic difference.

Cytotoxicity, cytocompatibility, cell-labeling efficiency, and in vitro cellular magnetic resonance imaging of gadolinium-catalyzed single-walled carbon nanotubes.

Cell tracking by magnetic resonance imaging (MRI) is an emerging technique that typically requires the use of MRI contrast agents (CAs). A MRI CA for cellular imaging should label cells efficiently at potentially safe concentrations, have high relaxivity, and not affect the cellular machinery. In this article, we report the cytotoxicity, cytocompatibility, and cell labeling efficiency in NIH/3T3 fibroblasts of novel, single-walled carbon nanotubes synthesized using gadolinium nanoparticles as catalysts (Gd-SWCNTs). Cells incubated with the Gd-SWCNT showed a dose- (50-100 µg/mL nanotube concentration) and time- (12-48 h) dependent decrease in viability. 30% cell death was observed for cells incubated with Gd-SWCNTs at the maximum dose of 100 µg/mL for 48 h. Cells incubated with the Gd-SWCNTs at concentrations between 1-10 µg/mL for 48 h showed no change in viability or proliferation compared to untreated controls. Additionally, at these potentially safe concentrations, up to 48 h, the cells showed no phosphatidyl serine externalization (pre-apoptotic condition), caspase-3 activity (point of no return for apoptosis), genetic damage, or changes in their division cycle. Localization of Gd-SWCNTs within the cells was confirmed by transmission electron microscopy (TEM) and Raman microscopy, and these results show 100% cell labeling efficiency. Elemental analysis also indicates significant uptake of Gd-SWCNTs by the cells (10(8) -10(9) Gd(3+) ions per cell). Finally, T1 -weighted MRI at 3 T of Gd-SWCNT-labelled cells show up to a four-fold increase in MR signal intensities as compared to untreated cells. These results indicate that Gd-SWCNTs label cells efficiently at potentially safe concentrations, and enhance MRI contrast without any structural damage to the cells.

Induced magnetic force in human heads exposed to 4 T MRI.

PURPOSE: To map the distribution of the magnetic force induced in the human head during magnetic resonance imaging (MRI) at 4 T for a large group of healthy volunteers. MATERIALS AND METHODS: The magnetic field distribution in the head of 100 men and 18 women was mapped using phase mapping techniques. Statistical parametric mapping methods using a family-wise error (FWE) corrected threshold P < 0.05 and region-of-interest analyses were used to assess the significance of the results. RESULTS: Eyeballs, orbitofrontal and temporal cortices, subcallosal gyrus, anterior cingulate, midbrain, and brainstem (pons) are the brain regions most susceptible to magnetic force. The strength of the magnetic force density in the head was lower than 11.5 +/- 5.3 N/m(3) (right eyeball). The strength of the magnetic force density induced in occipital cortex varied linearly with the x-rotation (pitch) angle. CONCLUSION: We found that the induced magnetic force is highly significant in the eyeballs, orbitofrontal and temporal cortices, subcallosal gyrus, anterior cingulate as well as midbrain and brainstem (pons), regardless of subjects' age or gender. The maximum induced magnetic force was 6 x 10(5) times weaker than the gravitational force; thus, biological effects of the magnetic force during imaging are not expected to be significant.

Effects of low-field magnetic stimulation on brain glucose metabolism.

Echo planar imaging (EPI), the gold standard technique for functional MRI (fMRI), is based on fast magnetic field gradient switching. These time-varying magnetic fields induce electric (E) fields in the brain that could influence neuronal activity; but this has not been tested. Here we assessed the effects of EPI on brain glucose metabolism (marker of brain function) using PET and 18F 2-fluoro-2-deoxy-D-glucose ((18)FDG). Fifteen healthy subjects were in a 4 T magnet during the (18)FDG uptake period twice: with (ON) and without (OFF) EPI gradients pulses along the z-axis (G(z): 23 mT/m; 250 mus rise-time; 920 Hz). The E-field from these EPI pulses is non-homogeneous, increasing linearly from the gradient's isocenter (radial and z directions), which allowed us to assess the correlation between local strength of the E-field and the regional metabolic differences between ON and OFF sessions. Metabolic images were normalized to metabolic activity in the plane positioned at the gradient's isocenter where E=0 for both ON and OFF conditions. Statistical parametric analyses used to identify regions that differed between ON versus OFF (p<0.05, corrected) showed that the relative metabolism was lower in areas at the poles of the brain (inferior occipital and frontal and superior parietal cortices) for ON than for OFF, which was also documented with individual region of interest analysis. Moreover the magnitude of the metabolic decrements was significantly correlated with the estimated strength of E (r=0.68, p<0.0001); the stronger the E-field the larger the decreases. However, we did not detect differences between ON versus OFF conditions on mood ratings nor on absolute whole brain metabolism. This data provides preliminary evidence that EPI sequences may affect neuronal activity and merits further investigation.

Thalamo-cortical dysfunction in cocaine abusers: implications in attention and perception.

Cocaine affects sensory perception and attention, but little is known about the neural substrates underlying these effects in the human brain. We used functional magnetic resonance imaging (fMRI) and a sustained visuospatial attention task to assess if the visual attention network is dysfunctional in cocaine abusers (n=14) compared to age-, gender-, and education-matched controls (n=14). Compared with controls, cocaine abusers showed (1) hypo-activation of the thalamus, which may reflect noradrenergic and/or dopaminergic deficits; (2) hyper-activation in occipital and prefrontal cortices, which may reflect increased visual cortical processing to compensate for inefficient visual thalamic processing; and (3) larger deactivation of parietal and frontal regions possibly to support the larger hemodynamic supply to the hyper-activated brain regions. These findings provide evidence of abnormalities in thalamo-cortical responses in cocaine abusers that are likely to contribute to the impairments in sensory processing and in attention. The development of therapies that diminish these thalamo-cortical deficits could improve the treatment of cocaine addiction.

Is decreased prefrontal cortical sensitivity to monetary reward associated with impaired motivation and self-control in cocaine addiction?

OBJECTIVE: This study attempted to examine the brain's sensitivity to monetary rewards of different magnitudes in cocaine abusers and to study its association with motivation and self-control. METHOD: Sixteen cocaine abusers and 13 matched healthy comparison subjects performed a forced-choice task under three monetary value conditions while brain activation was measured with functional magnetic resonance imaging. Objective measures of state motivation were assessed by reaction time and accuracy, and subjective measures were assessed by self-reports of task engagement. Measures of trait motivation and self-control were assessed with the Multidimensional Personality Questionnaire. RESULTS: The cocaine abusers demonstrated an overall reduced regional brain responsivity to differences between the monetary value conditions. Also, in comparison subjects but not in cocaine abusers, reward-induced improvements in performance were associated with self-reports of task engagement, and money-induced activations in the lateral prefrontal cortex were associated with parallel activations in the orbitofrontal cortex. For cocaine abusers, prefrontal cortex sensitivity to money was instead associated with motivation and self-control. CONCLUSIONS: These findings suggest that in cocaine addiction 1) activation of the corticolimbic reward circuit to gradations of money is altered; 2) the lack of a correlation between objective and subjective measures of state motivation may be indicative of disrupted perception of motivational drive, which could contribute to impairments in self-control; and 3) the lateral prefrontal cortex modulates trait motivation and deficits in self-control, and a possible underlying mechanism may encompass a breakdown in prefrontal-orbitofrontal cortical communication.

Macrovascular contribution in activation patterns of working memory.

Brain activation maps of blood oxygenation level dependent (BOLD) signals during functional magnetic resonance imaging (fMRI) are sensitive to unwanted contributions from large vessels. Most BOLD-fMRI studies are based on a stimulus-correlated modulation of the MRI signal amplitude that is sensitive to desired microvascular effects and unwanted macrovascular effects. Aiming to suppress macrovascular effects in activation patterns, this BOLD-fMRI study evaluates brain activation during a verbal working memory task (2-back) in healthy volunteers (n=18) using the amplitude and phase components of the MRI signal. The use of the first time point as a phase reference allowed us to eliminate phase wrapping artifacts and increase the statistical power of 'phase' activation, and this information was used to filter out voxels with significant macrovascular (i.e., draining and pial veins) contribution in 'amplitude' activation patterns. Across subjects, the task produced large modulations of the relative phase in the occipital, dorsolateral prefrontal, and parietal cortices, suggesting a common distribution of draining veins in these regions across subjects, and in the rostral frontal cortex, probably associated to stimulus-correlated motion of the head. The phase filtering method partially suppressed BOLD responses in the superior and lateral prefrontal, parietal, and occipital cortices; therefore the commonly reported brain activation in these cortices during working memory tasks may include significant macrovascular contributions. This study suggests that the phase information embedded in the MRI signal can be used to suppress unwanted macrovascular contributions in fMRI studies.

Common deactivation patterns during working memory and visual attention tasks: an intra-subject fMRI study at 4 Tesla.

This parametric functional magnetic resonance imaging (fMRI) study investigates the balance of negative and positive fMRI signals in the brain. A set of visual attention (VA) and working memory (WM) tasks with graded levels of difficulty was used to deactivate separate but overlapping networks that include the frontal, temporal, occipital, and limbic lobes; regions commonly associated with auditory and emotional processing. Brain activation (% signal change and volume) was larger for VA tasks than for WM tasks, but deactivation was larger for WM tasks. Load-related increases of blood oxygenation level-dependent (BOLD) responses for different levels of task difficulty cross-correlated strongly in the deactivated network during VA but less so during WM. The variability of the deactivated network across different cognitive tasks supports the hypothesis that global cerebral blood flow vary across different tasks, but not between different levels of task difficulty of the same task. The task-dependent balance of activation and deactivation might allow maximization of resources for the activated network.