Connectome alterations following perinatal deafness in the cat.

Following sensory deprivation, areas and networks in the brain may adapt and reorganize to compensate for the loss of input. These adaptations are manifestations of compensatory crossmodal plasticity, which has been documented in both human and animal models of deafness-including the domestic cat. Although there are abundant examples of structural plasticity in deaf felines from retrograde tracer-based studies, there is a lack of diffusion-based knowledge involving this model compared to the current breadth of human research. The purpose of this study was to explore white matter structural adaptations in the perinatally-deafened cat via tractography, increasing the methodological overlap between species. Plasticity was examined by identifying unique group connections and assessing altered connectional strength throughout the entirety of the brain. Results revealed a largely preserved connectome containing a limited number of group-specific or altered connections focused within and between sensory networks, which is generally corroborated by deaf feline anatomical tracer literature. Furthermore, five hubs of cortical plasticity and altered communication following perinatal deafness were observed. The limited differences found in the present study suggest that deafness-induced crossmodal plasticity is largely built upon intrinsic structural connections, with limited remodeling of underlying white matter.

Dissecting structural connectivity of the left and right inferior frontal cortex in children who stutter.

Inferior frontal cortex pars opercularis (IFCop) features a distinct cerebral dominance and vast functional heterogeneity. Left and right IFCop are implicated in developmental stuttering. Weak left IFCop connections and divergent connectivity of hyperactive right IFCop regions have been related to impeded speech. Here, we reanalyzed diffusion magnetic resonance imaging data from 83 children (41 stuttering). We generated connection probability maps of functionally segregated area 44 parcels and calculated hemisphere-wise analyses of variance. Children who stutter showed reduced connectivity of executive, rostral-motor, and caudal-motor corticostriatal projections from the left IFCop. We discuss this finding in the context of tracing studies from the macaque area 44, which leads to the need to reconsider current models of speech motor control. Unlike the left, the right IFCop revealed increased connectivity of the inferior posterior ventral parcel and decreased connectivity of the posterior dorsal parcel with the anterior insula, particularly in stuttering boys. This divergent connectivity pattern in young children adds to the debate on potential core deficits in stuttering and challenges the theory that right hemisphere differences might exclusively indicate compensatory changes that evolve from lifelong exposure. Instead, early right prefrontal connectivity differences may reflect additional brain signatures of aberrant cognition-emotion-action influencing speech motor control.

White matter tract alterations in schizophrenia identified by DTI-based probabilistic tractography: a multisite harmonisation study.

INTRODUCTION: It has been suggested that schizophrenia involves dysconnectivity between functional brain regions and also the white matter structural disorganisation. Thus, diffusion tensor imaging (DTI) has widely been used for studying schizophrenia. However, most previous studies have used the region of interest (ROI) based approach. We, therefore, performed the probabilistic tractography method in this study to reveal the alterations of white matter tracts in the schizophrenia brain. METHODS: A total of four different datasets consisted of 189 patients with schizophrenia and 213 healthy controls were investigated. We performed retrospective harmonisation of raw diffusion MRI data by dMRIharmonisation and used the FMRIB Software Library (FSL) for probabilistic tractography. The connectivities between different ROIs were then compared between patients and controls. Furthermore, we evaluated the relationship between the connection probabilities and the symptoms and cognitive measures in patients with schizophrenia. RESULTS: After applying Bonferroni correction for multiple comparisons, 11 different tracts showed significant differences between patients with schizophrenia and healthy controls. Many of these tracts were associated with the basal ganglia or cortico-striatal structures, which aligns with the current literature highlighting striatal dysfunction. Moreover, we found that these tracts demonstrated statistically significant relationships with few cognitive measures related to language, executive function, or processing speed. CONCLUSION: We performed probabilistic tractography using a large, harmonised dataset of diffusion MRI data, which enhanced the statistical power of our study. It is important to note that most of the tracts identified in this study, particularly callosal and cortico-striatal streamlines, have been previously implicated in schizophrenia within the current literature. Further research with harmonised data focusing specifically on these brain regions could be recommended.

Distance-dependent distribution thresholding in probabilistic tractography.

Tractography is widely used in human studies of connectivity with respect to every brain region, function, and is explored developmentally, in adulthood, ageing, and in disease. However, the core issue of how to systematically threshold, taking into account the inherent differences in connectivity values for different track lengths, and to do this in a comparable way across studies has not been solved. By utilising 54 healthy individuals' diffusion-weighted image data taken from HCP, this study adopted Monte Carlo derived distance-dependent distributions (DDDs) to generate distance-dependent thresholds with various levels of alpha for connections of varying lengths. As a test case, we applied the DDD approach to generate a language connectome. The resulting connectome showed both short- and long-distance structural connectivity in the close and distant regions as expected for the dorsal and ventral language pathways, consistent with the literature. The finding demonstrates that the DDD approach is feasible to generate data-driven DDDs for common thresholding and can be used for both individual and group thresholding. Critically, it offers a standard method that can be applied to various probabilistic tracking datasets.

Cholinergic white matter pathways in dementia with Lewy bodies and Alzheimer's disease.

Patients who have dementia with Lewy bodies and Alzheimer's disease show early degeneration of the cholinergic nucleus basalis of Meynert. However, how white matter projections between the nucleus basalis of Meynert and the cortex are altered in neurodegenerative disease is unknown. Tractography of white matter pathways originating from the nucleus basalis of Meynert was performed using diffusion-weighted imaging in 46 patients with Alzheimer's disease dementia, 48 with dementia with Lewy bodies, 35 with mild cognitive impairment with Alzheimer's disease, 38 with mild cognitive impairment with Lewy bodies and 71 control participants. Mean diffusivity of the resulting pathways was compared between groups and related to cognition, attention, functional EEG changes and dementia conversion in the mild cognitive impairment groups. We successfully tracked a medial and a lateral pathway from the nucleus basalis of Meynert. Mean diffusivity of the lateral pathway was higher in both dementia and mild cognitive impairment groups than controls (all P < 0.03). In the patient groups, increased mean diffusivity of this pathway was related to more impaired global cognition (ß = -0.22, P = 0.06) and worse performance on an attention task (ß = 0.30, P = 0.03). In patients with mild cognitive impairment, loss of integrity of both nucleus basalis of Meynert pathways was associated with increased risk of dementia progression [hazard ratio (95% confidence interval), medial pathway: 2.51 (1.24-5.09); lateral pathway: 2.54 (1.24-5.19)]. Nucleus basalis of Meynert volume was reduced in all clinical groups compared to controls (all P < 0.001), but contributed less strongly to cognitive impairment and was not associated with attention or dementia conversion. EEG slowing in the patient groups as assessed by a decrease in dominant frequency was associated with smaller nucleus basalis of Meynert volumes (ß = 0.22, P = 0.02) and increased mean diffusivity of the lateral pathway (ß = -0.47, P = 0.003). We show that degeneration of the cholinergic nucleus basalis of Meynert in Alzheimer's disease and dementia with Lewy bodies is accompanied by an early reduction in integrity of white matter projections that originate from this structure. This is more strongly associated with cognition and attention than the volume of the nucleus basalis of Meynert itself and might be an early indicator of increased risk of dementia conversion in people with mild cognitive impairment.

Topological alterations in white matter structural networks in fibromyalgia.

PURPOSE: Neuroimaging studies employing analyses dependent on regional assumptions and specific neuronal circuits could miss characteristics of whole-brain structural connectivity critical to the pathophysiology of fibromyalgia (FM). This study applied the whole-brain graph-theoretical approach to identify whole-brain structural connectivity disturbances in FM. METHODS: This cross-sectional study used probabilistic diffusion tractography and graph theory analysis to evaluate the topological organization of brain white matter networks in 20 patients with FM and 20 healthy controls (HCs). The relationship between brain network metrics and clinical variables was evaluated. RESULTS: Compared with HCs, FM patients had lower clustering coefficient, local efficiency, hierarchy, synchronization, and higher normalized characteristic path length. Regionally, patients demonstrated a significant reduction in nodal efficiency and centrality; these regions were mainly located in the prefrontal, temporal cortex, and basal ganglia. The network-based statistical analysis (NBS) identified decreased structural connectivity in a subnetwork of prefrontal cortex, basal ganglia, and thalamus in FM. There was no correlation between network metrics and clinical variables (false discovery rate corrected). CONCLUSIONS: The current research demonstrated disrupted topological architecture of white matter networks in FM. Our results suggested compromised neural integration and segregation and reduced structural connectivity in FM.

Structural Connectivity Changes After Fornix Transection in Macaques Using Probabilistic Diffusion Tractography.

The fornix, the limbic system's white matter tract connecting the extended hippocampal system to subcortical structures of the medial diencephalon, is strongly associated with learning and memory in humans and nonhuman primates (NHPs). Here, we sought to investigate alterations in structural connectivity across key cortical and subcortical regions after fornix transection in NHPs. We collected diffusion-weighted MRI (dMRI) data from three macaque monkeys that underwent bilateral fornix transection during neurosurgery and from four age- and cohort-matched control macaques that underwent surgery to implant a head-post but remained neurologically intact. dMRI data were collected from both groups at two time points, before and after the surgeries, and scans took place at around the same time for the two groups. We used probabilistic tractography and employed the number of tracking streamlines to quantify connectivity across our regions of interest (ROIs), in all dMRI sessions. In the neurologically intact monkeys, we observed high connectivity across certain ROIs, including the CA3 hippocampal subfield with the retrosplenial cortex (RSC), the anterior thalamus with the RSC, and the RSC with the anterior cingulate cortex (ACC). However, we found that, compared to the control group, the fornix-transected monkeys showed marked, significant, connectivity changes including increases between the anterior thalamus and the ACC and between the CA3 and the ACC, as well as decreases between the CA3 and the RSC. Our results highlight cortical and subcortical network changes after fornix transection and identify candidate indirect connectivity routes that may support memory functions after damage and/or neurodegeneration.

Mediation of Tremor Control by the Decussating and Nondecussating Part of the Dentato-Rubro-Thalamic Tract in Deep Brain Stimulation in Essential Tremor: Which Part Should Be Stimulated?

OBJECTIVES: The dentato-rubro-thalamic tract (DRTT) has been found to play a major role in the mechanisms of tremor alleviation by deep brain stimulation (DBS) in essential tremor (ET). Still, the influence of the two different parts of the DRTT, consisting of crossing and nondecussating fibers, is not yet clear with respect to tremor reduction. The aim of this study was to assess the influence of the crossing and the nondecussating part of the DRTT on tremor control in ET. MATERIALS AND METHODS: We investigated 80 electrode contacts in ten patients with ET who received bilateral DBS of the Nucleus ventralis intermedius of the thalamus (VIM). Preoperatively and with patients under general anesthesia, 3T magnetic resonance imaging scans were performed, including Diffusion Tensor Imaging scans with 64 gradient directions. We calculated the course of the two parts of the DRTT based on a workflow for probabilistic fiber tracking including protocols for correction of susceptibility- and eddy current-induced distortions. Distances of electrode contacts were correlated with clinical data from neurologic single pole testing. RESULTS: Voltage- and current-steered systems were analyzed separately. Regarding postural tremor, effective contacts showed significantly lower distances to both parts of the DRTT (crossing p < 0.001, nondecussating p < 0.05) in voltage-steered systems. Regarding intentional tremor, significant results were only found for the crossing part (p < 0.01). Regarding both tremor types, effective contacts were closer to the crossing part, unlike less effective contacts. Nonlinear regression analyses using a logistic model showed higher coefficients for the crossing part of the DRTT. Multivariate regression models including distances to both parts of the DRTT showed a significant influence of only the crossing part. Analysis of current-steered systems showed unstable data, probably because of the small number of analyzed patients. CONCLUSIONS: Our data suggest an involvement of both parts of the DRTT in tremor reduction, indicating mediation of DBS effects by both fiber bundles, although the crossing part showed stronger correlations with good clinical responses. Nevertheless, special attention should be paid to methodologic aspects when using probabilistic tractography for patient-specific targeting to avoid uncertain and inaccurate results.

The Structural and Functional Correlates of Frailty in Persons With Human Immunodeficiency Virus.

BACKGROUND: Persons with HIV (PWH) are at increased risk of frailty, a clinically recognizable state of increased vulnerability resulting from aging-associated decline in multiple physiologic systems. Frailty is often defined by the Fried criteria, which includes subjective and objective standards concerning health resiliency. However, these frailty metrics do not incorporate cognitive performance or neuroimaging measures. METHODS: We compared structural (diffusion tensor imaging [DTI]) and functional (cerebral blood flow [CBF]) neuroimaging markers in PWH with frailty and cognitive performance. Virologically controlled PWH were dichotomized as either frail (≥3) or nonfrail (<3) using the Fried criteria. Cognitive Z-scores, both domain (executive, psychomotor speed, language, and memory) and global, were derived from a battery of tests. We identified three regions of reduced CBF, based on a voxel-wise comparison of frail PWH compared with nonfrail PWH. These clusters (bilateral frontal and posterior cingulate) were subsequently used as seed regions of interest (ROIs) for DTI probabilistic white matter tractography. RESULTS: White matter integrity connecting the ROIs was significantly decreased in frail compared with nonfrail PWH. No differences in cognition were observed between frail and nonfrail PWH. However, reductions in white matter integrity among these ROIs was significantly associated with worse psychomotor speed and executive function across the entire cohort. CONCLUSIONS: We conclude that frailty in PWH can lead to structural and functional brain changes, including subtle changes that are not detectable by standard neuropsychological tests. Multimodal neuroimaging in conjunction with frailty assessment could identify pathological brain changes observed in PWH.

Tractography indicates lateralized differences between trigeminal and olfactory pathways.

Odorous sensations are based on trigeminal and olfactory perceptions. Both trigeminal and olfactory stimuli generate overlapping as well as distinctive activations in the olfactory cortex including the piriform cortex. Orbitofrontal cortex (OFC), an integrative center for all senses, is directly activated in the presence of olfactory stimulations. In contrast, the thalamus, a very important midbrain structure, is not directly activated in the presence of odors, but rather acts as a relay for portions of olfactory information between primary olfactory cortex and higher-order processing centers. The aims of the study were (1) to examine the number of streamlines between the piriform cortex and the OFC and also between the piriform cortex and the thalamus and (2) to explore potential correlations between these streamlines and trigeminal and olfactory chemosensory perceptions. Thirty-eight healthy subjects were recruited for the study and underwent diffusion MRI using a 3T MRI scanner with 67 diffusion directions. ROIs were adapted from two studies looking into olfaction in terms of functional and structural properties of the olfactory system. The "waytotal number" was used which corresponds to number of streamlines between two regions of interests. We found the number of streamlines between the piriform cortex and the thalamus to be higher in the left hemisphere, whereas the number of streamlines between the piriform cortex and the OFC were higher in the right hemisphere. We also found streamlines between the piriform cortex and the thalamus to be positively correlated with the intensity of irritating (trigeminal) odors. On the other hand, streamlines between the piriform cortex and the OFC were correlated with the threshold scores for these trigeminal odors. This is the first studying the correlations between streamlines and olfactory scores using tractography. Results suggest that different chemosensory stimuli are processed through different networks in the chemosensory system involving the thalamus.

Abnormal white-matter rich-club organization in obsessive-compulsive disorder.

Rich-club organization is key to efficient global neuronal signaling and integration of information. Alterations interfere with higher-order cognitive processes, and are common to several psychiatric and neurological conditions. A few studies examining the structural connectome in obsessive-compulsive disorder (OCD) suggest lower efficiency of information transfer across the brain. However, it remains unclear whether this is due to alterations in rich-club organization. In the current study, the structural connectome of 28 unmedicated OCD patients, 8 of their unaffected siblings and 28 healthy controls was reconstructed by means of diffusion-weighted imaging and probabilistic tractography. Topological and weighted measures of rich-club organization and connectivity were computed, alongside global and nodal measures of network integration and segregation. The relationship between clinical scores and network properties was explored. Compared to healthy controls, OCD patients displayed significantly lower topological and weighted rich-club organization, allocating a smaller fraction of all connection weights to the rich-club core. Global clustering coefficient, local efficiency, and clustering of nonrich club nodes were significantly higher in OCD patients. Significant three-group differences emerged, with siblings displaying highest and lowest values in different measures. No significant correlation with any clinical score was found. Our results suggest weaker structural connectivity between rich-club nodes in OCD patients, possibly resulting in lower network integration in favor of higher network segregation. We highlight the need of looking at network-based alterations in brain organization and function when investigating the neurobiological basis of this disorder, and stimulate further research into potential familial protective factors against the development of OCD.

Ventralis intermedius nucleus anatomical variability assessment by MRI structural connectivity.

The ventralis intermedius nucleus (Vim) is centrally placed in the dentato-thalamo-cortical pathway (DTCp) and is a key surgical target in the treatment of severe medically refractory tremor. It is not visible on conventional MRI sequences; consequently, stereotactic targeting currently relies on atlas-based coordinates. This fails to capture individual anatomical variability, which may lead to poor long-term clinical efficacy. Probabilistic tractography, combined with known anatomical connectivity, enables localisation of thalamic nuclei at an individual subject level. There are, however, a number of confounds associated with this technique that may influence results. Here we focused on an established method, using probabilistic tractography to reconstruct the DTCp, to identify the connectivity-defined Vim (cd-Vim) in vivo. Using 100 healthy individuals from the Human Connectome Project, our aim was to quantify cd-Vim variability across this population, measure the discrepancy with atlas-defined Vim (ad-Vim), and assess the influence of potential methodological confounds. We found no significant effect of any of the confounds. The mean cd-Vim coordinate was located within 1.88 mm (left) and 2.12 mm (right) of the average midpoint and 3.98 mm (left) and 5.41 mm (right) from the ad-Vim coordinates. cd-Vim location was more variable on the right, which reflects hemispheric asymmetries in the probabilistic DTC reconstructed. The method was reproducible, with no significant cd-Vim location differences in a separate test-retest cohort. The superior cerebellar peduncle was identified as a potential source of artificial variance. This work demonstrates significant individual anatomical variability of the cd-Vim that atlas-based coordinate targeting fails to capture. This variability was not related to any methodological confound tested. Lateralisation of cerebellar functions, such as speech, may contribute to the observed asymmetry. Tractography-based methods seem sensitive to individual anatomical variability that is missed by conventional neurosurgical targeting; these findings may form the basis for translational tools to improve efficacy and reduce side-effects of thalamic surgery for tremor.

Structural alterations in cortical and thalamocortical white matter tracts after recovery from prefrontal cortex lesions in macaques.

Unilateral damage to the frontoparietal network typically impairs saccade target selection within the contralesional visual hemifield. Severity of deficits and the degree of recovery have been associated with widespread network dysfunction, yet it is not clear how these behavioural and functional brain changes relate with the underlying structural white matter tracts. Here, we investigated whether recovery after unilateral prefrontal cortex (PFC) lesions was associated with changes in white matter microstructure across large-scale frontoparietal cortical and thalamocortical networks. Diffusion-weighted imaging was acquired in four male rhesus macaques at pre-lesion, week 1, and week 8-16 post-lesion when target selection deficits largely recovered. Probabilistic tractography was used to reconstruct cortical frontoparietal fiber tracts, including the superior longitudinal fasciculus (SLF) and transcallosal fibers connecting the PFC or posterior parietal cortex (PPC), as well as thalamocortical fiber tracts connecting the PFC and PPC to thalamic nuclei. We found that the two animals with small PFC lesions showed increased fractional anisotropy in both cortical and thalamocortical fiber tracts when behaviour had recovered. However, we found that fractional anisotropy decreased in cortical frontoparietal tracts after larger PFC lesions yet increased in some thalamocortical tracts at the time of behavioural recovery. These findings indicate that behavioural recovery after small PFC lesions may be supported by both cortical and subcortical areas, whereas larger PFC lesions may have induced widespread structural damage and hindered compensatory remodeling in the cortical frontoparietal network.

Variability of white matter anatomy in the subcallosal cingulate area.

The subcallosal cingulate (SCC) area is a putative hub in the brain network underlying depression. Deep brain stimulation (DBS) targeting a particular subregion of SCC, identified as the intersection of forceps minor (FM), uncinate fasciculus (UCF), cingulum and fronto-striatal fiber bundles, may be critical to a therapeutic response in patients with severe, treatment-resistant forms of major depressive disorder (MDD). The pattern and variability of the white matter anatomy and organization within SCC has not been extensively characterized across individuals. The goal of this study is to investigate the variability of white matter bundles within the SCC that structurally connect this region with critical nodes in the depression network. Structural and diffusion data from 100 healthy subjects from the Human Connectome Project database were analyzed. Anatomically defined SCC regions were used as seeds to perform probabilistic tractography and to estimate the connectivity from the SCC to subject-specific target areas believed to be involved in the pathology of MDD including ventral striatum (VS), UCF, anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC). Four distinct areas of connectivity were identified within SCC across subjects: (a) postero-lateral SCC connectivity to medial temporal regions via UCF, (b) postero-medial connectivity to VS, (c) superior-medial connectivity to ACC via cingulum bundle, and (d) antero-lateral connectivity to mPFC regions via forceps minor. Assuming white matter connectivity is critical to therapeutic response, the improved anatomic understanding of SCC as well as an appreciation of the intersubject variability are critical to developing optimized therapeutic targeting for SCC DBS.

Structural connectivity of the human massa intermedia: A probabilistic tractography study.

The role of massa intermedia (MI) is poorly understood in humans. Recent studies suggest its presence may play a role in normal human neurocognitive function while prior studies have shown the absence of MI correlated with psychiatric disorders. There is growing evidence that MI is likely a midline white matter conduit, responsible for interhemispheric connectivity, similar to other midline commissures. MI presence was identified in an unrelated sample using the Human Connectome Project database. MI structural connectivity maps were created and gray matter target regions were identified using probabilistic tractography of the whole brain. Probabilistic tractography revealed an extensive network of connections between MI and limbic, frontal and temporal lobes as well as insula and pericalcarine cortices. Women compared to men had stronger connectivity via their MI. The presented results support the role of MI as a midline commissure with strong connectivity to the amygdala, hippocampus, and entorhinal cortex.

Connectome analysis of male world-class gymnasts using probabilistic multishell, multitissue constrained spherical deconvolution tracking.

In athletes, long-term intensive training has been shown to increase unparalleled athletic ability and might induce brain plasticity. We evaluated the structural connectome of world-class gymnasts (WCGs), as mapped by diffusion-weighted magnetic resonance imaging probabilistic tractography and a multishell, multitissue constrained spherical deconvolution method to increase the precision of tractography at the tissue interfaces. The connectome was mapped in 10 Japanese male WCGs and in 10 age-matched male controls. Network-based statistic identified subnetworks with increased connectivity density in WCGs, involving the sensorimotor, default mode, attentional, visual, and limbic areas. It also revealed a significant association between the structural connectivity of some brain structures with functions closely related to the gymnastic skills and the D-score, which is used as an index of the gymnasts' specific physical abilities for each apparatus. Furthermore, graph theory analysis demonstrated the characteristics of brain anatomical topology in the WCGs. They displayed significantly increased global connectivity strength with decreased characteristic path length at the global level and higher nodal strength and degree in the sensorimotor, default mode, attention, and limbic/subcortical areas at the local level as compared with controls. Together, these findings extend the current understanding of neural mechanisms that distinguish WCGs from controls and suggest brain anatomical network plasticity in WCGs resulting from long-term intensive training. Future studies should assess the contribution of genetic or early-life environmental factors in the brain network organization of WCGs. Furthermore, the indices of brain topology (i.e., connection density and graph theory indices) could become markers for the objective evaluation of gymnastic performance.

Language Without Speech: Segregating Distinct Circuits in the Human Brain.

Language is a fundamental part of human cognition. The question of whether language is processed independently of speech, however, is still heavily discussed. The absence of speech in deaf signers offers the opportunity to disentangle language from speech in the human brain. Using probabilistic tractography, we compared brain structural connectivity of adult deaf signers who had learned sign language early in life to that of matched hearing controls. Quantitative comparison of the connectivity profiles revealed that the core language tracts did not differ between signers and controls, confirming that language is independent of speech. In contrast, pathways involved in the production and perception of speech displayed lower connectivity in deaf signers compared to hearing controls. These differences were located in tracts towards the left pre-supplementary motor area and the thalamus when seeding in Broca's area, and in ipsilateral parietal areas and the precuneus with seeds in left posterior temporal regions. Furthermore, the interhemispheric connectivity between the auditory cortices was lower in the deaf than in the hearing group, underlining the importance of the transcallosal connection for early auditory processes. The present results provide evidence for a functional segregation of the neural pathways for language and speech.

Structural Thalamofrontal Hypoconnectivity Is Related to Oculomotor Corollary Discharge Dysfunction in Schizophrenia.

By predicting sensory consequences of actions, humans can distinguish self-generated sensory inputs from those that are elicited externally. This is one mechanism by which we achieve a subjective sense of agency over our actions. Corollary discharge (CD) signals-"copies" of motor signals sent to sensory areas-permit such predictions, and CD abnormalities are a hypothesized mechanism for the agency disruptions in schizophrenia that characterize a subset of symptoms. Indeed, behavioral evidence of altered CD, including in the oculomotor system, has been observed in schizophrenia patients. A pathway projecting from the superior colliculus to the frontal eye fields (FEFs) via the mediodorsal thalamus (MD) conveys oculomotor CD associated with saccadic eye movements in nonhuman primates. This animal work provides a promising translational framework in which to investigate CD abnormalities in clinical populations. In the current study, we examined whether structural connectivity of this MD-FEF pathway relates to oculomotor CD functioning in schizophrenia. Twenty-two schizophrenia patients and 24 healthy control participants of both sexes underwent diffusion tensor imaging, and a large subset performed a trans-saccadic perceptual task that yields measures of CD. Using probabilistic tractography, we identified anatomical connections between FEF and MD and extracted indices of microstructural integrity. Patients exhibited compromised microstructural integrity in the MD-FEF pathway, which was correlated with greater oculomotor CD abnormalities and more severe psychotic symptoms. These data reinforce the role of the MD-FEF pathway in transmitting oculomotor CD signals and suggest that disturbances in this pathway may relate to psychotic symptom manifestation in patients.SIGNIFICANCE STATEMENT People with schizophrenia sometimes experience abnormalities in a sense of agency, which may stem from abnormal sensory predictions about their own actions. Consistent with this notion, the current study found reduced structural connectivity in patients with schizophrenia in a specific brain pathway found to transmit such sensorimotor prediction signals in nonhuman primates. Reduced structural connectivity was correlated with behavioral evidence for impaired sensorimotor predictions and psychotic symptoms.

White Matter Microstructure Reflects Individual Differences in Music Reward Sensitivity.

People show considerable variability in the degree of pleasure they experience from music. These individual differences in music reward sensitivity are driven by variability in functional connectivity between the nucleus accumbens (NAcc), a key structure of the reward system, and the right superior temporal gyrus (STG). However, it is unknown whether a neuroanatomical basis exists for this variability. We used diffusion tensor imaging and probabilistic tractography to study the relationship between music reward sensitivity and white matter microstructure connecting these two regions via the orbitofrontal cortex (OFC) in 38 healthy human participants (24 females and 14 males). We found that right axial diffusivity (AD) in the STG-OFC connectivity inversely correlated with music reward sensitivity. Additionally, right mean diffusivity and left AD in the NAcc-OFC tract also showed an inverse correlation. Further, AD in this tract also correlated with previously acquired BOLD activity during music listening, but not for a control monetary reward task in the NAcc. Finally, we used mediation analysis to show that AD in the NAcc-OFC tract explains the influence of NAcc activation during a music task on music reward sensitivity. Overall, our results provide further support for the idea that the exchange of information among perceptual, integrative, and reward systems is important for musical pleasure, and that individual differences in the structure of the relevant anatomical connectivity influences the degree to which people are able to derive such pleasure.SIGNIFICANCE STATEMENT Music is one of the most important sources of pleasure for many people, but at the same time there are important individual differences in the sensitivity to musical reward. Previous studies have revealed the critical involvement of the functional connectivity between perceptual and subcortical brain areas in the enjoyment of music. However, it is unknown whether individual differences in music sensitivity might arise from variability in the structural connectivity among these areas. Here we show that structural connectivity between supratemporal and orbitofrontal cortices, and between orbitofrontal and nucleus accumbens, predict individual differences in sensibility to music reward. These results provide evidence for the critical involvement of the interaction between the subcortical reward system and higher-order cortical areas in music-induced pleasure.

Persistent abnormalities in Rolandic thalamocortical white matter circuits in childhood epilepsy with centrotemporal spikes.

OBJECTIVE: Childhood epilepsy with centrotemporal spikes (CECTS) is a common, focal, transient, developmental epilepsy syndrome characterized by unilateral or bilateral, independent epileptiform spikes in the Rolandic regions of unknown etiology. Given that CECTS presents during a period of dramatic white matter maturation and thatspikes in CECTS are activated during non-rapid eye movement (REM) sleep, we hypothesized that children with CECTS would have aberrant development of white matter connectivity between the thalamus and the Rolandic cortex. We further tested whether Rolandic thalamocortical structural connectivity correlates with spike rate during non-REM sleep. METHODS: Twenty-three children with CECTS (age = 8-15 years) and 19 controls (age = 7-15 years) underwent 3-T structural and diffusion-weighted magnetic resonance imaging and 72-electrode electroencephalographic recordings. Thalamocortical structural connectivity to Rolandic and non-Rolandic cortices was quantified using probabilistic tractography. Developmental changes in connectivity were compared between groups using bootstrap analyses. Longitudinal analysis was performed in four subjects with 1-year follow-up data. Spike rate was quantified during non-REM sleep using manual and automated techniques and compared to Rolandic connectivity using regression analyses. RESULTS: Children with CECTS had aberrant development of thalamocortical connectivity to the Rolandic cortex compared to controls (P = .01), where the expected increase in connectivity with age was not observed in CECTS. There was no difference in the development of thalamocortical connectivity to non-Rolandic regions between CECTS subjects and controls (P = .19). Subjects with CECTS observed longitudinally had reductions in thalamocortical connectivity to the Rolandic cortex over time. No definite relationship was found between Rolandic connectivity and non-REM spike rate (P > .05). SIGNIFICANCE: These data provide evidence that abnormal maturation of thalamocortical white matter circuits to the Rolandic cortex is a feature of CECTS. Our data further suggest that the abnormalities in these tracts do not recover, but are increasingly dysmature over time, implicating a permanent but potentially compensatory process contributing to disease resolution.