Connectivity In Healthy Subjects Research Articles

Network Architecture of Verticality Processing in the Human Thalamus.

Thalamic dysfunction in lesions or neurodegeneration may alter verticality perception and lead to postural imbalance and falls. The aim of the current study was to delineate the structural and functional connectivity network architecture of the vestibular representations in the thalamus by multimodal magnetic resonance imaging. Seventy-four patients with acute unilateral isolated thalamic infarcts were studied prospectively with emphasis on the perception of verticality (tilts of the subjective visual vertical [SVV]). We used multivariate lesion-symptom mapping based on support-vector regression to determine the thalamic nuclei associated with ipsiversive and contraversive tilts of the SVV. The lesion maps were used to evaluate the white matter disconnection and whole brain functional connectivity in healthy subjects. Contraversive SVV tilts were associated with lesions of the ventral posterior lateral/medial, ventral lateral, medial pulvinar, and medial central/parafascicular nuclei. Clusters associated with ipsiversive tilts were located inferiorly (ventral posterior inferior nucleus) and laterally (ventral lateral, ventral posterior lateral, and reticular nucleus) to these areas. Distinct ascending vestibular brainstem pathways terminated in the subnuclei for ipsi- or contraversive verticality processing. The functional connectivity analysis showed specific patterns of cortical connections with the somatomotor network for lesions with contraversive tilts, and with the core multisensory vestibular representations (areas Ri, OP2-3, Ig, 3av, 2v) for lesions with ipsiversive tilts. The functional specialization may allow both a stable representation of verticality for sensorimotor integration and flexible adaption to sudden changes in the environment. A targeted modulation of this circuitry could be a novel therapeutic strategy for higher level balance disorders of thalamocortical origin. ANN NEUROL 2023.

Probiotic Mixture Containing Lactobacillus helveticus, Bifidobacterium longum and Lactiplantibacillus plantarum Affects Brain Responses Toward an Emotional Task in Healthy Subjects: A Randomized Clinical Trial.

BackgroundEvidence from preclinical studies suggests that probiotics affect brain function via the microbiome-gut-brain axis, but evidence in humans remains limited.ObjectiveThe present proof-of-concept study investigated if a probiotic product containing a mixture of Bifidobacterium longum R0175, Lactobacillus helveticus R0052 and Lactiplantibacillus plantarum R1012 (in total 3 × 109 CFU/day) affected functional brain responses in healthy subjects during an emotional attention task.DesignIn this double-blinded, randomized, placebo-controlled crossover study (Clinicaltrials.gov, NCT03615651), 22 healthy subjects (24.2 ± 3.4 years, 6 males/16 females) were exposed to a probiotic intervention and a placebo for 4 weeks each, separated by a 4-week washout period. Subjects underwent functional magnetic resonance imaging while performing an emotional attention task after each intervention period. Differential brain activity and functional connectivity were assessed.ResultsAltered brain responses were observed in brain regions implicated in emotional, cognitive and face processing. Increased activation in the orbitofrontal cortex, a region that receives extensive sensory input and in turn projects to regions implicated in emotional processing, was found after probiotic intervention compared to placebo using a cluster-based analysis of functionally defined areas. Significantly reduced task-related functional connectivity was observed after the probiotic intervention compared to placebo. Fecal microbiota composition was not majorly affected by probiotic intervention.ConclusionThe probiotic intervention resulted in subtly altered brain activity and functional connectivity in healthy subjects performing an emotional task without major effects on the fecal microbiota composition. This indicates that the probiotic effects occurred via microbe-host interactions on other levels. Further analysis of signaling molecules could give possible insights into the modes of action of the probiotic intervention on the gut-brain axis in general and brain function specifically. The presented findings further support the growing consensus that probiotic supplementation influences brain function and emotional regulation, even in healthy subjects. Future studies including patients with altered emotional processing, such as anxiety or depression symptoms are of great interest.Clinical Trial Registration[http://clinicaltrials.gov/], identifier [NCT03615651].

Clinical and electrophysiological effects of two dTMS protocols in ADHD

Background: Attention deficit hyperactivity disorder (ADHD) is a highly prevalent neuropsychiatric disorder. The right prefrontal cortex (rPFC), which plays a central role in regulation of behavior and attention is one of the primary areas showing deficits in ADHD. Transcranial magnetic stimulation (TMS) can induce alterations in neural excitability and neural networks. Our recent study has shown lasting electrophysiological alterations and clinical improvement following 15 daily high-frequency (HF) deep TMS (dTMS) sessions directed to the rPFC. This improvement was highly correlated with an electrophysiological marker measured during the first treatment session. To validate this finding we now pre-screen participants and offer HF dTMS treatment only to those who are likely to benefit from it. Patients who are not compatible for HF dTMS may benefit from an alternative treatment strategy of paired associative stimulation (PAS), which aims to balance interhemispheric activity. PAS was recently shown in our lab to modulate both behavior and interhemispheric connectivity in healthy subjects.

Is Rest Really Rest? Resting-State Functional Connectivity During Rest and Motor Task Paradigms.

Numerous studies have identified several large-scale networks within the brain of healthy individuals, some of which have been attributed to ongoing mental activity during the wakeful resting state. While engaged during specific resting-state functional magnetic resonance imaging (fMRI) paradigms, it remains unclear as to whether traditional block-design simple movement fMRI experiments significantly influence these mode networks or other areas. Using blood-oxygen level-dependent fMRI, we characterized the pattern of functional connectivity in healthy subjects during a resting-state paradigm and compared this with the same resting-state analysis performed on motor task data residual time courses after regressing out the task paradigm. Using seed-voxel analysis to define the default mode network, the executive control network (ECN), and sensorimotor, auditory, and visual networks, the resting-state analysis of the residual time courses demonstrated reduced functional connectivity in the motor network and reduced connectivity between the insula and the ECN compared with the standard resting-state data sets. Overall, performance of simple self-directed motor tasks does little to change the resting-state functional connectivity across the brain, especially in nonmotor areas. This would suggest that previously acquired fMRI studies incorporating simple block-design motor tasks could be mined retrospectively for assessment of the resting-state connectivity.

Test-retest reliability of prefrontal transcranial Direct Current Stimulation (tDCS) effects on functional MRI connectivity in healthy subjects

Transcranial Direct Current Stimulation (tDCS) of the prefrontal cortex (PFC) can be used for probing functional brain connectivity and meets general interest as novel therapeutic intervention in psychiatric and neurological disorders. Along with a more extensive use, it is important to understand the interplay between neural systems and stimulation protocols requiring basic methodological work. Here, we examined the test-retest (TRT) characteristics of tDCS-induced modulations in resting-state functional-connectivity MRI (RS fcMRI). Twenty healthy subjects received 20minutes of either active or sham tDCS of the dorsolateral PFC (2mA, anode over F3 and cathode over F4, international 10–20 system), preceded and ensued by a RS fcMRI (10minutes each). All subject underwent three tDCS sessions with one-week intervals in between. Effects of tDCS on RS fcMRI were determined at an individual as well as at a group level using both ROI-based and independent-component analyses (ICA). To evaluate the TRT reliability of individual active-tDCS and sham effects on RS fcMRI, voxel-wise intra-class correlation coefficients (ICC) of post-tDCS maps between testing sessions were calculated. For both approaches, results revealed low reliability of RS fcMRI after active tDCS (ICC(2,1) = −0.09 – 0.16). Reliability of RS fcMRI (baselines only) was low to moderate for ROI-derived (ICC(2,1) = 0.13 – 0.50) and low for ICA-derived connectivity (ICC(2,1) = 0.19 – 0.34). Thus, for ROI-based analyses, the distribution of voxel-wise ICC was shifted to lower TRT reliability after active, but not after sham tDCS, for which the distribution was similar to baseline. The intra-individual variation observed here resembles variability of tDCS effects in motor regions and may be one reason why in this study robust tDCS effects at a group level were missing. The data can be used for appropriately designing large scale studies investigating methodological issues such as sources of variability and localisation of tDCS effects.

The influence of corticospinal activity on TMS-evoked activity and connectivity in healthy subjects: A TMS-EEG study.

Combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) can be used to analyze cortical reactivity and connectivity. However, the effects of corticospinal and peripheral muscle activity on TMS-evoked potentials (TEPs) are not well understood. The aim of this paper is to evaluate the relationship between cortico-spinal activity, in the form of peripheral motor-evoked potentials (MEPs), and the TEPs from motor areas, along with the connectivity among activated brain areas. TMS was applied to left and right motor cortex (M1), separately, at motor threshold while multi-channel EEG responses were recorded in 17 healthy human subjects. Cortical excitability and source imaging analysis were performed for all trials at each stimulation location, as well as comparing trials resulting in MEPs to those without. Connectivity analysis was also performed comparing trials resulting in MEPs to those without. Cortical excitability results significantly differed between the MEP and no-MEP conditions for left M1 TMS at 60 ms (CP1, CP3, C1) and for right M1 TMS at 54 ms (CP6, C6). Connectivity analysis revealed higher outflow and inflow between M1 and somatosensory cortex bi-directionally for trials with MEPs than those without for both left M1 TMS (at 60, 100, 164 ms) and right M1 TMS (at 54, 100, and 164 ms). Both TEP amplitudes and connectivity measures related to motor and somatosensory areas ipsilateral to the stimulation were shown to correspond with peripheral MEP amplitudes. This suggests that cortico-spinal activation, along with the resulting somatosensory feedback, affects the cortical activity and dynamics within motor areas reflected in the TEPs. The findings suggest that TMS-EEG, along with adaptive connectivity estimators, can be used to evaluate the cortical dynamics associated with sensorimotor integration and proprioceptive manipulation along with the influence of peripheral muscle feedback.

P123 Repeated measure stability of prefrontal transcranial direct current stimulation (tDCS) on functional MRI connectivity in healthy subjects

Previous studies have shown that transcranial Direct Current Stimulation (tDCS) modulates functional brain connectivity. For example, increased connectivity within the Frontal Parietal Network (FPN) was found following anodal stimulation of the prefrontal cortex (PFC) (Keeser et al., 2011; Pena-Gomez et al., 2012), potentially reflecting a state of enhanced alertness. The aim of this study is two-folded: First, we want to investigate the stability of tDCS- and tACS-induced resting state network (RSN) modulations. Secondly, we are looking at additive effects of tACS on RSN modulations by comparing tACS stimulation preceded by sham tDCS to tACS stimulations preceded by active tDCS. We applied tDCS and tACS over the dorsolateral PFC (anode placed over F3, cathode over F4; intensity: 2 mA (tDCS), 25 Hz (tACS)) during concurrently acquired resting-state functional Magnetic Resonance Imaging (MRI). 20 male participants were tested according to a between-subject, double-blinded design. Each participant received 20 min of either real or sham tDCS and 10 min of tACS stimulation, each preceded and ensued by a resting state examination of 10 min. This procedure was conducted three times with at least seven days between each measurement to avoid carry-over effects. Within one participant, stimulation condition (real vs. sham tDCS) was held constant across all time points. The tACS stimulation was always an active stimulation. Based on whole-brain dual-regression analysis, preliminary results showed a significant effect for the comparison post tDCS > baseline across time points in two RSNs at an uncorrected p 20 voxels). For the Default Mode Network (DMN), an increased coactivation in the left superior frontal gyrus was observed for group 2. In the same group, increased coactivations were also identified for the right FPN in the left and right superior frontal gyrus. In group 1, no significant differences were found for the left FPN, but there was increased activation in the sub gyral for the DMN in this group. Group comparisons (post tDCS > baseline) across time points show increased activations within the left and right superior frontal gyrus for group 2. To test for test–retest reliability of tDCS, correlations between the tDCS effects of each time point can be calculated.

Global tractography of multi-shell diffusion-weighted imaging data using a multi-tissue model

Diffusion-weighted imaging and tractography provide a unique, non-invasive technique to study the macroscopic structure and connectivity of brain white matter in vivo. Global tractography methods aim at reconstructing the full-brain fiber configuration that best explains the measured data, based on a generative signal model. In this work, we incorporate a multi-shell multi-tissue model based on spherical convolution, into a global tractography framework, which allows to deal with partial volume effects. The required tissue response functions can be estimated from and hence calibrated to the data. The resulting track reconstruction is quantitatively related to the apparent fiber density in the data. In addition, the fiber orientation distribution for white matter and the volume fractions of gray matter and cerebrospinal fluid are produced as ancillary results. Validation results on simulated data demonstrate that this data-driven approach improves over state-of-the-art streamline and global tracking methods, particularly in the valid connection rate. Results in human brain data correspond to known white matter anatomy and show improved modeling of partial voluming. This work is an important step toward detecting and quantifying white matter changes and connectivity in healthy subjects and patients.

White matter microstructure in bipolar disorder is influenced by the serotonin transporter gene polymorphism 5-HTTLPR.

Bipolar disorder (BD) is associated with signs of widespread disruption of white matter (WM) integrity. A polymorphism in the promoter of the serotonin transporter (5-HTTLPR) influenced functional cortico-limbic connectivity in healthy subjects and course of illness in BD, with the short (s) allele being associated with lower functional connectivity, and with earlier onset of illness and poor response to treatment. We tested the effects of 5-HTTLPR on diffusion tensor imaging (DTI) measures of WM microstructure in 140 inpatients, affected by a major depressive episode in course of BD, of Italian descent. We used whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial, radial and mean diffusivity and fractional anisotropy. Compared with l/l homozygotes, 5-HTTLPR*s carriers showed significantly increased radial and mean diffusivity in several brain WM tracts, including corpus callosum, cingulum bundle, uncinate fasciculus, corona radiata, thalamic radiation, inferior and superior longitudinal fasciculus and inferior fronto-occipital fasciculus. An increase of mean and radial diffusivity, perpendicular to the main axis of the WM tract, is thought to signify increased space between fibers, thus suggesting demyelination or dysmyelination, or loss of bundle coherence. The effects of 5-HTTLPR on the anomalous emotional processing in BD might be mediated by changes of WM microstructure in key WM tracts contributing to the functional integrity of the brain.

Abnormal asymmetry of brain connectivity in schizophrenia.

Recently, a growing body of data has revealed that beyond a dysfunction of connectivity among different brain areas in schizophrenia patients (SCZ), there is also an abnormal asymmetry of functional connectivity compared with healthy subjects. The loss of the cerebral torque and the abnormalities of gyrification, with an increased or more complex cortical folding in the right hemisphere may provide an anatomical basis for such aberrant connectivity in SCZ. Furthermore, diffusion tensor imaging studies have shown a significant reduction of leftward asymmetry in some key white-matter tracts in SCZ. In this paper, we review the studies that investigated both structural brain asymmetry and asymmetry of functional connectivity in healthy subjects and SCZ. From an analysis of the existing literature on this topic, we can hypothesize an overall generally attenuated asymmetry of functional connectivity in SCZ compared to healthy controls. Such attenuated asymmetry increases with the duration of the disease and correlates with psychotic symptoms. Finally, we hypothesize that structural deficits across the corpus callosum may contribute to the abnormal asymmetry of intra-hemispheric connectivity in schizophrenia.

6. Hyperventilation increases brain connectivity in healthy subjects and in focal cryptogenic epileptic patients

Hyperventilation is a widely used EEG activation method. Aim of the study was to evaluate the modifications in brain connectivity due to hyperventilation in normal subjects and in cryptogenic focal epileptic patients. We examined EEG recordings from 19 scalp electrodes of 22 normal subjects and 22 focal cryptogenic epileptic patients. Exclusion criteria were: migraine, cerebrovascular disease, MRI abnormalities and use of drugs, apart from Antiepileptic drugs in epileptic group. We selected segments before (PRE), during (HYPER) and five minutes after (POST) hyperventilation. We analyzed neural generators through low resolution electromagnetic tomography (sLORETA) for the following bands: delta (1–4 Hz), theta (5–7 Hz), alpha (8–13 Hz), beta (14–30 Hz) and gamma (31–60 Hz). We also computed EEG lagged coherence between 19 Regions Of Interest for the same bands. Finally, we performed intergroup analysis of Mean Lagged Coherence. In both groups hyperventilation significantly increases EEG (p < 0.01), particularly in posterior cingulate cortex, and lagged coherence (p < 0.01). Intergroup analysis of mean lagged coherence showed significant differences between the two groups (p < 0.001). Our findings demonstrate that hyperventilation is associated with activation of posterior cingulate cortex. Moreover it increases brain connectivity, with significant differences between healthy subjects and focal cryptogenic epileptic patients.

Sex and disease-related alterations of anterior insula functional connectivity in chronic abdominal pain.

Resting-state functional magnetic resonance imaging has been used to investigate intrinsic brain connectivity in healthy subjects and patients with chronic pain. Sex-related differences in the frequency power distribution within the human insula (INS), a brain region involved in the integration of interoceptive, affective, and cognitive influences, have been reported. Here we aimed to test sex and disease-related alterations in the intrinsic functional connectivity of the dorsal anterior INS. The anterior INS is engaged during goal-directed tasks and modulates the default mode and executive control networks. By comparing functional connectivity of the dorsal anterior INS in age-matched female and male healthy subjects and patients with irritable bowel syndrome (IBS), a common chronic abdominal pain condition, we show evidence for sex and disease-related alterations in the functional connectivity of this region: (1) male patients compared with female patients had increased positive connectivity of the dorsal anterior INS bilaterally with the medial prefrontal cortex (PFC) and dorsal posterior INS; (2) female patients compared with male patients had greater negative connectivity of the left dorsal anterior INS with the left precuneus; (3) disease-related differences in the connectivity between the bilateral dorsal anterior INS and the dorsal medial PFC were observed in female subjects; and (4) clinical characteristics were significantly correlated to the insular connectivity with the dorsal medial PFC in male IBS subjects and with the precuneus in female IBS subjects. These findings are consistent with the INS playing an important role in modulating the intrinsic functional connectivity of major networks in the resting brain and show that this role is influenced by sex and diagnosis.

Task-dependent reorganization of functional connectivity networks during visual semantic decision making.

IntroductionFunctional MRI is widely used to study task-related changes in neuronal activity as well as resting-state functional connectivity. In this study, we explore task-related changes in functional connectivity networks using fMRI. Dynamic connectivity may represent a new measure of neural network robustness that would impact both clinical and research efforts. However, prior studies of task-related changes in functional connectivity have shown apparently conflicting results, leading to several competing hypotheses regarding the relationship between task-related and resting-state brain networks.MethodsWe used a graph theory-based network approach to compare functional connectivity in healthy subjects between the resting state and when performing a clinically used semantic decision task. We analyzed fMRI data from 21 healthy, right-handed subjects.ResultsWhile three nonoverlapping, highly intraconnected functional modules were observed in the resting state, an additional language-related module emerged during the semantic decision task. Both overall and within-module connectivity were greater in default mode network (DMN) and classical language areas during semantic decision making compared to rest, while between-module connectivity was diffusely greater at rest, revealing a more widely distributed pattern of functional connectivity at rest.ConclusionsThe results of this study suggest that there are differences in network topology between resting and task states. Specifically, semantic decision making is associated with a reduction in distributed connectivity through hub areas of the DMN as well as an increase in connectivity within both default and language networks.

The impact of MIR137 on dorsolateral prefrontal-hippocampal functional connectivity in healthy subjects.

A recent mega-analysis combining genome-wide association study data revealed that a variant of microRNA 137 (MIR137) exhibits the most significant association with schizophrenia. Other biological evidence also consistently suggests that MIR137 may have a pivotal role in the pathogenesis of schizophrenia. However, the underlying neural mechanism remains unclear. As the disrupted dorsolateral prefrontal cortex (DLPFC) coupling with the hippocampal formation (HF) has been widely observed in schizophrenia patients, DLPFC-HF dysconnectivity can therefore be thought of as a pivotal intermediate phenotype that links genetic variants of psychiatric risk genes to schizophrenia. This study used resting-state functional magnetic resonance imaging to test whether the MIR137 variant (rs1625579) impacts DLPFC-HF functional connectivity and cognitive performance in 290 young, healthy Han Chinese individuals. To identify functional connectivity between DLPFC and HF, a seed-based functional connectivity analysis was used. The association between DLPFC-HF connectivity and working memory performance was further examined in individuals with different MIR137 genotypes. The individuals who are homozygous for the MIR137 risk allele (TT), which confers a high risk for schizophrenia, exhibited significantly different DLPFC-HF functional connectivity compared with TG individuals. Moreover, the DLPFC-HF connectivity could predict the working memory performance in MIR137 TG individuals, but not in TT individuals. The current findings obtained in a large sample of healthy participants identified potential neural mechanisms linking MIR137 with the risk of developing schizophrenia via the intermediate phenotype of DLPFC-HF connectivity.

Functional Connectivity in Healthy Subjects Is Nonlinearly Modulated by the COMT and DRD2 Polymorphisms in a Functional System-Dependent Manner

The dopamine system is known to modulate brain function in an inverted U-shaped manner. Recently, the functional networks of the brain were categorized into two systems, a "control system" and a "processing system." However, it remains unclear whether the inverted U-shaped model of dopaminergic modulation could be applied to both of these functional systems. The catechol-O-methyltransferase (COMT) and dopamine D2 receptor (DRD2) were genotyped in 258 healthy young human subjects. The local and long-range functional connectivity densities (FCDs) of each voxel were calculated and compared in a voxel-wise manner using a two-way (COMT and DRD2 genotypes) analysis of covariance. The resting-state functional connectivity analysis was performed to determine the functional networks to which brain regions with significant FCD differences belonged. Significant COMT × DRD2 interaction effects were found in the local FCDs of the superior portion of the right temporal pole (sTP) and left lingual gyrus (LG) and in the long-range FCDs of the right putamen and left medial prefrontal cortex (MPFC). Post hoc tests showed nonlinear relationships between the genotypic subgroups and FCD. In the control system, the sTP and putamen, components of the salience network, showed a U-shaped modulation by dopamine signaling. In the processing system, however, the MPFC of the default-mode network and the LG of the visual network showed an inverted U-shaped modulation by the dopamine system. Our findings suggest an interaction between COMT and DRD2 genotypes and show a functional system-dependent modulation of dopamine signaling.

Catastrophizing mediates pressure pain induced change in brain functional connectivity in fibromyalgia

Fibromyalgia (FM) is a chronic pain syndrome characterized bywidespreadpain and amplified pain sensitivity. We previously found that experimentally-induced cuff pressure pain alters functional brain connectivity in healthy subjects. Here we investigate whether this phenomenon can be observed in FM patients, and whether it is affected by pain catastrophizing (CAT), which is known to be amplified in FM. Functional connectivity MRI (fcMRI) data were acquired from 37 FM patients (44.6611.9yr) and 15 HC (45.6614.7yr) during separate 6-minute resting (REST) and sustained cuff pain stimulus (PAIN) scans. Cuff-pressure was individually calibrated to produce moderate ( 40/ 100) pain intensity. Data were analyzed with dual regression ICA (FSL). We found increased salience network (SLN) connectivity to contralateral S1 during PAIN compared to REST, in both HC and FM. Decreased sensorimotor network (SMN) to bilateral S1/M1 during PAINwas observed in HC, not in FM. Compared to HC, FM showed diminished SMN connectivity to S1/M1 at REST. In FM, CAT scores were positively correlated with right frontoparietal control network (rFCN) connectivity to S1 during PAIN, but not REST. Consistent with previous results, increased SLN-S1 connectivity during evoked pain likely reflects the inherent attention-demanding effects of a pain stimulus. Diminished SMN-S1/M1 connectivity at rest in FMmight reflect attenuated connectivity due to ongoing spontaneous clinical pain. Individual variability in cognitive and affective variables may be important in shaping pain processing, as patients with greater CATshowed greater cognitive control network (rFCN) connectivity to S1, which may represent elevated cross-talk between somatosensory and cognitive (rumination, helplessness, etc.) processing of evoked-pain stimuli. Future studies should explore if therapies that normalize CAT do so by modulating this somatosensory/cognitive brain connectivity, both at rest and during sustained evoked-pain.

Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.

The contribution of the putamen to sensory aspects of pain: insights from structural connectivity and brain lesions

Cerebral cortical activity is heavily influenced by interactions with the basal ganglia. These interactions occur via cortico-basal ganglia-thalamo-cortical loops. The putamen is one of the major sites of cortical input into basal ganglia loops and is frequently activated during pain. This activity has been typically associated with the processing of pain-related motor responses. However, the potential contribution of putamen to the processing of sensory aspects of pain remains poorly characterized. In order to more directly determine if the putamen can contribute to sensory aspects of pain, nine individuals with lesions involving the putamen underwent both psychophysical and functional imaging assessment of perceived pain and pain-related brain activation. These individuals exhibited intact tactile thresholds, but reduced heat pain sensitivity and widespread reductions in pain-related cortical activity in comparison with 14 age-matched healthy subjects. Using magnetic resonance imaging to assess structural connectivity in healthy subjects, we show that portions of the putamen activated during pain are connected not only with cortical regions involved in sensory-motor processing, but also regions involved in attention, memory and affect. Such a framework may allow cognitive information to flow from these brain areas to the putamen where it may be used to influence how nociceptive information is processed. Taken together, these findings indicate that the putamen and the basal ganglia may contribute importantly to the shaping of an individual subjective sensory experience by utilizing internal cognitive information to influence activity of large areas of the cerebral cortex.

Local brain connectivity and associations with gender and age

Regional homogeneity measures synchrony of resting-state brain activity in neighboring voxels, or local connectivity. The effects of age and gender on local connectivity in healthy subjects are unknown. We performed regional homogeneity analyses on resting state BOLD time series data acquired from 58 normal, healthy participants, ranging in age from 11 to 35 (mean 18.1 ± 5.0 years, 32 males). Regional homogeneity was found to be highest for gray matter, with brain regions within the default mode network having the highest local connectivity values. There was a general decrease in regional homogeneity with age with the greatest reduction seen in the anterior cingulate and temporal lobe. Greater female local connectivity in the right hippocampus and amygdala was also noted, regardless of age. These findings suggest that local connectivity at the millimeter scale decreases during development as longer connections are formed, and underscores the importance of examining gender differences in imaging studies of healthy and clinical populations.

P.1.e.008 Impact of genetic polymorphism on resting state functional connectivity in healthy subjects

Brain-derived neurotrophic factor (BDNF) regulates food intake and energy metabolism. It has also been suggested that mutations in the human BDNF gene and its receptor TrkB account for disturbed eating and obesity. The Met-allele of the BDNF Val66Met polymorphism has been associated with eating disorders, but the underlying mechanism of its contribution is not known. We report herewith that the effect of BDNF Val66Met polymorphism on binge eating in adolescent girls is dependent on severe food restriction. The scores on EDI-2 Bulimia subscale were significantly higher in BDNF Met-allele carriers who made attempts to regulate their body weight by reducing their meal frequency or by starving. This finding may help to explain why some people develop binge eating in response to dieting and others do not.