Distinct neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex.

Functional magnetic resonance imaging (fMRI) is among the foremost methods for mapping human brain function but provides only an indirect measure of underlying neural activity. Recent findings suggest that the neurophysiological correlates of the fMRI blood-oxygen-level-dependent (BOLD) signal might be regionally specific. We examined the neurophysiological correlates of the fMRI BOLD signal in the hippocampus and neocortex, where differences in neural architecture might result in a different relationship between the respective signals. Fifteen human neurosurgical patients (10 female, 5 male) implanted with depth electrodes performed a verbal free recall task while electrophysiological activity was recorded simultaneously from hippocampal and neocortical sites. The same patients subsequently performed a similar version of the task during a later fMRI session. Subsequent memory effects (SMEs) were computed for both imaging modalities as patterns of encoding-related brain activity predictive of later free recall. Linear mixed-effects modelling revealed that the relationship between BOLD and gamma-band SMEs was moderated by the lobar location of the recording site. BOLD and high gamma (70-150 Hz) SMEs positively covaried across much of the neocortex. This relationship was reversed in the hippocampus, where a negative correlation between BOLD and high gamma SMEs was evident. We also observed a negative relationship between BOLD and low gamma (30-70 Hz) SMEs in the medial temporal lobe more broadly. These results suggest that the neurophysiological correlates of the BOLD signal in the hippocampus differ from those observed in the neocortex.Significance Statement:The blood-oxygen-level-dependent (BOLD) signal forms the basis of fMRI but provides only an indirect measure of neural activity. Task-related modulation of BOLD signals are typically equated with changes in gamma-band activity; however, relevant empirical evidence comes largely from the neocortex. We examined neurophysiological correlates of the BOLD signal in the hippocampus, where the differing neural architecture might result in a different relationship between the respective signals. We identified a positive relationship between encoding-related changes in BOLD and gamma-band activity in frontal and parietal cortex. This effect was reversed in the hippocampus, where BOLD and gamma-band effects negatively covaried. These results suggest regional variability in the transfer function between neural activity and the BOLD signal in the hippocampus and neocortex.

Episodic boundary cells in human medial temporal lobe during the free recall task.

A necessary condition for forming episodic memories is the construction of specific episodes demarcated from other episodes in space and time. Evidence from studies of episodic memory formation using rodent models suggest that the medial temporal lobe (MTL) supports the representation of boundary information. Building on recent work using human microelectrode recordings as well, we hypothesized of human MTL neurons with firing rates sensitive to episodic boundary information. We identified 27 episodic boundary neurons out of 736 single neurons recorded across 27 subjects. Firing of these neurons increased at the beginning and end of mnemonically relevant episodes in the free recall task. We distinguish episodic boundary neurons from a population of ramping neurons (n = 58), which are time-sensitive neurons whose activity provides complementary information during episodic representation. Episodic boundary neurons exhibited a U-shaped activity pattern demonstrating increased activity after both beginning and end boundaries of encoding and retrieval epochs. We also describe evidence that the firing of boundary neurons within episodic boundaries is organized by hippocampal theta oscillations, using spike-field coherence metrics.

Neurons in the human medial temporal lobe track multiple temporal contexts during episodic memory processing.

Episodic memory requires associating items with temporal context, a process for which the medial temporal lobe (MTL) is critical. This study uses recordings from 27 human subjects who were undergoing surgical intervention for intractable epilepsy. These same data were also utilized in Umbach et al. (2020). We identify 103 memory-sensitive neurons in the hippocampus and entorhinal cortex, whose firing rates predicted successful episodic memory encoding as subjects performed a verbal free recall task. These neurons exhibit important properties. First, as predicted from the temporal context model, they demonstrate reinstatement of firing patterns observed during encoding at the time of retrieval. The magnitude of reinstatement predicted the tendency of subjects to cluster retrieved memory items according to input serial position. Also, we found that spiking activity of these neurons was locked to the phase of hippocampal theta oscillations, but that the mean phase of spiking shifted between memory encoding versus retrieval. This unique observation is consistent with predictions of the "Separate Phases at Encoding And Retrieval (SPEAR)" model. Together, the properties we identify for memory-sensitive neurons characterize direct electrophysiological mechanisms for the representation of contextual information in the human MTL.

Dynamic functional connectivity between nucleus accumbens and the central executive network relates to chronic cannabis use.

The neural mechanisms of drug cue-reactivity regarding the temporal fluctuations of functional connectivity, namely the dynamic connectivity, are sparsely studied. Quantifying the task-modulated variability in dynamic functional connectivity at cue exposure can aid the understanding. We analyzed changes in dynamic connectivity in 54 adult cannabis users and 90 controls during a cannabis cue exposure task. The variability was measured as standard deviation in the (a) connectivity weights of the default mode, the central executive, and the salience networks and two reward loci (amygdalae and nuclei accumbens); and (b) topological indexes of the whole brain (global efficiency, modularity and network resilience). These were compared for the main effects of task conditions and the group (users vs. controls), and correlated with pre- and during-scan subjective craving. The variability of connectivity weights between the central executive network and nuclei accumbens was increased in users throughout the cue exposure task, and, was positively correlated with during-scan craving for cannabis. The variability of modularity was not different by groups, but positively correlated with prescan craving. The variability of dynamic connectivity during cannabis cue exposure task between the central executive network and the nuclei accumbens, and, the level of modularity, seem to relate to the neural underpinning of cannabis use and the subjective craving.

Interaction of Cannabis Use and Aging: From Molecule to Mind.

Given the aging Baby Boomer generation, changes in cannabis legislation, and the growing acknowledgment of cannabis for its therapeutic potential, it is predicted that cannabis use in the older population will escalate. It is, therefore, important to determine the interaction between the effects of cannabis and aging. The aim of this report is to describe the link between cannabis use and the aging brain. Our review of the literature found few and inconsistent empirical studies that directly address the impact of cannabis use on the aging brain. However, research focused on long-term cannabis use points toward cumulative effects on multimodal systems in the brain that are similarly affected during aging. Specifically, the effects of cannabis and aging converge on overlapping networks in the endocannabinoid, opioid, and dopamine systems that may affect functional decline particularly in the hippocampus and prefrontal cortex, which are critical areas for memory and executive functioning. To conclude, despite the limited current knowledge on the potential interactive effects between cannabis and aging, evidence from the literature suggests that cannabis and aging effects are concurrently present across several neurotransmitter systems. There is a great need for future research to directly test the interactions between cannabis and aging.

Comparison of Neural Activity in Chronic Pain Patients During Tonic and Burst Spinal Cord Stimulation Using Fluorodeoxyglucose Positron Emission Tomography.

OBJECTIVE: Burst spinal cord stimulation (SCS) is a novel stimulation paradigm that seems to provide better pain relief compared to the classic tonic SCS with minimal paresthesia sensation. Based on source localized electroencephalography and clinical data, it has been proposed that burst stimulation as defined by Dirk De Ridder exerts this greater effect by not only modulating the lateral and the descending pain-inhibitory pathways (similar to tonic SCS) but also modulating the medial pain pathway, which encodes the affective, motivational aspects of pain. MATERIAL AND METHODS: The current study evaluates the supraspinal differences between burst and tonic stimulation with another functional imaging technique, namely fluorodeoxyglucose positron emission tomography (FGD-PET) scanning, in seven patients, who underwent both burst and tonic SCS, to confirm this notion of medial pain pathway modulation. RESULTS: The results of the current FGD-PET study show that burst stimulation, in contrast to tonic stimulation, indeed modulates the dorsal anterior cingulate cortex (i.e., medial pain pathway) more than tonic stimulation. DISCUSSION: Our data suggest an inherent difference in the central neural mechanisms during burst and tonic stimulation, which could potentially alter the patient's perception of pain. CONFLICT OF INTEREST: Dr. Yearwood, Dr. De Ridder, Dr. Falowski, and Dr. Vanneste are the consultants of Abbott. Dr. Venkatesan is an employee of Abbott. Hye Bin Yoo and Dr. Wing Ting To have no conflicts of interest to report.

Frontostriatal network dysfunction as a domain-general mechanism underlying phantom perception.

In the present study, we use resting state fMRI to investigate whether nucleus accumbens (NAc) and extended frontostriatal networks are involved in the pathology of auditory phantom perception, i.e., tinnitus, through a study of functional connectivity. We hypothesize that resting state functional connectivity involving NAc will be increased relative to what is observed in healthy subjects and that this connectivity will correlate with clinical measures of tinnitus such as percept loudness, duration of symptoms, etc. We show that a large sample of patients with chronic tinnitus (n = 90) features extensive functional connectivity involving NAc that is largely absent in healthy subjects (n = 94). We further show that connectivity involving NAc correlates significantly with tinnitus percept loudness and the duration of tinnitus symptoms, even after controlling for the effects of age and hearing loss. The loudness correlation, which involves NAc and parahippocampal cortex, is consistent with existing literature identifying the parahippocampus as a tinnitus generator. Our results further suggest that frontostriatal connectivity may predict the transition from acute to chronic tinnitus, analogous to what is seen in the pain literature. We discuss these ideas and suggest fruitful avenues for future research.

The Importance of Aging in Gray Matter Changes Within Tinnitus Patients Shown in Cortical Thickness, Surface Area and Volume.

Aging and sensorineural hearing loss are known to be involved in the development of chronic tinnitus. This study explores the structural changes of gray matter using surface base methods and focuses more specifically on changes in cortical thickness in 127 tinnitus patients. The linear relationships between cortical thickness and behavioral measures including aging, tinnitus loudness, tinnitus duration, tinnitus distress, and hearing loss were analyzed. Three dimensional T1-weighted MR images were acquired and cortical gray matter volumes were segmented using FreeSurfer on Talairach space. The results showed that cortical thickness and volume are negatively correlated to age in widespread regions of frontal cortices, and positively to bilateral entorhinal cortex and left rostral anterior cingulate cortex. The cortical thickness changes related to hearing loss overlap with those related to normal aging. The gray matter volumes of bilateral amygdalae, hippocampi, nuclei accumbens, and thalami are all significantly negatively correlated to age. Tinnitus-related distress level and subjective loudness were negatively correlated only to the thalamic volume. The results suggest that the primary factor of long-term structural changes in chronic tinnitus patients is age and age related hearing loss, rather than hearing loss per se. Tinnitus related factors such as subjective tinnitus loudness, tinnitus duration, and the level of chronic tinnitus related distress were not correlated to important morphometric changes in this study.

Extrastriatal dopaminergic changes in Parkinson's disease patients with impulse control disorders.

OBJECTIVE: To investigate the extrastriatal dopaminergic neural changes in relation to the medication-related impulse control disorders (ICD) in Parkinson's disease (PD). METHOD: A total of 31 subjects (11 and 11 drug-treated PD patients with and without medication-related ICDs and 9 healthy controls) having no other co-morbid psychiatric disorders participated in this study. Each subject underwent dynamic N-(3-[(18)F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography scans. Binding potentials (BP) at nucleus accumbens, amygdala, orbitofrontal and ventromedial prefrontal cortex (VMPFC), putamen and caudate nucleus were estimated, and whole brain parametric maps of [(18)F]-FP-CIT binding were analysed by original and putaminal normalised manners. RESULTS: Compared with the healthy controls, BPs at both VMPFCs were significantly high and the extrastriatal to putaminal BP ratios at all regions were approximately three times higher in both PD groups. The PD ICD patients showed significantly higher BPs at the right VMPFC and tendency to lower BPs at the left nucleus accumbens compared with those free of ICD. The ICD subjects also showed reduced uptakes at both ventral striatal regions in the original parametric analysis and higher uptakes at the left insular and right posterior cingulate cortex and lower uptakes at both ventral pallidums in the putaminal normalised parametric analysis compared with the non-ICD subjects. CONCLUSIONS: A great gap in extrastriatal versus striatal dopaminergic fibre degenerations is an intrinsic condition predisposing to ICD in PD. Distinct pattern of extrastriatal changes between the ICD and non-ICD patients could provide a further insight into a mechanism of ICD in PD.

Paradoxical relationship between distress and functional network topology in phantom sound perception.

Distress is a domain-general symptom that accompanies several disorders, including tinnitus. Based on previous studies, we know that distress is encoded by changes in functional connectivity between cortical and subcortical regions. However, how distress relates to large-scale brain networks is not yet clear. In the current study, we investigate the relationship between distress and the efficiency of a network by examining its topological properties using resting state fMRI collected from 90 chronic tinnitus patients. The present results indicate that distress negatively correlates with path length and positively correlates with clustering coefficient, small-worldness, and efficiency of information transfer. Specifically, path analysis showed that the relationship between distress and efficiency is significantly mediated by the resilience of the feeder connections and the centrality of the rich-club connections. In other words, the higher the network efficiency, the lower the resilience of the feeder connections and the centrality of the rich-club connections, which in turn reflects in higher distress in tinnitus patients. This indicates a reorganization of the network towards a paradoxically more efficient topology in patients with high distress, potentially explaining their increased rumination on the tinnitus percept itself.

Structural correlates of the audiological and emotional components of chronic tinnitus.

The objective is to investigate white matter tracts, more specifically the arcuate fasciculus and acoustic radiation, in tinnitus and assess their relationship with distress, loudness and hearing loss. DTI images were acquired for 58 tinnitus patients and 65 control subjects. Deterministic tractography was first performed to visualize the arcuate fasciculus and acoustic radiation tracts bilaterally and to calculate tract density, fractional anisotropy, radial diffusivity, and axial diffusivity for tinnitus and control subjects. Tinnitus patients had a significantly reduced tract density compared to controls in both tracts of interest. They also exhibited increased axial diffusivity in the left acoustic radiation, as well as increased radial diffusivity in the left arcuate fasciculus, and both the left and right acoustic radiation. Furthermore, they exhibited decreased fractional anisotropy in the left arcuate fasciculus, as well as the left and right acoustic radiation tracts. Partial correlation analysis showed: (1) a negative correlation between arcuate fasciculus tract density and tinnitus distress, (2) a negative correlation between acoustic radiation tract density and hearing loss, (3) a negative correlation between acoustic radiation tract density and loudness, (4) a positive correlation between left arcuate fasciculus and tinnitus distress for radial diffusivity, (5) a negative correlation between left arcuate fasciculus and tinnitus distress for fractional anisotropy, (6) a positive correlation between left and right acoustic radiation and hearing loss for radial diffusivity, (7) No correlation between any of the white matter characteristics and tinnitus loudness. Structural alterations in the acoustic radiation and arcuate fasciculus correlate with hearing loss and distress in tinnitus but not tinnitus loudness showing that loudness is a more functional correlate of the disorder which does not manifest structurally.

The peripheral effect of direct current stimulation on brain circuits involving memory.

An ongoing debate surrounding transcranial direct current stimulation (tDCS) of the scalp is whether it modulates brain activity both directly and in a regionally constrained manner enough to positively affect symptoms in patients with neurological disorders. One alternative explanation is that direct current stimulation affects neural circuits mainly indirectly, i.e., via peripheral nerves. Here, we report that noninvasive direct current stimulation indirectly affects neural circuits via peripheral nerves. In a series of studies, we show that direct current stimulation can cause activation of the greater occipital nerve (ON-tDCS) and augments memory via the ascending fibers of the occipital nerve to the locus coeruleus, promoting noradrenaline release. This noradrenergic pathway plays a key role in driving hippocampal activity by modifying functional connectivity supporting the consolidation of a memory event.

Efficacy of Cilostazol Administration in Alzheimer's Disease Patients with White Matter Lesions: A Positron-Emission Tomography Study.

This study tested the efficacy of the phosphodiesterase type III inhibitor cilostazol in Alzheimer's disease patients with white matter lesions treated with donepezil in comparison with donepezil monotherapy using fluorodeoxyglucose (18F) positron-emission tomography (FDG PET). A 24-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted. Thirty-six Alzheimer's disease patients with white matter lesions who received donepezil (n = 18 each in the cilostazol and placebo groups) were enrolled. Participants underwent pre and post FDG PET imaging scans and three rounds of clinical and neuropsychological tests. The cilostazol group did not show a significant decrease of regional glucose metabolism; however, regional glucose metabolism was significantly decreased in the parietal and frontal lobes of the placebo group. The repeated measures ANOVA measuring differences in uptake change revealed that regional glucose metabolism in the left inferior frontal gyrus was significantly more preserved in the cilostazol group than that in the placebo group (p < 0.005). Mean changes from baseline on the Mini-Mental State Exam, Alzheimer's Disease Assessment Scale-cognitive subscale, Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, and the Clinical Dementia Rating Sum of Boxes did not differ between the two groups. In the cilostazol group, the increase of glucose metabolism correlated with the improvment of the Alzheimer's Disease Assessment Scale-cognitive score. We conclude that cilostazol treatment added to donepezil may delay the decline in regional cerebral metabolism in Alzheimer's disease with white matter lesions compared with donepezil monotherapy. In additon, our results verified the efficacy of cilostazol in improving or protecting cognitive function in Alzheimer's disease through increased glucose metabolism. However, the long-term effect of cilostazol on cognitive function and Alzheimer's disease modification must be tested in further studies with larger sample size and longer study period. Trial registration: http://clinicaltrials.gov : NCT01409564.

Adding Prefrontal Transcranial Direct Current Stimulation Before Occipital Nerve Stimulation in Fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a type of chronic musculoskeletal pain without a clear peripheral origin of nociception, often associated with depression. The underlying pathophysiology involves changes in a functional network that is related to pain and emotional processing in the central nervous system. Transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex or the occipital nerve (ON) is a noninvasive neuromodulation technique capable of improving fibromyalgia symptoms. This study aims to test the effect of combining 2 targets of stimulation using tDCS. MATERIALS AND METHODS: We applied ON-tDCS in isolation or coupled with pre-ONS right-anode bifrontal tDCS and assessed its effect on fibromyalgia using the Fibromyalgia Impact Questionnaire, the Beck Depression Inventory, and Numeric Rating Scale for pain scores. These measures were compared with a sham control group using repeated measures analysis of variance. RESULTS: The interaction effect of stimulation trials and the protocols of sham versus ON-tDCS were significant for the impact, distress, and pain caused by fibromyalgia (P<0.05). The interaction effect of trials and protocols of sham versus ON-tDCS with bifrontal tDCS was significant for distress (P<0.01), and it showed a trend of improvement for impact and pain (P<0.1). On the basis of the nonsignificant interaction effect of ON-tDCS versus ON-tDCS with bifrontal tDCS (P>0.1), adding bifrontal tDCS was found not to improve the treatment effect of ON-tDCS in any of the tested clinical outcome measures. DISCUSSION: This study suggests that adding right-anode bifrontal tDCS to ONS has no added benefit in improving fibromyalgia-related symptoms.

White Matter Changes in Tinnitus: Is It All Age and Hearing Loss?

Tinnitus is a condition characterized by the perception of auditory phantom sounds. It is known as the result of complex interactions between auditory and nonauditory regions. However, previous structural imaging studies on tinnitus patients showed evidence of significant white matter changes caused by hearing loss that are positively correlated with aging. Current study focused on which aspects of tinnitus pathologies affect the white matter integrity the most. We used the diffusion tensor imaging technique to acquire images that have higher contrast in brain white matter to analyze how white matter is influenced by tinnitus-related factors using voxel-based methods, region of interest analysis, and deterministic tractography. As a result, white matter integrity in chronic tinnitus patients was both directly affected by age and also mediated by the hearing loss. The most important changes in white matter regions were found bilaterally in the anterior corona radiata, anterior corpus callosum, and bilateral sagittal strata. In the tractography analysis, the white matter integrity values in tracts of right parahippocampus were correlated with the subjective tinnitus loudness.

Noninvasive bi-graphical analysis for the quantification of slowly reversible radioligand binding.

In this paper, we presented a novel reference-region-based (noninvasive) bi-graphical analysis for the quantification of a reversible radiotracer binding that may be too slow to reach relative equilibrium (RE) state during positron emission tomography (PET) scans. The proposed method indirectly implements the noninvasive Logan plot, through arithmetic combination of the parameters of two other noninvasive methods and the apparent tissue-to-plasma efflux rate constant for the reference region ([Formula: see text]). We investigated its validity and statistical properties, by performing a simulation study with various noise levels and [Formula: see text] values, and also evaluated its feasibility for [18F]FP-CIT PET in human brain. The results revealed that the proposed approach provides distribution volume ratio estimation comparable to the Logan plot at low noise levels while improving underestimation caused by non-RE state differently depending on [Formula: see text]. Furthermore, the proposed method was able to avoid noise-induced bias of the Logan plot, and the variability of its results was less dependent on [Formula: see text] than the Logan plot. Therefore, this approach, without issues related to arterial blood sampling given a pre-estimate of [Formula: see text] (e.g. population-based), could be useful in parametric image generation for slow kinetic tracers staying in a non-RE state within a PET scan.

Whole-brain diffusion-tensor changes in parkinsonian patients with impulse control disorders.

BACKGROUND AND PURPOSE: The aim of this study was to determine the changes in diffusion-tensor images associated with medication-related impulse control disorder (ICD) in Parkinson's disease (PD) patients undergoing chronic dopamine-replacement therapy. METHODS: Nineteen PD patients, comprising 10 with ICD (PD-ICD) and 9 without ICD (PD-nonICD), and 18 age-matched healthy controls (HCs) with no cognitive or other psychiatric disorders were analyzed. All subjects underwent 3-T magnetic resonance diffusion-tensor imaging. For all PD patients, clinical data on PD duration, antiparkinsonian medication dosages, Unified Parkinson's Disease Rating Scale and Mini-Mental State Examination were collected. Whole-brain voxel-based measures of fractional anisotropy (FA) and mean diffusivity (MD) were analyzed. RESULTS: In comparison with HCs, the PD-nonICD subjects had low FA at the bilateral orbitofrontal areas. While the PD-ICD subjects exhibited no such difference, their FA was significantly elevated at the anterior corpus callosum. Analysis of FA between the two PD groups revealed that FA in the anterior corpus callosum, right internal capsule posterior limbs, right posterior cingulum, and right thalamic radiations were significantly higher (corrected p<0.05) in the PD-ICD than in the PD-nonICD patients. MD did not differ between the PD-ICD and PD-nonICD groups in any brain regions. CONCLUSIONS: The PD-ICD patients appear to have relatively preserved white-matter integrity in the regions involved in reward-related behaviors compared to PD-nonICD patients. Further investigation is required to determine whether the difference in FA between PD-ICD and PD-nonICD patients reflects microstructural differences in the pathological progression of PD or is secondary to ICD.

Spatial memory impairments in amnestic mild cognitive impairment in a virtual radial arm maze.

OBJECTIVE: This study aims to apply the virtual radial arm maze (VRAM) task to find spatial working memory and reference memory impairments in patients of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). Spatial memory functions between aMCI converters and nonconverters are also compared using VRAM results. METHODS: We assessed the spatial memory in 20 normal controls, 20 aMCI, and 20 mild AD subjects using VRAM. The Mini-Mental State Examination, Clinical Dementia Rating scale, and other neuropsychological tests were given to the subjects in conjunction with the VRAM test. Scores in working memory errors and reference memory errors were compared among the three groups using repeated measures analysis of variance. In addition, aMCI patients were followed-up after 5 years and surveyed for AD conversion rate. RESULTS: In AD patients, both spatial working and reference memory were impaired. However, in aMCI subjects, only spatial reference memory was impaired. Significant spatial reference memory impairment was found in the aMCI converter group when compared to the nonconverter group. CONCLUSION: Spatial working memory is less impaired in aMCI while reference memory is similarly damaged in AD. In aMCI patients, more severe spatial reference memory deficit is a neuropsychological marker for AD conversion. VRAM may be well utilized in humans to assess spatial memory in normal aging, in aMCI, and in AD.