White Matter Changes after Neurobehavioral Therapy for Functional Seizures.

OBJECTIVE: We aimed to prospectively quantify changes in white matter morphology after neurobehavioral therapy (NBT) for functional seizures (FS) using neurite orientation dispersion and density imaging (NODDI). We hypothesized that patients with FS would exhibit white matter plasticity in the uncinate fasciculus, fornix/stria terminalis, cingulum, and corticospinal tract following NBT that would correlate with improvements in affective symptoms, postconcussive symptoms, and quality of life (QOL). METHODS: Forty-two patients with traumatic brain injury (TBI) and FS (TBI+FS) underwent NBT and provided pre-/postintervention neuroimaging and behavioral data; 47 controls with TBI without FS (TBI-only) completed the same measures but did not receive NBT. Changes in neurite density, orientation dispersion (orientation dispersion index [ODI]), and extracellular free water (FW) were compared between groups. RESULTS: Significant ODI increases in the left uncinate fasciculus in TBI+FS (mean difference = 0.017, p = 0.039) correlated with improvements in posttraumatic symptoms (r = -0.395, p = 0.013), QOL (r = 0.474, p = 0.002), emotional well-being (r = 0.524, p < 0.001), and energy (r = 0.474, p = 0.002). In TBI-only, ODI decreased (mean difference = -0.008, p = 0.047) and FW increased (mean difference = 0.011, p = 0.003) in the right cingulum. FW increases correlated with increased psychological problems (r = 0.383, p = 0.013). In TBI+FS, NBT resulted in FS decreases of 3.5 seizures per week. None of the imaging changes correlated with FS frequency. INTERPRETATION: We identified white matter changes after NBT in patients with FS that were associated with improved psychosocial functioning. NODDI could be incorporated into future mechanistic assessments of interventions in patients with FS. ANN NEUROL 2023;94:350-365.

Diffusion Tensor Imaging-Along the Perivascular-Space Index Is Associated with Disease Progression in Parkinson's Disease.

BACKGROUND: The glymphatic clearance pathway is a waste clearance system that allows for removal of soluble proteins such as amyloid ß (Aß) from the brain. Higher Aß levels are associated with cognitive dysfunction in Parkinson's disease (PD). Diffusion tensor imaging-along the perivascular space (DTI-ALPS) is an imaging measure proposed to indirectly measure glymphatic function. OBJECTIVES: Evaluate differences in DTI-ALPS-index between PD and healthy controls (HC) and characterize relationships between this proposed measure of glymphatic clearance, cognition, and disease severity in PD. METHODS: PD (n = 32) and HC (n = 23) participants underwent brain imaging to assess DTI-ALPS. PD participants were classified as PD-normal cognition (PD-NC; n = 20) or PD-mild cognitive impairment (PD-MCI; n = 12) based on a Level II comprehensive cognitive assessment. A subgroup of PD participants (n = 21) returned for annual assessments for up to 4 years after baseline. Longitudinal outcomes included changes in performance on the comprehensive cognitive assessment and changes in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). RESULTS: PD participants had lower DTI-ALPS-index compared to HC. PD participants classified as PD-MCI had significantly lower DTI-ALPS-index compared to PD-NC. Lower DTI-ALPS-index at baseline was associated with longitudinal cognitive decline and worse longitudinal disease severity. CONCLUSIONS: Glymphatic clearance, as measured with DTI-ALPS, has potential to serve as a marker of longitudinal disease progression. Interventions targeting glymphatic function should be explored for potential to slow cognitive decline in PD. © 2024 International Parkinson and Movement Disorder Society.

Relationship between intrinsic network connectivity and psychiatric symptom severity in functional seizures.

BACKGROUND: Traumatic brain injury (TBI) may precipitate the onset of functional seizures (FSs). Many patients with FS report at least one prior TBI, and these patients typically present with more severe psychiatric comorbidities. TBI and psychopathology are linked to changes in neural network connectivity, but their combined effects on these networks and relationship to the effects of FS remain unclear. We hypothesised that resting-state functional connectivity (rsFC) would differ between patients with FS and TBI (FS+TBI) compared with TBI without FS (TBI only), with variability only partially explained by the presence of psychopathology. METHODS: Patients with FS+TBI (n=52) and TBI only (n=54) were matched for age and sex. All participants completed psychiatric assessments prior to resting-state functional MRI at 3 T. Independent component analysis identified five canonical rsFC networks related to emotion and motor functions. RESULTS: Five linear mixed-effects analyses identified clusters of connectivity coefficients that differed between groups within the posterior cingulate of the default mode network, insula and supramarginal gyrus of the executive control network and bilateral anterior cingulate of the salience network (all α=0.05, corrected). Cluster signal extractions revealed decreased contributions to each network for FS+TBI compared to TBI only. Planned secondary analyses demonstrated correlations between signal and severity of mood, anxiety, somatisation and global functioning symptoms. CONCLUSIONS: These findings indicate the presence of aberrant connectivity in FS and extend the biopsychosocial network model by demonstrating that common aetiology is linked to both FS and comorbidities, but the overlap in affected networks varies by comorbid symptoms.

Concordance between focal brain temperature elevations and focal edema in temporal lobe epilepsy.

OBJECTIVE: Neuroinflammation (NI) is a pathophysiological factor in many neurological disorders, including epilepsy. Because NI causes microstructural tissue damage that worsens with increasing brain temperature, abnormally elevated brain temperatures may be a surrogate measure of the biochemical consequences of NI. This study investigated whether patients with temporal lobe epilepsy (TLE) have abnormal brain temperature elevations (TCRE ) in seizure-producing regions that show evidence of edema and/or microstructural damage. METHODS: Twenty adults with TLE and 20 healthy controls (HCs) were scanned at 3-Tesla. TCRE in each voxel was calculated (TCRE  = -102.61(ΔH20-CRE) + 206.1°C) by non-invasive volumetric magnetic resonance spectroscopic imaging and thermometry (MRSI-t). Multi-shell diffusion images were processed by neurite orientation and density imaging (NODDI). Voxel wise two-sample t tests computed group differences in imaging data. Multimodal data fusion (joint independent component analysis [ICA]) determined the spatial coupling of TCRE with NODDI. RESULTS: TCRE analyses showed that, compared to HCs, TLEs had higher TCRE (p < .001). NODDI analyses showed increased extracellular free water (pFWE < 0.05) in the medial temporal lobes, with the most pronounced increases ipsilateral to seizure onset. TLEs also had increased angular dispersion of neurites (p < .001) and decreased neurite density (pFWE <0.05) in the ictal-onset medial temporal lobe, as well as more widespread, bilateral patterns of abnormalities. Focal increases in TCRE were spatially concordant with increased free water in the left inferior and middle temporal gyri and the associated cortex. In TLE, ICA loadings extracted from this region of overlap were associated with greater mood disturbance (r = .34, p = .02) and higher depression scores (r = .37, p = .009). SIGNIFICANCE: The spatial concordance between focal TCRE elevations and edema in TLE supports the notion that brain thermometry visualizes the correlates of focal NI. MRSI-t-based TCRE elevations may, therefore, be a useful biomarker for identifying seizure-producing tissue in patients with focal epilepsy caused by brain damage.

A Pilot Randomized Controlled Trial of Intermittent Theta Burst Stimulation as Stand-Alone Treatment for Post-Stroke Aphasia: Effects on Language and Verbal Functional Magnetic Resonance Imaging (fMRI).

BACKGROUND There is an ongoing need for facilitating language recovery in chronic post-stroke aphasia. The primary aim of this study (NCT01512264) was to examine if noninvasive intermittent theta burst stimulation (iTBS) applied to the injured left-hemispheric cortex promotes language improvements and fMRI changes in post-stroke aphasia. MATERIAL AND METHODS Participants were randomized to 3 weeks of sham (Tx0) or 1-3 weeks of iTBS (Tx123). We assessed participants who completed the first 2 functional MRI (fMRI) sessions (T1, T2) where they performed 2 overt language fMRI tasks, and examined longitudinal response after 3 months (T3). Language performance and fMRI activation changes, and relationships between these changes were assessed. RESULTS From T1 to T2, both groups showed improvements on the Boston Naming Test (BNT). From T1 to T3, Tx123 improved on the Aphasia Quotient, post-scan word recognition on the verbal paired associates task (VPAT), and perceived communicative ability. Each group exhibited significant activation changes between T1 and T2 for both tasks. Only the Tx123 group exhibited fMRI activation changes between T2 to T3 on the verb-generation task and between T1 and T3 on VPAT. Delayed aphasia symptom improvement for Tx123 was associated with increased left ventral visual stream activation from T1 to T3 (rho=0.74, P=0.0058), and with decreased bilateral supplementary motor area activation related to VPAT encoding from T2 to T3 (rho=-0.80, P=0.0016). CONCLUSIONS Observed iTBS-induced language improvements and associations between delayed fMRI changes and aphasia improvements support the therapeutic and neurorehabilitative potential of iTBS in post-stroke aphasia recovery.

Functional Magnetic Resonance Imaging of Language Following Constraint-Induced Aphasia Therapy Primed with Intermittent Theta Burst Stimulation in 13 Patients with Post-Stroke Aphasia.

BACKGROUND Aphasia is a debilitating consequence of stroke. This study aimed to investigate the role of functional magnetic resonance imaging (fMRI) activation changes during overt language tasks in promoting language improvements following constraint-induced aphasia therapy (CIAT) primed with intermittent theta burst stimulation (iTBS) in 13 patients with aphasia following ischemic stroke. MATERIAL AND METHODS Participants with post-stroke aphasia participated in CIAT primed with iTBS on 10 consecutive weekdays. They also underwent language testing and fMRI while performing overt language tasks at baseline (N=13), immediately post-treatment (N=13), and after 3 months (N=12). Outcome measures were compared between time points, and relationships between changes in language ability and fMRI activation were examined. RESULTS We observed improvements in naming (p<0.001), aphasia symptoms (p=0.038), apraxia of speech symptoms (p=0.040), perception of everyday communicative ability (p=0.001), and the number of spoken words produced during fMRI (p=0.028). Pre- to post-treatment change in naming was negatively correlated with change in right postcentral gyrus activation related to noun-verb associations (rho=-0.554, p=0.0497). Change in aphasia symptoms from immediately after to 3 months post-treatment was negatively correlated with change in bilateral supplementary motor area activation related to verbal encoding (rho=-0.790, p=0.0022). CONCLUSIONS Aphasia improvements coupled with fMRI activation changes over time provide support for treatment-induced neuroplasticity with CIAT primed with iTBS. However, a larger randomized sham-controlled study is warranted to confirm our findings and further our understanding of how iTBS can potentiate beneficial effects of language therapy in post-stroke aphasia.

Intermittent Theta Burst Stimulation (iTBS) for Treatment of Chronic Post-Stroke Aphasia: Results of a Pilot Randomized, Double-Blind, Sham-Controlled Trial.

BACKGROUND Research indicates intermittent theta burst stimulation (iTBS) is a potential treatment of post-stroke aphasia. MATERIAL AND METHODS In this double-blind, sham-controlled trial (NCT01512264) participants were randomized to receive 3 weeks of sham (G0), 1 week of iTBS/2 weeks of sham (G1), 2 weeks of iTBS/1 week of sham (G2), or 3 weeks of iTBS (G3). FMRI localized residual language function in the left hemisphere; iTBS was applied to the maximum fMRI activation in the residual language cortex in the left frontal lobe. FMRI and aphasia testing were conducted pre-treatment, at ≤1 week after completing treatment, and at 3 months follow-up. RESULTS 27/36 participants completed the trial. We compared G0 to each of the individual treatment group and to all iTBS treatment groups combined (G1₋3). In individual groups, participants gained (of moderate or large effect sizes; some significant at P<0.05) on the Boston Naming Test (BNT), the Semantic Fluency Test (SFT), and the Aphasia Quotient of the Western Aphasia Battery-Revised (WAB-R AQ). In G1₋3, BNT, and SFT improved immediately after treatment, while the WAB-R AQ improved at 3 months. Compared to G0, the other groups showed greater fMRI activation in both hemispheres and non-significant increases in language lateralization to the left hemisphere. Changes in IFG connectivity were noted with iTBS, showing differences between time-points, with some of them correlating with the behavioral measures. CONCLUSIONS The results of this pilot trial support the hypothesis that iTBS applied to the ipsilesional hemisphere can improve aphasia and result in cortical plasticity.

Cannabidiol normalizes resting-state functional connectivity in treatment-resistant epilepsy.

OBJECTIVE: Resting-state (rs) network dysfunction is a contributing factor to treatment resistance in epilepsy. In treatment-resistant epilepsy (TRE), pharmacological and nonpharmacological therapies have been shown to improve such dysfunction. In this study, our goal was to prospectively evaluate the effect of highly purified plant-derived cannabidiol (CBD; Epidiolex®) on rs functional magnetic resonance imaging (fMRI) functional connectivity (rs-FC). We hypothesized that CBD would change and potentially normalize the rs-FC in TRE. METHODS: Twenty-two of 27 participants with TRE completed all study procedures including longitudinal pre-/on-CBD rs-fMRI (8M/14F, mean age = 36.2 ±â€¯15.9 years, TRE duration = 18.3 ±â€¯12.6 years); there were no differences in age (p = 0.99) or sex (p = 0.15) between groups. Assessments collected included seizure frequency (SF), Chalfont Seizure Severity Scale (CSSS), Columbia Suicide Severity Rating Scale (C-SSRS), Adverse Events Profile (AEP), and Profile of Mood States (POMS). Twenty-three healthy controls (HCs) received rs-fMRI and POMS once. RESULTS: Participants with TRE showed average decrease of 71.7% in SF (p < 0.0001) and improved CSSS, AEP, and POMS confusion, depression, and fatigue subscores (all p < 0.05) on-CBD with POMS scores becoming similar to those of HCs. Paired t-tests showed significant pre-/on-CBD changes in rs-FC in cerebellum, frontal areas, temporal areas, hippocampus, and amygdala with some of them correlating with improvement in behavioral measures. Significant differences in rs-FC between pre-CBD and HCs were found in cerebellum, frontal, and occipital regions. After controlling for changes in SF with CBD, these differences were no longer present when comparing on-CBD to HCs. SIGNIFICANCE: This study indicates that highly purified CBD modulates and potentially normalizes rs-FC in the epileptic brain. This effect may underlie its efficacy. This study provides Class III evidence for CBD's normalizing effect on rs-FC in TRE.

Background connectivity between frontal and sensory cortex depends on task state, independent of stimulus modality.

The human brain has the ability to process identical information differently depending on the task. In order to perform a given task, the brain must select and react to the appropriate stimuli while ignoring other irrelevant stimuli. The dynamic nature of environmental stimuli and behavioral intentions requires an equally dynamic set of responses within the brain. Collectively, these responses act to set up and maintain states needed to perform a given task. However, the mechanisms that allow for setting up and maintaining a task state are not fully understood. Prior evidence suggests that one possible mechanism for maintaining a task state may be through altering 'background connectivity,' connectivity that exists independently of the trials of a task. Although previous studies have suggested that background connectivity contributes to a task state, these studies have typically not controlled for stimulus characteristics, or have focused primarily on relationships among areas involved with visual sensory processing. In the present study we examined background connectivity during tasks involving both visual and auditory stimuli. We examined the connectivity profiles of both visual and auditory sensory cortex that allow for selection of task-relevant stimuli, demonstrating the existence of a potentially universal pattern of background connectivity underlying attention to a stimulus. Participants were presented with simultaneous auditory and visual stimuli and were instructed to respond to only one, while ignoring the other. Using functional MRI, we observed task-based modulation of the background connectivity profile for both the auditory and visual cortex to certain brain regions. There was an increase in background connectivity between the task-relevant sensory cortex and control areas in the frontal cortex. This increase in synchrony when receiving the task-relevant stimulus as compared to the task irrelevant stimulus may be maintaining paths for passing information within the cortex. These task-based modulations of connectivity occur independently of stimuli and could be one way the brain sets up and maintains a task state.

Cortical excitability affects mood state in patients with idiopathic generalized epilepsies (IGEs).

Previously, we demonstrated an association between cortical hyperexcitability and mood disturbance in healthy adults. Studies have documented hyperexcitability in patients with idiopathic generalized epilepsies (IGEs; long-interval intracortical inhibition [LICI]) and high prevalence of mood comorbidities. This study aimed to investigate the influences of cortical excitability and seizure control on mood state in patients with IGEs. Single and paired-pulse transcranial magnetic stimulation (TMS) was applied to 30 patients with IGEs (16 controlled IGEs [cIGEs], 14 with treatment-resistant IGEs [trIGEs]), and 22 healthy controls (HCs) to assess cortical excitability with LICI. The Profile of Mood Sates (POMS) questionnaire was used to assess total mood disturbance (TMD), as well as, six mood domains: Depression, Confusion, Anger, Anxiety, Fatigue, and Vigor. To assess the effects of seizure control (HC vs. cIGEs vs. trIGEs) and LICI response (inhibitory vs. excitatory) on TMD, a two-way multivariate analysis of variance (MANOVA) was performed. Analyses revealed a significant main effect of long-interval intracortical inhibition (LICI) response on TMD (F(1, 46) = 4.69, p = 0.04), but not seizure control (F(2, 46) = 0.288, p = 0.75). Excitatory responders endorsed significantly higher TMD scores, indicating greater mood disturbance, than inhibitory responders (MD = -2.12; T (50) = -2.47, p = 0.04). Also, excitatory responders endorsed more items than inhibitory responders on the Depression (MD = -2.12; T (50) = -2.47, p = 0.04) and Fatigue (MD = -3.42; T (50) = -2.96, p = 0.03) subscales of the POMS. These findings provide further evidence of a relationship between hyperexcitability and mood disturbance, and indicate that cortical excitability may have greater influence on mood state than seizure control in patients with IGEs. Results also support theories for the underlying role of gamma-aminobutyric acid (GABA) network dysfunction in the etiology of depression. To better understand the clinical relevance and causal nature of these relationships, further investigation is warranted.

fMRI study of cannabidiol-induced changes in attention control in treatment-resistant epilepsy.

Patients with treatment-resistant epilepsy (TRE) frequently exhibit memory and attention deficits that contribute to their poor personal and societal outcomes. We studied the effects of adjunct treatment with pharmaceutical grade cannabidiol (CBD) oral solution (Epidiolex®; Greenwich Biosciences, Inc.) on attention control processes related to stimulus conflict resolution in patients with TRE. Twenty-two patients with TRE underwent 3 T magnetic resonance imaging (MRI) before receiving (PRE) and after achieving a stable dose of CBD (ON). Functional MRI (fMRI) data were collected while patients performed 2 runs of a flanker task (FT). Patients were instructed to indicate via button press the congruent (CON) and incongruent (INC) conditions. We performed t-tests to examine with FT attention control processes at PRE and ON visits and to compare the 2 visits using derived general linear model (GLM) data (INC - CON). We performed generalized psychophysiological interaction (gPPI) analyses to assess changes in condition-based functional connectivity on FT. Median time between fMRI visits was 10 weeks, and median CBD dose at follow-up was 25 mg/kg/d. From PRE to ON, participants experienced improvements in seizure frequency (SF) (p = 0.0009), seizure severity (Chalfont Seizure Severity Scale (CSSS); p < 0.0001), and mood (Total Mood Disturbance (TMD) score from Profile of Mood States (POMS); p = 0.0026). Repeated measures analysis of variance showed nonsignificant improvements in executive function from 34.6 (23.5)% to 41.9 (22.4)% CON accuracy and from 34.2 (25.7)% to 37.6 (24.4)% INC accuracy (p = 0.199). Change in CON accuracy was associated with change in INC accuracy (rS = 0.81, p = 0.0005). Participants exhibited CBD-induced increases in fMRI activation in the right superior frontal gyrus (SFG) and right insula/middle frontal gyrus (MFG) and decrease in activation for both regions at ON relative to PRE (corrected p = 0.05). The subset of patients who improved in FT accuracy with CBD showed a negative association between change in right insula/MFG activation and change in accuracy for the INC condition (rS = -0.893, p = 0.0068). The gPPI analysis revealed a CBD-induced decrease in condition-based functional connectivity differences for the right SFG seed region (corrected p = 0.05). Whole-brain regression analysis documented a negative association of change in right insula/MFG condition-based connectivity with change in INC accuracy (corrected p = 0.005). Our results suggest that CBD modulates attention control processing in patients with TRE by reducing right SFG and right insula/MFG activation related to stimulus conflict resolution and by dampening differences in condition-based functional connectivity of the right SFG. Our study is the first to provide insight into how CBD affects the neural substrates involved in attention processing and how modulation of the activity and functional connectivity related to attentional control processes in the right insula/MFG may be working to improve cognitive performance in TRE.

A pilot study of combined endurance and resistance exercise rehabilitation for verbal memory and functional connectivity improvement in epilepsy.

Memory impairment is common in persons with epilepsy (PWE), and exercise may be a strategy for its improvement. In this pilot study, we hypothesized that exercise rehabilitation would improve physical fitness and verbal memory and induce changes in brain networks involved in memory processes. We examined the effects of combined endurance and resistance exercise rehabilitation on memory and resting state functional connectivity (rsFC). Participants were randomized to exercise (PWE-E) or control (PWE-noE). The exercise intervention consisted of 18 supervised sessions on nonconsecutive days over 6 weeks. Before and after the intervention period, both groups completed self-report assessments (Short Form-36 (SF-36), Baecke Questionnaire (BQ) of habitual physical activity, and Profile of Mood States (POMS)), cognitive testing (California Verbal Learning Test-II (CVLT-II)), and magnetic resonance imaging (MRI); PWE-E also completed exercise performance tests. After completing the study, PWE-noE were offered cross-over to the exercise arm. There were no differences in baseline demographic, clinical, or assessment variables between 8 PWE-noE and 9 PWE-E. Persons with epilepsy that participated in exercise intervention increased maximum voluntary strength (all strength tests p < 0.05) and exhibited nonsignificant improvement in cardiorespiratory fitness (p = 0.15). Groups did not show significant changes in quality of life (QOL) or habitual physical activity between visits. However, there was an effect of visit on POMS total mood disturbance (TMD) measure showing improvement from baseline to visit 2 (p = 0.023). There were significant group by visit interactions on CVLT-II learning score (p = 0.044) and total recognition discriminability (d') (p = 0.007). Persons with epilepsy that participated in exercise intervention had significant reductions in paracingulate rsFC with the anterior cingulate and increases in rsFC for the cerebellum, thalamus, posterior cingulate cortex (PCC), and left and right inferior parietal lobule (IPL) (corrected p < 0.05). Change in CVLT-II learning score was associated with rsFC changes for the paracingulate cortex (rS = -0.67; p = 0.0033), left IPL (rS = 0.70; p = 0.0019), and right IPL (rS = 0.71; p = 0.0015) while change in d' was associated with change in cerebellum rsFC to angular/middle occipital gyrus (rS = 0.68; p = 0.0025). Our conclusion is that exercise rehabilitation may facilitate verbal memory improvement and brain network functional connectivity changes in PWE and that improved memory performance is associated with changes in rsFC. A larger randomized controlled trial of exercise rehabilitation for cognitive improvement in PWE is warranted.

Cortical excitability and seizure control influence attention performance in patients with idiopathic generalized epilepsies (IGEs).

We recently found that higher cortical excitability is associated with poorer attention performance in healthy adults. While patients with idiopathic generalized epilepsies (IGEs), previously termed genetic generalized epilepsies, are known to demonstrate increased cortical excitability and cognitive deficits, a relationship between these variables in IGEs has not been investigated. Therefore, we aimed to characterize the effects of cortical excitability and seizure control on cognitive performance in IGEs. We studied 30 patients with IGEs (16 patients with controlled IGEs (cIGEs) and 14 patients with treatment-resistant IGEs (trIGEs)) and 24 healthy controls (HCs). Transcranial magnetic stimulation (TMS) was used to measure cortical excitability, including long-interval intracortical inhibition (LICI). Attention was assessed with the Digit Span Forwards, Digit Span Backwards, Trails A, and Flanker tasks. Executive functioning was assessed using Trails B, Stroop Color and Word, and the Wisconsin Card Sorting Task. Two-way multivariate analyses of variance (MANOVAs) were conducted to assess the influences of seizure control (HCs vs. cIGEs vs. trIGEs) and cortical excitability (inhibitory vs. excitatory) on composite measures of attention and executive functions. Attention performance was significantly affected by cortical excitability and seizure control. Participants with primarily excitatory LICI responses, indicating higher cortical excitability, performed worse than inhibitory responders on composite attention (Wilks' lambda = 0.748, F(4, 44) = 3.72, p = 0.011). While participants with cIGEs and trIGEs did not significantly differ in attention performance, participants with trIGEs performed worse on the Digit Forwards (False Discovery Rate (FDR)p < 0.001), Digit Backwards (FDRp = 0.015), and Flanker (FDRp = 0.0075) tasks compared with HCs. These results provide support for the relationship between cortical excitability and attention dysfunction in IGEs. Further investigation is needed to determine whether there is a causal relationship between these variables and whether intracortical gamma-aminobutyric acid (GABA)B networks may be targeted to improve attention deficits in clinical populations with decreased LICI. Findings also suggest that additional research directly comparing cognition in patients with cIGEs and trIGEs is warranted.

Facial emotion processing in patients with seizure disorders.

Studies of emotion processing are needed to better understand the pathophysiology of psychogenic nonepileptic seizures (PNES). We examined the differences in facial emotion processing between 12 patients with PNES, 12 patients with temporal lobe epilepsy (TLE), and 24 matched healthy controls (HCs) using fMRI with emotional faces task (EFT) (happy/sad/fearful/neutral) and resting state connectivity. Compared with TLE, patients with PNES exhibited increased fMRI response to happy, neutral, and fearful faces in visual, temporal, and/or parietal regions and decreased fMRI response to sad faces in the putamen bilaterally. Regions showing significant differences between PNES and TLE were used as functional seed regions of interest (ROIs), in addition to amygdala structural seed ROIs for resting state functional connectivity analyses. Whole brain analyses showed that compared with TLE and HCs, patients with PNES exhibited increased functional connectivity of the functional seed ROIs to several brain regions, particularly to cerebellar, visual, motor, and frontotemporal regions. Connectograms showed increased functional connections between left parahippocampal gyrus/uncus ROIs and right temporal ROIs in PNES compared with both the TLE and HC groups. Resting state functional connectivity of the left and right amygdala to various brain regions including emotion regulation and motor control circuits was increased in PNES when compared with those with TLE. This study provides preliminary evidence that patients with PNES exhibit altered facial emotion processing compared with patients with TLE and HCs and increased amygdala functional connectivity compared with TLE. These findings identify potential key differences in facial emotion processing reflective of neurophysiologic markers of neural circuitry alterations that can be used to generate further hypotheses for developing studies that examine the contributions of emotion processing to the development and maintenance of PNES.

The canonical semantic network supports residual language function in chronic post-stroke aphasia.

Current theories of language recovery after stroke are limited by a reliance on small studies. Here, we aimed to test predictions of current theory and resolve inconsistencies regarding right hemispheric contributions to long-term recovery. We first defined the canonical semantic network in 43 healthy controls. Then, in a group of 43 patients with chronic post-stroke aphasia, we tested whether activity in this network predicted performance on measures of semantic comprehension, naming, and fluency while controlling for lesion volume effects. Canonical network activation accounted for 22%-33% of the variance in language test scores. Whole-brain analyses corroborated these findings, and revealed a core set of regions showing positive relationships to all language measures. We next evaluated the relationship between activation magnitudes in left and right hemispheric portions of the network, and characterized how right hemispheric activation related to the extent of left hemispheric damage. Activation magnitudes in each hemispheric network were strongly correlated, but four right frontal regions showed heightened activity in patients with large lesions. Activity in two of these regions (inferior frontal gyrus pars opercularis and supplementary motor area) was associated with better language abilities in patients with larger lesions, but poorer language abilities in patients with smaller lesions. Our results indicate that bilateral language networks support language processing after stroke, and that right hemispheric activations related to extensive left hemispheric damage occur outside of the canonical semantic network and differentially relate to behavior depending on the extent of left hemispheric damage. Hum Brain Mapp 38:1636-1658, 2017. © 2016 Wiley Periodicals, Inc.

Neuroimaging Correlates of Post-Stroke Aphasia Rehabilitation in a Pilot Randomized Trial of Constraint-Induced Aphasia Therapy.

BACKGROUND Recovery from post-stroke aphasia is a long and complex process with an uncertain outcome. Various interventions have been proposed to augment the recovery, including constraint-induced aphasia therapy (CIAT). CIAT has been applied to patients suffering from post-stroke aphasia in several unblinded studies to show mild-to-moderate linguistic gains. The aim of the present study was to evaluate the neuroimaging correlates of CIAT in patients with chronic aphasia related to left middle cerebral artery stroke. MATERIAL AND METHODS Out of 24 patients recruited in a pilot randomized blinded trial of CIAT, 19 patients received fMRI of language. Eleven of them received CIAT (trained) and eight served as a control group (untrained). Each patient participated in three fMRI sessions (before training, after training, and 3 months later) that included semantic decision and verb generation fMRI tasks, and a battery of language tests. Matching healthy control participants were also included (N=38; matching based on age, handedness, and sex). RESULTS Language testing showed significantly improved performance on Boston Naming Test (BNT; p<0.001) in both stroke groups over time and fMRI showed differences in the distribution of the areas involved in language production between groups that were not present at baseline. Further, regression analysis with BNT indicated changes in brain regions correlated with behavioral performance (temporal gyrus, postcentral gyrus, precentral gyrus, thalamus, left middle and superior frontal gyri). CONCLUSIONS Overall, our results suggest the possibility of language-related cortical plasticity following stroke-induced aphasia with no specific effect from CIAT training.

Arcuate fasciculus asymmetry has a hand in language function but not handedness.

The importance of relationships between handedness, language lateralization and localization, and white matter tracts for language performance is unclear. The goal of the study was to investigate these relationships by examining arcuate fasciculus (AF) structural asymmetry (DTI) and functional asymmetry (fMRI) in language circuits, handedness, and linguistic performance. A large sample of right-handed (n = 158) and atypical-handed (n = 82) healthy adults underwent DTI at 3 T to assess number of streamlines and fractional anisotropy (FA) of the AF, and language fMRI. Language functions were assessed using standard tests of vocabulary, naming, verbal fluency, and complex ideation. Laterality indices (LIs) illustrated degree of asymmetry and lateralization patterns for the AF (streamlines and FA) and verb generation fMRI. Both handedness groups showed leftward lateralization bias for streamline and fMRI LIs and symmetry for FA LI. The proportion of subjects with left, right, or symmetric lateralization were similar between groups if based on AF LIs, but differed if based on fMRI LIs (p = 0.0016). Degree of right-handedness was not associated with AF lateralization, but was associated with fMRI language lateralization (p = 0.0014). FA LI was not associated with performance on language assessments, but streamline LI was associated with better vocabulary and complex ideation performance in atypical-handed subjects (p = 0.022 and p = 0.0098, respectively), and better semantic fluency in right-handed subjects (p = 0.047); however, these did not survive multiple comparisons correction. We provide evidence that AF asymmetry is independent of hand preference, and while degree of right-handedness is associated with hemispheric language lateralization, the majority of atypical-handed individuals are left-lateralized for language. Hum Brain Mapp 37:3297-3309, 2016. © 2016 Wiley Periodicals, Inc.

Interhemispheric Plasticity following Intermittent Theta Burst Stimulation in Chronic Poststroke Aphasia.

The effects of noninvasive neurostimulation on brain structure and function in chronic poststroke aphasia are poorly understood. We investigated the effects of intermittent theta burst stimulation (iTBS) applied to residual language-responsive cortex in chronic patients using functional and anatomical MRI data acquired before and after iTBS. Lateralization index (LI) analyses, along with comparisons of inferior frontal gyrus (IFG) activation and connectivity during covert verb generation, were used to assess changes in cortical language function. Voxel-based morphometry (VBM) was used to assess effects on regional grey matter (GM). LI analyses revealed a leftward shift in IFG activity after treatment. While left IFG activation increased, right IFG activation decreased. Changes in right to left IFG connectivity during covert verb generation also decreased after iTBS. Behavioral correlations revealed a negative relationship between changes in right IFG activation and improvements in fluency. While anatomical analyses did not reveal statistically significant changes in grey matter volume, the fMRI results provide evidence for changes in right and left IFG function after iTBS. The negative relationship between post-iTBS changes in right IFG activity during covert verb generation and improvements in fluency suggests that iTBS applied to residual left-hemispheric language areas may reduce contralateral responses related to language production and facilitate recruitment of residual language areas after stroke.

Brain temperature and free water increases after mild COVID-19 infection.

The pathophysiology underlying the post-acute sequelae of COVID-19 remains understudied and poorly understood, particularly in healthy adults with a history of mild infection. Chronic neuroinflammation may underlie these enduring symptoms, but studying neuroinflammatory phenomena in vivo is challenging, especially without a comparable pre-COVID-19 dataset. In this study, we present a unique dataset of 10 otherwise healthy individuals scanned before and after experiencing mild COVID-19. Two emerging MR-based methods were used to map pre- to post-COVID-19 brain temperature and free water changes. Post-COVID-19 brain temperature and free water increases, which are indirect biomarkers of neuroinflammation, were found in structures functionally associated with olfactory, cognitive, and memory processing. The largest pre- to post-COVID brain temperature increase was observed in the left olfactory tubercle (p = 0.007, 95% CI [0.48, 3.01]), with a mean increase of 1.75 °C. Notably, the olfactory tubercle is also the region of the primary olfactory cortex where participants with chronic olfactory dysfunction showed the most pronounced increases as compared to those without lingering olfactory dysfunction (adjusted pFDR = 0.0189, 95% CI [1.42, 5.27]). These preliminary insights suggest a potential link between neuroinflammation and chronic cognitive and olfactory dysfunction following mild COVID-19, although further investigations are needed to improve our understanding of what underlies these phenomena.

Relationship between sleep, physical fitness, brain microstructure, and cognition in healthy older adults: A pilot study.

BACKGROUND: There is a critical need for neuroimaging markers of brain integrity to monitor effects of modifiable lifestyle factors on brain health. This observational, cross-sectional study assessed relationships between brain microstructure and sleep, physical fitness, and cognition in healthy older adults. METHODS: Twenty-three adults aged 60 and older underwent whole-brain multi-shell diffusion imaging, comprehensive cognitive testing, polysomnography, and exercise testing. Neurite Orientation Dispersion and Density Imaging (NODDI) was used to quantify neurite density (NDI) and orientation dispersion (ODI). Diffusion tensor imaging (DTI) was used to quantify axial diffusivity (AxD), fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD). Relationships between sleep efficiency (SE), time and percent in N3 sleep, cognitive function, physical fitness (VO2 peak) and the diffusion metrics in regions of interest and the whole brain were evaluated. RESULTS: Higher NDI in bilateral white and gray matter was associated with better executive functioning. NDI in the right anterior cingulate and adjacent white matter was positively associated with language skills. Higher NDI in the left posterior corona radiata was associated with faster processing speed. Physical fitness was positively associated with NDI in the left precentral gyrus and corticospinal tract. N3 % was positively associated with NDI in the left caudate and right pre- and postcentral gyri. Higher ODI in the left putamen and adjacent white matter was associated with better executive function. CONCLUSION: NDI and ODI derived from NODDI are potential neuroimaging markers for associations between brain microstructure and modifiable risk factors in aging. If these associations are observable in clinical samples, NODDI could be incorporated into clinical trials assessing the effects of modifiable risk factors on brain integrity in aging and neurodegenerative diseases.