Investigation of brain functional connectivity in patients with mild cognitive impairment: A functional near‐infrared spectroscopy (fNIRS) study

This study examines brain functional connectivity in both cognitively normal seniors and patients with mild cognitive impairment (MCI) to elucidate prospective markers of MCI. A homemade four‐channel functional near‐infrared spectroscopy (fNIRS) system was employed to measure hemodynamic responses in the subjects' prefrontal cortex during a resting state, an oddball task, a 1‐back task, and a verbal fluency task. Brain functional connectivity was calculated as the Pearson correlation coefficients between fNIRS channels. The results show that during the verbal fluency task, while the healthy control (HC) group presents a significantly stronger inter‐hemispheric connectivity compared to intra‐hemispheric connectivity, there is no difference between the inter‐ and intra‐hemispheric connectivity in the MCI group. In addition, a comparison between the MCI and HC connectivity reveals that the MCI group has a statistically higher right and inter‐hemispheric connectivity during the resting state, but a significantly lower left and inter‐hemispheric connectivity during the verbal fluency test. These findings demonstrate the potential of fNIRS to study brain functional connectivity in neurodegenerative diseases.     

The Effect of Online Violent Video Games on Levels of Aggression

Background

In recent years the video game industry has surpassed both the music and video industries in sales. Currently violent video games are among the most popular video games played by consumers, most specifically First-Person Shooters (FPS). Technological advancements in game play experience including the ability to play online has accounted for this increase in popularity. Previous research, utilising the General Aggression Model (GAM), has identified that violent video games increase levels of aggression. Little is known, however, as to the effect of playing a violent video game online.

Methods/Principal Findings

Participants (N = 101) were randomly assigned to one of four experimental conditions; neutral video game—offline, neutral video game—online, violent video game—offline and violent video game—online. Following this they completed questionnaires to assess their attitudes towards the game and engaged in a chilli sauce paradigm to measure behavioural aggression. The results identified that participants who played a violent video game exhibited more aggression than those who played a neutral video game. Furthermore, this main effect was not particularly pronounced when the game was played online.

Conclusions/Significance

These findings suggest that both playing violent video games online and offline compared to playing neutral video games increases aggression.     

fMRI Validation of fNIRS Measurements During a Naturalistic Task

We present a method to compare brain activity recorded with near-infrared spectroscopy (fNIRS) in a dance video game task to that recorded in a reduced version of the task using fMRI (functional magnetic resonance imaging). Recently, it has been shown that fNIRS can accurately record functional brain activities equivalent to those concurrently recorded with functional magnetic resonance imaging for classic psychophysical tasks and simple finger tapping paradigms. However, an often quoted benefit of fNIRS is that the technique allows for studying neural mechanisms of complex, naturalistic behaviors that are not possible using the constrained environment of fMRI. Our goal was to extend the findings of previous studies that have shown high correlation between concurrently recorded fNIRS and fMRI signals to compare neural recordings obtained in fMRI procedures to those separately obtained in naturalistic fNIRS experiments. Specifically, we developed a modified version of the dance video game Dance Dance Revolution (DDR) to be compatible with both fMRI and fNIRS imaging procedures. In this methodology we explain the modifications to the software and hardware for compatibility with each technique as well as the scanning and calibration procedures used to obtain representative results. The results of the study show a task-related increase in oxyhemoglobin in both modalities and demonstrate that it is possible to replicate the findings of fMRI using fNIRS in a naturalistic task. This technique represents a methodology to compare fMRI imaging paradigms which utilize a reduced-world environment to fNIRS in closer approximation to naturalistic, full-body activities and behaviors. Further development of this technique may apply to neurodegenerative diseases, such as Parkinson’s disease, late states of dementia, or those with magnetic susceptibility which are contraindicated for fMRI scanning.     

Identification of the Pain Process by Cold Stimulation: Using Dynamic Causal Modeling of Effective Connectivity in Functional Near-Infrared Spectroscopy (fNIRS)

Background

Pain is an unpleasant sensory and emotional experience followed by anxiety, depression, and frustration. Functional Near-Infrared Spectroscopy (fNIRS) as an optical technique identifies the brain functional networks by investigating connectivity between functionally linked of different anatomical regions in response to pain stimulation.

Functional near infrared spectroscopy using spatially resolved data to account for tissue scattering: A numerical study and arm‐cuff experiment

Functional Near‐Infrared Spectroscopy (fNIRS) aims to recover changes in tissue optical parameters relating to tissue hemodynamics, to infer functional information in biological tissue. A widely‐used application of fNIRS relies on continuous wave (CW) methodology that utilizes multiple distance measurements on human head for study of brain health. The typical method used is spatially resolved spectroscopy (SRS), which is shown to recover tissue oxygenation index (TOI) based on gradient of light intensity measured between two detectors. However, this methodology does not account for tissue scattering which is often assumed. A new parameter recovery algorithm is developed, which directly recovers both the scattering parameter and scaled chromophore concentrations and hence TOI from the measured gradient of light‐attenuation at multiple wavelengths. It is shown through simulations that in comparison to conventional SRS which estimates cerebral TOI values with an error of ±12.3%, the proposed method provides more accurate estimate of TOI exhibiting an error of ±5.7% without any prior assumptions of tissue scatter, and can be easily implemented within CW fNIRS systems. Using an arm‐cuff experiment, the obtained TOI using the proposed method is shown to provide a higher and more realistic value as compared to utilizing any prior assumptions of tissue scatter.     

The mechanism of acute fasting‐induced antidepressant‐like effects in mice

Acute fasting induced antidepressant‐like effects. However, the exact brain region and mechanism of these actions are still largely unknown. Therefore, in this study the antidepressant‐like effects of acute fasting on c‐Fos expression and BDNF levels were investigated. Consistent with our previous findings, immobility time was remarkably shortened by 9 hrs fasting in the forced swimming test. Furthermore, these antidepressant‐like effects of 9 fasting were inhibited by a 5‐HT_2A/2C receptor agonist (±)‐1‐(2, 5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI), and the effect of DOI was blocked by pretreatment with a selective 5‐HT_2A receptor antagonist ketanserin. Immunohistochemical study has shown that c‐Fos level was significantly increased by 9 hrs fasting in prefrontal cortex but not hippocampus and habenular. Fasting‐induced c‐Fos expression was further enhanced by DOI in prefrontal cortex, and these enhancements were inhibited by ketanserin. The increased BDNF levels by fasting were markedly inhibited by DOI in frontal cortex and hippocampus, and these effects of DOI on BDNF levels were also blocked by ketanserin. These findings suggest that the antidepressant‐like effects of acute fasting may be exerted via 5‐HT_2A receptor and particularly sensitive to neural activity in the prefrontal cortex. Furthermore, these antidepressant‐like effects are also mediated by CREB and BDNF pathway in hippocampus and frontal cortex. Therefore, fasting may be potentially helpful against depression.     

Brain region‐specific changes in N‐acylethanolamine contents with time of day

The N‐acylethanolamines (NAEs) exert important behavioral, physiological, and immunological effects through actions at cannabinoid and other receptors. We measured concentrations of three NAEs, the K_m and V_max for fatty acid amide hydrolysis (FAAH), FAAH protein and FAAH mRNA in prefrontal cortex, hippocampus, hypothalamus, amygdala, striatum, and cerebellum at 4 h intervals, starting at 03:00. Significant differences in N‐arachidonylethanolamine contents among the times examined occur in the prefrontal cortex (PFC), hippocampus, hypothalamus, and striatum. N‐Oleoylethanolamine concentrations exhibit large fluctuations over the day in the cerebellum, including a threefold decrease between 19:00 and 23:00. N‐Palmitoylethanolamine and N‐oleoylethanolamine were significantly, positively correlated in all regions examined except the hypothalamus. FAAH K_m values are significantly affected by time of day in PFC, hippocampus and amygdala and FAAH V_max values are significantly affected in PFC, hippocampus and cerebellum. However, correlational data indicate that FAAH does not play a primary role in the circadian regulation of the NAE concentrations. FAAH protein expression is not significantly different among the harvest times in any brain region examined. Concentrations of 2‐arachidonoylglycerol are significantly affected by time of harvest in the striatum and cerebellum, but not in other brain regions. Together, these data indicate that the NAEs exhibit diverse patterns of change with time of day that are likely the result of alterations in biosynthesis, and support the hypothesis that N‐arachidonylethanolamine is a tonic activator of cannabinoid receptor signaling.

     

rTMS of the Left Dorsolateral Prefrontal Cortex Modulates Dopamine Release in the Ipsilateral Anterior Cingulate Cortex and Orbitofrontal Cortex

Background

Brain dopamine is implicated in the regulation of movement, attention, reward and learning and plays an important role in Parkinson''s disease, schizophrenia and drug addiction. Animal experiments have demonstrated that brain stimulation is able to induce significant dopaminergic changes in extrastriatal areas. Given the up-growing interest of non-invasive brain stimulation as potential tool for treatment of neurological and psychiatric disorders, it would be critical to investigate dopaminergic functional interactions in the prefrontal cortex and more in particular the effect of dorsolateral prefrontal cortex (DLPFC) (areas 9/46) stimulation on prefrontal dopamine (DA).

Methodology/Principal Findings

Healthy volunteers were studied with a high-affinity DA D2-receptor radioligand, [¹¹C]FLB 457-PET following 10 Hz repetitive transcranial magnetic stimulation (rTMS) of the left and right DLPFC. rTMS on the left DLPFC induced a significant reduction in [¹¹C]FLB 457 binding potential (BP) in the ipsilateral subgenual anterior cingulate cortex (ACC) (BA 25/12), pregenual ACC (BA 32) and medial orbitofrontal cortex (BA 11). There were no significant changes in [¹¹C]FLB 457 BP following right DLPFC rTMS.

Conclusions/Significance

To our knowledge, this is the first study to provide evidence of extrastriatal DA modulation following acute rTMS of DLPFC with its effect limited to the specific areas of medial prefrontal cortex. [¹¹C]FLB 457-PET combined with rTMS may allow to explore the neurochemical functions of specific cortical neural networks and help to identify the neurobiological effects of TMS for the treatment of different neurological and psychiatric diseases.     

Gray matter deficits in bipolar disorder are associated with genetic variability at interleukin‐1 beta gene (2q13)

Twin, family and recent molecular studies support the hypothesis of genetic overlapping between schizophrenia and bipolar disorder. Brain structural features shared by both psychiatric disorders might be the phenotypic expression of a common genetic risk background. Interleukin‐1 (IL‐1) cluster (chromosome 2q13) genetic variability, previously associated with an increased risk both for schizophrenia and for bipolar disorder, has been also associated with gray matter (GM) deficits, ventricular enlargement and hypoactivity of prefrontal cortex in schizophrenia. The aim of the present study was to analyze the influence of IL‐1 cluster on brain morphology in bipolar disorder. Genetic variability at IL‐1B and IL‐1RN genes was analyzed in 20 DSM‐IV ( Diagnostic and Statistical Manual of Mental Disorders ‐Fourth Edition) bipolar patients. Magnetic resonance imaging (MRI) measurements were obtained for whole‐brain GM and white matter, dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus, hippocampus and lateral ventricles. MRI data were corrected for age and cranial size using regression parameters from a group of 45 healthy subjects. A ?511C/T polymorphism (rs16944) of IL‐1B gene was associated with whole‐brain GM deficits (P = 0.031) and left DLPFCGM deficits (P = 0.047) in bipolar disorder patients. These findings support the hypothesis of IL‐1 cluster variability as a shared genetic risk factor contributing to GM deficits both in bipolar disorder and in schizophrenia. Independent replication in larger samples would be of interest to confirm these results.     

Effects of VMAT2 inhibitors lobeline and GZ‐793A on methamphetamine‐induced changes in dopamine release,metabolism and synthesis in vivo

Vesicular monoamine transporter‐2 (VMAT2) inhibitors reduce methamphetamine (METH) reward in rats. The current study determined the effects of VMAT2 inhibitors lobeline (LOB; 1 or 3 mg/kg) and N‐(1,2R‐dihydroxylpropyl)‐2,6‐cis‐di(4‐methoxyphenethyl)piperidine hydrochloride (GZ‐793A; 15 or 30 mg/kg) on METH‐induced (0.5 mg/kg, SC) changes in extracellular dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) in the reward‐relevant nucleus accumbens (NAc) shell using in vivo microdialysis. The effect of GZ‐793A (15 mg/kg) on DA synthesis in tissue also was investigated in NAc, striatum, medial prefrontal cortex and orbitofrontal cortex. In NAc shell, METH produced a time‐dependent increase in extracellular DA and decrease in DOPAC. Neither LOB nor GZ‐793A alone altered extracellular DA; however, both drugs increased extracellular DOPAC. In combination with METH, LOB did not alter the effects of METH on DA; however, GZ‐793A, which has greater selectivity than LOB for inhibiting VMAT2, reduced the duration of the METH‐induced increase in extracellular DA. Both LOB and GZ‐793A enhanced the duration of the METH‐induced decrease in extracellular DOPAC. METH also increased tissue DA synthesis in NAc and striatum, whereas GZ‐793A decreased synthesis; no effect of METH or GZ‐793A on DA synthesis was found in medial prefrontal cortex or orbitofrontal cortex. These results suggest that selective inhibition of VMAT2 produces a time‐dependent decrease in DA release in NAc shell as a result of alterations in tyrosine hydroxylase activity, which may play a role in the ability of GZ‐793A to decrease METH reward.

     

Genetic variation in the serotonin transporter modulates neural system-wide response to fearful faces

A distributed, serotonergically innervated neural system comprising extrastriate cortex, amygdala and ventral prefrontal cortex is critical for identification of socially relevant emotive stimuli. The extent to which a genetic variation of serotonin transporter gene 5-HTTLPR impacts functional connectivity between the amygdala and the other components of this neural system remains little examined. In our study, neural activity was measured using event-related functional magnetic resonance imaging in 29 right-handed, white Caucasian healthy subjects as they viewed mild or prototypical fearful and neutral facial expressions. 5-HTTLPR genotype was classified as homozygous for the short allele ( S/S ), homozygous for the long allele ( L/L ) or heterozygous ( S/L ). S/S showed greater activity than L/L within right fusiform gyrus (FG) to prototypically fearful faces. To these fearful faces, S/S more than other genotype subgroups showed significantly greater positive functional connectivity between right amygdala and FG and between right FG and right ventrolateral prefrontal cortex (VLPFC). There was a positive association between measure of psychoticism and degree of functional connectivity between right FG and right VLPFC in response to prototypically fearful faces. Our data are the first to show that genotypic variation in 5-HTTLPR modulates both the amplitude within and the functional connectivity between different components of the visual object-processing neural system to emotionally salient stimuli. These effects may underlie the vulnerability to mood and anxiety disorders potentially triggered by socially salient, emotional cues in individuals with the S allele of 5-HTTLPR.     

Empathy Moderates the Effect of Repetitive Transcranial Magnetic Stimulation of the Right Dorsolateral Prefrontal Cortex on Costly Punishment

Humans incur considerable costs to punish unfairness directed towards themselves or others. Recent studies using repetitive transcranial magnetic stimulation (rTMS) suggest that the right dorsolateral prefrontal cortex (DLPFC) is causally involved in such strategic decisions. Presently, two partly divergent hypotheses are discussed, suggesting either that the right DLPFC is necessary to control selfish motives by implementing culturally transmitted social norms, or is involved in suppressing emotion-driven prepotent responses to perceived unfairness. Accordingly, we studied the role of the DLPFC in costly (i.e. third party) punishment by applying rTMS to the left and right DLPFC before playing a Dictator Game with the option to punish observed unfair behavior (DG-P). In addition, sham stimulation took place. Individual differences in empathy were assessed with the German version of the Interpersonal Reactivity Index. Costly punishment increased (non-significantly) upon disruption of the right – but not the left – DLPFC as compared to sham stimulation. However, empathy emerged as a highly significant moderator variable of the effect of rTMS over the right, but not left, DLPFC, suggesting that the right DLPFC is involved in controlling prepotent emotional responses to observed unfairness, depending on individual differences in empathy.     

Functional disconnection and compensation in mild cognitive impairment: evidence from DLPFC connectivity using resting-state fMRI

The known regional abnormality of the dorsolateral prefrontal cortex (DLPFC) and its role in various neural circuits in mild cognitive impairment (MCI) has given prominence to its importance in studies on the disconnection associated with MCI. The purpose of the current study was to examine the DLPFC functional connectivity patterns during rest in MCI patients and the impact of regional grey matter (GM) atrophy on the functional results. Structural and functional MRI data were collected from 14 MCI patients and 14 age, gender-matched healthy controls. We found that both the bilateral DLPFC showed reduced functional connectivity with the inferior parietal lobule (IPL), superior/medial frontal gyrus and sub-cortical regions (e.g., thalamus, putamen) in MCI patients when compared with healthy controls. Moreover, the DLPFC connectivity with the IPL and thalamus significantly correlated with the cognitive performance of patients as measured by mini-mental state examination (MMSE), clock drawing test (CDT), and California verbal learning test (CVLT) scores. When taking GM atrophy as covariates, these results were approximately consistent with those without correction, although there may be a decrease in the statistical power. These results suggest that the DLPFC disconnections may be the substrates of cognitive impairments in MCI patients. In addition, we also found enhanced functional connectivity between the left DLPFC and the right prefrontal cortex in MCI patients. This is consistent with previous findings of MCI-related increased activation during cognitive tasks, and may represent a compensatory mechanism in MCI patients. Together, the present study demonstrated the coexistence of functional disconnection and compensation in MCI patients using DLPFC functional connectivity analysis, and thus might provide insights into biological mechanism of the disease.     

Dissociable controlled retrieval and generalized selection mechanisms in ventrolateral prefrontal cortex

How does ventrolateral prefrontal cortex (VLPFC) control mnemonic processing? Alternative models propose that VLPFC guides top-down (controlled) retrieval of knowledge from long-term stores or selects goal-relevant products of retrieval from among competitors. A paucity of evidence supports a retrieval/selection distinction, raising the possibility that these models reduce to a common mechanism. Here, four manipulations varied semantic control demands during fMRI: judgment specificity, cue-target-associative strength, competitor dominance, and number of competitors. Factor analysis revealed evidence for a metafactor that accounted for common behavioral variance across manipulations and for functional variance in left mid-VLPFC. These data support a generalized control process that selects relevant knowledge from among competitors. By contrast, left anterior VLPFC and middle temporal cortex were sensitive to cue-target-associative strength, but not competition, consistent with a control process that retrieves knowledge stored in lateral temporal cortex. Distinct PFC mechanisms mediate top-down retrieval and postretrieval selection.     

Altered near‐infrared spectroscopy response to breath‐holding in patients with fibromyalgia

Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread pain and a heightened response to pressure. Most medical researches pointed out that FM patients with endothelial dysfunction and arterial stiffness. A continuous‐wave near‐infrared spectroscopy (NIRS) system is used in present study to measure the hemodynamic changes elicited by breath‐holding task in patients with FM. Each patient completed a questionnaire survey including demographics, characteristics of body pain, associated symptoms, headache profiles and Hospital Anxiety and Depression Scale. A total of 27 FM patients and 26 health controls were enrolled. In comparison with healthy controls, patients with FM showed lower maximal and averaged change of oxyhemoglobin concentration in both the left (1.634 ±0.890 and 0.810 ±0.525 μM) and the right (1.576 ±0.897 and 0.811 ±0.601 μM) prefrontal cortex than healthy controls (P < .05 for both sides) during the breath‐holding task. In conclusion, FM is associated with altered cerebrovascular reactivity measured by NIRS and breath‐holding task, which may reflect endothelial dysfunction or arterial stiffness. Oxygenated hemoglobin concentration changes of healthy controls and FM patients.      

In vivo full‐field functional optical hemocytometer

We present an in vivo lab‐free full‐field functional optical hemocytometer (FFOH) for application to the capillaries of a live biological specimen, based on the absorption intensity fluctuation modulation (AIFM) effect. Because of the absorption difference between the red blood cells (RBCs) and background tissue under low‐coherence light illumination, an endogenous instantaneous intensity fluctuation is generated by the AIFM effect when RBCs discontinuously traverse the capillary. The AIFM effect is used to highlight the RBC signal relative to the background tissue by computing the real‐time modulation depth. FFOH can simultaneously provide a flow video, the flow velocity and the RBC count. Ourexperimental results can potentially be applied to study the physiological mechanisms of the blood circulation systems of near‐transparent live biological samples.      

Resting‐state functional connectivity measured by diffuse correlation spectroscopy

Near‐infrared diffuse correlation spectroscopy (DCS) is used to record spontaneous cerebral blood flow fluctuations in the frontal cortex. Nine adult subjects participated in the experiments, in which 8‐minute spontaneous fluctuations were simultaneously recorded from the left and right dorsolateral and inferior frontal regions. Resting‐state functional connectivity (RSFC) was measured by the temporal correlation of the low frequency fluctuations. Our data shows the RSFC within the dorsolateral region is significantly stronger than that between the inferior and dorsolateral regions, in line with previous observations with functional near‐infrared spectroscopy. This indicates that DCS is capable of investigating brain functional connectivity in terms of cerebral blood flow.      

Functional role of the ventrolateral prefrontal cortex in decision making

To make deliberate decisions, we have to utilize detailed information about the environment and our internal states. The ventral visual pathway provides detailed information on object identity, including color and shape, to the ventrolateral prefrontal cortex (VLPFC). The VLPFC also receives motivational and emotional information from the orbitofrontal cortex and subcortical areas, and computes the behavioral significance of external events; this information can be used for elaborate decision making or design of goal-directed behavior. In this review, we discuss recent advances that are revealing the neural mechanisms that underlie the coding of behavioral significance in the VLPFC, and the functional roles of these mechanisms in decision making and action programming in the brain.     

Imipramine‐Induced c‐Fos Expression in the Medial Prefrontal Cortex is Decreased in the ACTH‐Treated Rats

Previous studies have shown that the antidepressive‐like effect of tricyclic antidepressants is blocked by repeated treatments with adrenocorticotropic hormone (ACTH). However, little is known about the neuroanatomy underlying the mechanism of the imipramine treatment‐resistant depression model. In the present study, first experimental evidence showed no significant difference of the serum imipramine concentrations between the saline and ACTH‐treated rats. In further study, imipramine produced significant increases in the c‐Fos expression in the medial prefrontal cortex (mPFC), the dentate gyrus of the hippocampus (DGH), and the central nucleus of the amygdala (CeA), in rats repeatedly treated with saline. The imipramine‐increased c‐Fos immunoreactivity was suppressed in the mPFC of rats repeatedly treated with ACTH. However, there was no significant difference in c‐Fos expression in the DGH and CeA between ACTH‐ and saline‐treated rats. These results suggest that the mPFC is maybe involved in effects of the imipramine in the ACTH‐treated rats. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:486‐491, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21510     

Neural Activity Changes Associated with Impulsive Responding in the Sustained Attention to Response Task

Humans can anticipate and prepare for uncertainties to achieve a goal. However, it is difficult to maintain this effort over a prolonged period of time. Inappropriate behavior is impulsively (or mindlessly) activated by an external trigger, which can result in serious consequences such as traffic crashes. Thus, we examined the neural mechanisms underlying such impulsive responding using functional magnetic resonance imaging (fMRI). Twenty-two participants performed a block-designed sustained attention to response task (SART), where each task block was composed of consecutive Go trials followed by a NoGo trial at the end. This task configuration enabled us to measure compromised preparation for NoGo trials during Go responses using reduced Go reaction times. Accordingly, parametric modulation analysis was conducted on fMRI data using block-based mean Go reaction times as an online marker of impulsive responding in the SART. We found that activity in the right dorsolateral prefrontal cortex (DLPFC) and the bilateral intraparietal sulcus (IPS) was positively modulated with mean Go reaction times. In addition, activity in the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) was negatively modulated with mean Go reaction times, albeit statistically weakly. Taken together, spontaneously reduced activity in the right DLPFC and the IPS and spontaneously elevated activity in the MPFC and the PCC were associated with impulsive responding in the SART. These results suggest that such a spontaneous transition of brain activity pattern results in impulsive responding in monotonous situations, which in turn, might cause human errors in actual work environments.