High-resolution virtual brain modeling personalizes deep brain stimulation for treatment-resistant depression: Spatiotemporal response characteristics following stimulation of neural fiber pathways.

Over the past 15 years, deep brain stimulation (DBS) has been actively investigated as a groundbreaking therapy for patients with treatment-resistant depression (TRD); nevertheless, outcomes have varied from patient to patient, with an average response rate of ∼50%. The engagement of specific fiber tracts at the stimulation site has been hypothesized to be an important factor in determining outcomes, however, the resulting individual network effects at the whole-brain scale remain largely unknown. Here we provide a computational framework that can explore each individual's brain response characteristics elicited by selective stimulation of fiber tracts. We use a novel personalized in-silico approach, the Virtual Big Brain, which makes use of high-resolution virtual brain models at a mm-scale and explicitly reconstructs more than 100,000 fiber tracts for each individual. Each fiber tract is active and can be selectively stimulated. Simulation results demonstrate distinct stimulus-induced event-related potentials as a function of stimulation location, parametrized by the contact positions of the electrodes implanted in each patient, even though validation against empirical patient data reveals some limitations (i.e., the need for individual parameter adjustment, and differential accuracy across stimulation locations). This study provides evidence for the capacity of personalized high-resolution virtual brain models to investigate individual network effects in DBS for patients with TRD and opens up novel avenues in the personalized optimization of brain stimulation.

Microstructural Abnormalities of the Dentatorubrothalamic Tract in Cervical Dystonia.

BACKGROUND: The dentatorubrothalamic tract (DRTT) remains understudied in idiopathic cervical dystonia (CD), despite evidence that the pathway is relevant in the pathophysiology of the disorder. OBJECTIVE: The aim of this study was to examine the DRTT in patients with CD using diffusion tensor imaging (DTI)-based tractography. METHODS: Magnetic resonance imaging scans from 67 participants were collected to calculate diffusion tractography metrics using a binary tractography-based DRTT template. Fractional anisotropy and diffusivity measures of left and right DRTT were computed and compared between 32 subjects with CD and 35 age-matched healthy volunteers. RESULTS: Fractional anisotropy of right DRTT and mean and axial diffusivity of left DRTT were significantly reduced in patients with CD. Similar abnormalities were observed in patients with focal CD and patients with CD without tremor. DTI metrics did not correlate with disease duration or severity. CONCLUSIONS: Significant reductions in DTI measures suggest microstructural abnormalities within the DRTT in CD, characterized by a tractography pattern consistent with decreased axonal integrity. © 2021 International Parkinson and Movement Disorder Society.

The effect of movie-watching on electroencephalographic responses to tactile stimulation.

Movie-watching is becoming a popular acquisition method to increase compliance and enable neuroimaging data collection in challenging populations such as children, with potential to facilitate studying the somatosensory system. However, relatively little is known about the possible crossmodal (audiovisual) influence of movies on cortical somatosensory processing. In this study, we examined the impact of dynamic audiovisual movies on concurrent cortical somatosensory processing using electroencephalography (EEG). Forty healthy young adults (18-25 years) received passive tactile fingertip stimulation while watching an "entertaining" movie and a novel "low-demand" movie called 'Inscapes' compared to eyes-open rest. Watching a movie did not modulate properties of early or late somatosensory-evoked potentials (SEPs). Similarly, no crossmodal influence on somatosensory adaptation, denoted by a reduction in SEP amplitude with repetitive tactile stimulation, was found. The prominent oscillatory responses in the alpha and beta frequency bands following tactile stimulation differed as a function of viewing condition, with stronger alpha/beta event-related desynchronization (ERD) during movie-watching compared to rest. These findings highlight that movie-watching is a valid acquisition method during which SEPs can be measured in basic research and clinical studies, but that the attentional demands of movies need to be taken into account when performing oscillatory analyses.

Imaging functional motor connectivity in hemiparetic children with perinatal stroke.

Perinatal stroke causes lifelong disability, particularly hemiparetic cerebral palsy. Arterial ischemic strokes (AIS) are large, cortical, and subcortical injuries acquired near birth due to acute occlusion of the middle cerebral artery. Periventricular venous infarctions (PVI) are smaller, subcortical strokes acquired prior to 34 weeks gestation involving injury to the periventricular white matter. Both stroke types can damage motor pathways, thus, we investigated resulting alterations in functional motor networks and probed function. We measured blood oxygen level dependent (BOLD) fluctuations at rest in 38 participants [10 arterial patients (age = 14.7 ± 4.1 years), 10 venous patients (age = 13.5 ± 3.7 years), and 18 typically developing controls (TDCs) (age = 15.3 ± 5.1 years)] and explored strength and laterality of functional connectivity in the motor network. Inclusion criteria included MRI-confirmed, unilateral perinatal stroke, symptomatic hemiparetic cerebral palsy, and 6-19 years old at time of imaging. Seed-based functional connectivity analyses measured temporal correlations in BOLD response over the whole brain using primary motor cortices as seeds. Laterality indices based on mean z-scores in lesioned and nonlesioned hemispheres explored laterality. In AIS patients, significant differences in both strength and laterality of motor network connections were observed compared with TDCs. In PVI patients, motor networks largely resembled those of healthy controls, albeit slightly weaker and asymmetric, despite subcortical damage and hemiparesis. Functional connectivity strengths were not related to motor outcome scores for either stroke group. This study serves as a foundation to better understand how resting-state fMRI can assess motor functional connectivity and potentially be applied to explore mechanisms of interventional therapies after perinatal stroke.

Revisiting mental rotation with stereoscopic disparity: A new spin for a classic paradigm.

To understand how the presence of stereoscopic disparity influences cognitive and neural processing, we recorded participants' behavior and scalp electrical activity while they performed a mental rotation task. Participants wore active shutter 3D goggles, allowing us to present stimuli with or without stereoscopic disparity on a trial-by-trial basis. Participants were more accurate and faster when stimuli were presented with stereoscopic disparity. This improvement in performance was accompanied by changes in neural activity recorded from scalp electrodes at parietal and occipital regions; stereoscopic disparity produced earlier P2 peaks, larger N2 amplitudes, and earlier, smaller P300 peak amplitudes. The presence of stereoscopic disparity also produced greater neural entropy at occipital electrode sites, and lower entropy at frontal sites. These findings suggest that the nature of the benefit afforded by stereoscopic disparity occurs at both low-level perceptual processing and higher-level cognitive processing, and results in more accurate and rapid performance.

The cholinergic forebrain arousal system acts directly on the circadian pacemaker.

Sleep and wake states are regulated by a variety of mechanisms. One such important system is the circadian clock, which provides temporal structure to sleep and wake. Conversely, changes in behavioral state, such as sleep deprivation (SD) or arousal, can phase shift the circadian clock. Here we demonstrate that the level of wakefulness is critical for this arousal resetting of the circadian clock. Specifically, drowsy animals with significant power in the 7- to 9-Hz band of their EEGs do not exhibit phase shifts in response to a mild SD procedure. We then show that treatments that both produce arousal and reset the phase of circadian clock activate (i.e., induce Fos expression in) the basal forebrain. Many of the activated cells are cholinergic. Using retrograde tract tracing, we demonstrate that cholinergic cells activated by these arousal procedures project to the circadian clock in the suprachiasmatic nuclei (SCN). We then demonstrate that arousal-induced phase shifts are blocked when animals are pretreated with atropine injections to the SCN, demonstrating that cholinergic activity at the SCN is necessary for arousal-induced phase shifting. Finally, we demonstrate that electrical stimulation of the substantia innominata of the basal forebrain phase shifts the circadian clock in a manner similar to that of our arousal procedures and that these shifts are also blocked by infusions of atropine to the SCN. These results establish a functional link between the major forebrain arousal center and the circadian system.

Changes in cortical activity measured with EEG during a high-intensity cycling exercise.

This study investigated the effects of a high-intensity cycling exercise on changes in spectral and temporal aspects of electroencephalography (EEG) measured from 10 experienced cyclists. Cyclists performed a maximum aerobic power test on the first testing day followed by a time-to-exhaustion trial at 85% of their maximum power output on 2 subsequent days that were separated by ∼48 h. EEG was recorded using a 64-channel system at 500 Hz. Independent component (IC) analysis parsed the EEG scalp data into maximal ICs. An equivalent current dipole model was calculated for each IC, and results were clustered across subjects. A time-frequency analysis of the identified electrocortical clusters was performed to investigate the magnitude and timing of event-related spectral perturbations. Significant changes (P < 0.05) in electrocortical activity were found in frontal, supplementary motor and parietal areas of the cortex. Overall, there was a significant increase in EEG power as fatigue developed throughout the exercise. The strongest increase was found in the frontal area of the cortex. The timing of event-related desynchronization within the supplementary motor area corresponds with the onset of force production and the transition from flexion to extension in the pedaling cycle. The results indicate an involvement of the cerebral cortex during the pedaling task that most likely involves executive control function, as well as motor planning and execution.

Amygdala responses to quetiapine XR and citalopram treatment in major depression: the role of 5-HTTLPR-S/Lg polymorphisms.

OBJECTIVES: Genotype and drug pharmacology may contribute to variations in brain response to antidepressants. We examined the impact of two antidepressants with differential actions on serotonin transporter and the 5-HHTLPR-S/Lg polymorphisms on amygdala responses in major depressive disorder (MDD). METHODS: Caucasians with MDD were given either citalopram or quetiapine extended release for 8 weeks. Patients were genotyped for 5-HTTLPR. Clinical efficacy was assessed using the Hamilton Depression Rating Scale. fMRI responses to negative emotional faces were acquired at baseline, week 1 and week 8. The outcome measure was change in amygdala responses at week 8. RESULTS: Citalopram had no effect on amygdala responses in MDD patients with S/Lg alleles at weeks 1 and 8 compared with baseline, whereas it induced changes in amygdala responses in LL homozygotes. By contrast, quetiapine decreased amygdala responses at both time points in S/Lg carriers, and changes in amygdala responses at week 8 correlated with a reduction in depression scores. The small number of LL homozygotes in quetiapine group was a limitation. Efficacy of both treatments was comparable. CONCLUSIONS: These preliminary data suggest that pharmacological mechanisms and genetics need to be considered in the development of neuroimaging markers for the evaluation of antidepressant treatments.

Hemispheric activation differences in novice and expert clinicians during clinical decision making.

Clinical decision making requires knowledge, experience and analytical/non-analytical types of decision processes. As clinicians progress from novice to expert, research indicates decision-making becomes less reliant on foundational biomedical knowledge and more on previous experience. In this study, we investigated how knowledge and experience were reflected in terms of differences in neural areas of activation. Novice and expert clinicians diagnosed simple or complex (easy, hard) cases while functional magnetic resonance imaging (fMRI) data were collected. Our results highlight key differences in the neural areas activated in novices and experts during the clinical decision-making process. fMRI data were collected from ten second year medical students (novices) and ten practicing gastroenterologists (experts) while they diagnosed sixteen (eight easy and eight hard) clinical cases via multiple-choice questions. Behavioral data were collected for diagnostic accuracy (correct/incorrect diagnosis) and time taken to assign a clinical diagnosis. Two analyses were performed with the fMRI data. First, data from easy and hard cases were compared within respective groups (easy > hard, hard > easy). Second, neural differences between novices and experts (novice > expert, expert > novice) were assessed. Experts correctly diagnosed more cases than novices and made their diagnoses faster than novices on both easy and hard cases (all p's < 0.05). Time taken to diagnose hard cases took significantly longer for both novices and experts. While similar neural areas were activated in both novices and experts during the decision making process, we identified significant hemispheric activation differences between novice and expert clinicians when diagnosing hard clinical cases. Specifically, novice clinicians had greater activations in the left anterior temporal cortex and left ventral lateral prefrontal cortex whereas expert clinicians had greater activations in the right dorsal lateral, right ventral lateral, and right parietal cortex. Hemispheric differences in activation were not observed between novices and experts while diagnosing easy clinical cases. While clinical decision-making engaged the prefrontal cortex (PFC) in both novices and experts, interestingly we observed expertise related differences in the regions and hemispheres of PFC activation between these groups for hard clinical cases. Specifically, in novices we observed activations in left hemisphere neural regions associated with factual rule-based knowledge, whereas in experts we observed right hemisphere activation in neural regions associated with experiential knowledge. Importantly, at the neural level, our data highlight differences in so called type 2 clinical decision-making processes related to prior knowledge and experience.

Working memory, reasoning, and expertise in medicine-insights into their relationship using functional neuroimaging.

Clinical reasoning is dependent upon working memory (WM). More precisely, during the clinical reasoning process stored information within long-term memory is brought into WM to facilitate the internal deliberation that affords a clinician the ability to reason through a case. In the present study, we examined the relationship between clinical reasoning and WM while participants read clinical cases with functional magnetic resonance imaging (fMRI). More specifically, we examined the impact of clinical case difficulty (easy, hard) and clinician level of expertise (2nd year medical students, senior gastroenterologists) on neural activity within regions of cortex associated with WM (i.e., the prefrontal cortex) during the reasoning process. fMRI was used to scan ten second-year medical students and ten practicing gastroenterologists while they reasoned through sixteen clinical cases [eight straight forward (easy) and eight complex (hard)] during a single 1-h scanning session. Within-group analyses contrasted the easy and hard cases which were then subsequently utilized for a between-group analysis to examine effects of expertise (novice > expert, expert > novice). Reading clinical cases evoked multiple neural activations in occipital, prefrontal, parietal, and temporal cortical regions in both groups. Importantly, increased activation in the prefrontal cortex in novices for both easy and hard clinical cases suggests novices utilize WM more so than experts during clinical reasoning. We found that clinician level of expertise elicited differential activation of regions of the human prefrontal cortex associated with WM during clinical reasoning. This suggests there is an important relationship between clinical reasoning and human WM. As such, we suggest future models of clinical reasoning take into account that the use of WM is not consistent throughout all clinical reasoning tasks, and that memory structure may be utilized differently based on level of expertise.

Influence of age of onset on limbic and paralimbic structures in depression.

AIM: Major depressive disorder (MDD) onset during childhood/adolescence is associated with a greater illness burden and distinct clinical profile. However, limited research exists on the effect of age of MDD onset on volumetric abnormalities in para/limbic structures during adulthood. METHODS: Subgenual anterior cingulate cortex (sgACC), hippocampus and caudate nucleus volumes were measured by manual tracing in depressed individuals (n = 45) and healthy controls (HC; n = 19). Volumetric comparisons were carried out between HC and MDD patients divided into those with pediatric (≤ 18 years; n = 17) and adult onset (≥ 19 years; n = 28). RESULTS: The adult MDD-onset group had smaller sgACC volumes than the pediatric-onset and HC groups (age, sex controlled). No differences in caudate and hippocampus volumes existed. sgACC and hippocampal volumes were inversely correlated with depression severity. CONCLUSIONS: Surprisingly, pediatric MDD-onset was not associated with more pronounced sgACC, hippocampus and caudate volume reductions. Nevertheless, age of illness onset appears to be a meaningful dimension of study in efforts to understand the neurobiological heterogeneity of MDD.

Multimodal Brain MRI of Deep Gray Matter Changes Associated With Inflammatory Bowel Disease.

BACKGROUND: Behavioral symptoms, including mood disorders, substantially impact the quality of life of patients with inflammatory bowel disease (IBD), even when clinical remission is achieved. Here, we used multimodal magnetic resonance imaging (MRI) to determine if IBD is associated with changes in the structure and function of deep gray matter brain regions that regulate and integrate emotional, cognitive, and stress responses. METHODS: Thirty-five patients with ulcerative colitis (UC) or Crohn's disease (CD) and 32 healthy controls underwent 3 Tesla MRIs to assess volume, neural activity, functional connection strength (connectivity), inflammation, and neurodegeneration of key deep gray matter brain regions (thalamus, caudate, pallidum, putamen, amygdala, hippocampus, and hypothalamus) involved in emotional, cognitive and stress processing. Associations with sex, presence of pain, disease activity, and C-reactive protein (CRP) concentration were examined. RESULTS: Significantly increased activity and functional connectivity were observed in cognitive and emotional processing brain regions, including parts of the limbic system, basal ganglia, and hypothalamus of IBD patients compared with healthy controls. Inflammatory bowel disease patients exhibited significantly increased volumes of the amygdala and hypothalamus, as well as evidence of neurodegeneration in the putamen and pallidum. Hippocampal neural activity was increased in IBD patients with active disease. The volume of the thalamus was positively correlated with CRP concentration and was increased in females experiencing pain. CONCLUSIONS: Patients with IBD exhibit functional and structural changes in the limbic and striatal systems. These changes may be targets for assessing or predicting the response to therapeutic interventions aimed at improving comorbid emotional and cognitive symptoms.

Magnetic resonance imaging revealed structural and functional changes within the brains of inflammatory bowel disease patients, in regions known to be involved in processing brain signals associated with behavioral symptoms, anxiety, pain, stress, and cognitive deficits.

Analysis of multifocal electroretinograms from a population with type 1 diabetes using partial least squares reveals spatial and temporal distribution of changes to retinal function.

Spatial-temporal partial least squares (ST-PLS) is a multivariate statistical analysis that has improved the analysis of modern imaging techniques. Multifocal electroretinograms (mfERGs) contain a large amount of data, and averaging and grouping have been used to reduce the amount of data to levels that can be handled using traditional statistical methods. In contrast, using all acquired data points, ST-PLS enables statistically rigorous testing of changes in waveform shape and in the distributed signal related to retinal function. We hypothesise that ST-PLS will improve analysis of the mfERG. Two mfERG protocols, a 103 hexagon clinical protocol and a slow-flash mfERG (sf-mfERG) protocol, were recorded from an adolescent population with type 1 diabetes and an age similar control population. The standard mfERGs were analysed using a template-fitting algorithm and the sf-mfERG using a signal-to-noise measure. The results of these traditional analysis techniques are compared with those of the ST-PLS analysis. Traditional analysis of the mfERG recordings revealed changes between groups for implicit time but not amplitude; however, the spatial location of these changes could not be identified. In contrast, ST-PLS detected significant changes between groups and displayed the spatial location of these changes on the retinal map and the temporal location within the mfERG waveforms. ST-PLS confirmed that changes to diabetic retinal function occur before the onset of clinical pathology. In addition, it revealed two distinct patterns of change depending on whether the multifocal paradigm was optimised to target outer retinal function (photoreceptors) or middle/inner retinal function (collector cells).

The modulatory effect of adaptive task-switching training on resting-state neural network dynamics in younger and older adults.

With increasing life expectancy and active aging, it becomes crucial to investigate methods which could compensate for generally detected cognitive aging processes. A promising candidate is adaptive cognitive training, during which task difficulty is adjusted to the participants' performance level to enhance the training and potential transfer effects. Measuring intrinsic brain activity is suitable for detecting possible distributed training-effects since resting-state dynamics are linked to the brain's functional flexibility and the effectiveness of different cognitive processes. Therefore, we investigated if adaptive task-switching training could modulate resting-state neural dynamics in younger (18-25 years) and older (60-75 years) adults (79 people altogether). We examined spectral power density on resting-state EEG data for measuring oscillatory activity, and multiscale entropy for detecting intrinsic neural complexity. Decreased coarse timescale entropy and lower frequency band power as well as increased fine timescale entropy and higher frequency band power revealed a shift from more global to local information processing with aging before training. However, cognitive training modulated these age-group differences, as coarse timescale entropy and lower frequency band power increased from pre- to post-training in the old-training group. Overall, our results suggest that cognitive training can modulate neural dynamics even when measured outside of the trained task.

Tactile cortical responses and association with tactile reactivity in young children on the autism spectrum.

BACKGROUND: Unusual behavioral reactions to sensory stimuli are frequently reported in individuals on the autism spectrum (AS). Despite the early emergence of sensory features (< age 3) and their potential impact on development and quality of life, little is known about the neural mechanisms underlying sensory reactivity in early childhood autism. METHODS: Here, we used electroencephalography (EEG) to investigate tactile cortical processing in young children aged 3-6 years with autism and in neurotypical (NT) children. Scalp EEG was recorded from 33 children with autism, including those with low cognitive and/or verbal abilities, and 45 age- and sex-matched NT children during passive tactile fingertip stimulation. We compared properties of early and later somatosensory-evoked potentials (SEPs) and their adaptation with repetitive stimulation between autistic and NT children and assessed whether these neural measures are linked to "real-world" parent-reported tactile reactivity. RESULTS: As expected, we found elevated tactile reactivity in children on the autism spectrum. Our findings indicated no differences in amplitude or latency of early and mid-latency somatosensory-evoked potentials (P50, N80, P100), nor adaptation between autistic and NT children. However, latency of later processing of tactile information (N140) was shorter in young children with autism compared to NT children, suggesting faster processing speed in young autistic children. Further, correlational analyses and exploratory analyses using tactile reactivity as a grouping variable found that enhanced early neural responses were associated with greater tactile reactivity in autism. LIMITATIONS: The relatively small sample size and the inclusion of a broad range of autistic children (e.g., with low cognitive and/or verbal abilities) may have limited our power to detect subtle group differences and associations. Hence, replications are needed to verify these results. CONCLUSIONS: Our findings suggest that electrophysiological somatosensory cortex processing measures may be indices of "real-world" tactile reactivity in early childhood autism. Together, these findings advance our understanding of the neurophysiological mechanisms underlying tactile reactivity in early childhood autism and, in the clinical context, may have therapeutic implications.

Heterogeneity in abstract verbs: An ERP study.

It has been well documented that different types of nouns and action verbs are associated with behavioral and neural differences. In contrast, abstract verbs (e.g., think, dissolve) are often treated as a homogeneous category. We compared event-related potentials recorded during a syntactic classification task of four verb types; 1) abstract mental, 2) abstract emotional, 3) abstract nonbodily, and 4) concrete. Abstract nonbodily state verbs showed a sustained negativity at frontocentral electrodes and sustained positivity at parietal and occipital electrodes beginning 400 ms post-stimulus onset relative to abstract mental state and concrete verbs. Discrete source localization revealed a right inferior parietal source for all verbs and a distributed source estimation localized sources that distinguished between abstract mental state and abstract nonbodily state verbs to bilateral parietal cortex, left temporal cortex and right ventromedial prefrontal cortex. These findings suggest that different types of abstract verbs are associated with representational differences.

The relation between Scrabble expertise and brain aging as measured with EEG brain signal variability.

Recent empirical work suggests that the dynamics of brain function, as measured by brain signal variability, differs between younger and older adults. We extended this work by examining how the relationship between brain signal variability and age is altered in the context of expertise. We recorded electroencephalography from Scrabble experts and controls during a visual word recognition task. To measure variability, we used multiscale entropy, which emphasizes the way brain signals behave over a range of timescales and can differentiate the variability of a complex system (the brain) from a purely random system. We replicated previously identified shifts from long-range interactions among neural populations to more local processing in late adulthood. In addition, we demonstrated an age-related increase in midrange neural interactions for experts, suggesting greater maintenance of network integration into late adulthood. Our results indicate that expertise-related differences in the context of age and brain dynamics occur across different timescales and that these differences are linked to task performance.