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BACKGROUND: The amygdala is highly implicated in an array of psychiatric disorders but is not accessible using currently available noninvasive neuromodulatory techniques. Low-intensity transcranial focused ultrasound (TFUS) is a neuromodulatory technique that has the capability of reaching subcortical regions noninvasively. METHODS: We studied healthy older adult participants (N = 21, ages 48-79 years) who received TFUS targeting the right amygdala and left entorhinal cortex (active control region) using a 2-visit within-participant crossover design. Before and after TFUS, behavioral measures were collected via the State-Trait Anxiety Inventory and an emotional reactivity and regulation task utilizing neutral and negatively valenced images from the International Affective Picture System. Heart rate and self-reported emotional valence and arousal were measured during the emotional reactivity and regulation task to investigate subjective and physiological responses to the task. RESULTS: Significant increases in both self-reported arousal in response to negative images and heart rate during emotional reactivity and regulation task intertrial intervals were observed when TFUS targeted the amygdala; these changes were not evident when the entorhinal cortex was targeted. No significant changes were found for state anxiety, self-reported valence to the negative images, cardiac response to the negative images, or emotion regulation. CONCLUSIONS: The results of this study provide preliminary evidence that a single session of TFUS targeting the amygdala may alter psychophysiological and subjective emotional responses, indicating some potential for future neuropsychiatric applications. However, more work on TFUS parameters and targeting optimization is necessary to determine how to elicit changes in a more clinically advantageous way.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinsons disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

BackgroundLow intensity, transcranial focused ultrasound (tFUS) is a re-emerging brain stimulation technique with the unique capability of reaching deep brain structures non-invasively.Objective/hypothesisWe sought to demonstrate that tFUS can selectively and accurately target and modulate deep brain structures in humans important for emotional functioning as well as learning and memory. We hypothesized that tFUS would result in significant longitudinal changes in perfusion in the targeted brain region as well as selective modulation of BOLD activity and BOLD-based functional connectivity of the target region.MethodsIn this study, we collected MRI before, simultaneously during, and after tFUS of two deep brain structures on different days in sixteen healthy adults each serving as their own control. Using longitudinal arterial spin labeling (ASL) MRI and simultaneous blood oxygen level dependent (BOLD) functional MRI, we found changes in cerebral perfusion, regional brain activity and functional connectivity specific to the targeted regions of the amygdala and entorhinal cortex (ErC).ResultstFUS selectively increased perfusion in the targeted brain region and not in the contralateral homolog or either bilateral control region. Additionally, tFUS directly affected BOLD activity in a target specific fashion without engaging auditory cortex in any analysis. Finally, tFUS resulted in selective modulation of the targeted functional network connectivity.ConclusionWe demonstrate that tFUS can selectively modulate perfusion, neural activity and connectivity in deep brain structures and connected networks. Lack of auditory cortex findings suggests that the mechanism of tFUS action is not due to auditory or acoustic startle response but rather a direct neuromodulatory process. Our findings suggest that tFUS has the potential for future application as a novel therapy in a wide range of neurological and psychiatric disorders associated with subcortical pathology.

The amygdala plays a role in emotion, learning, and memory and has been implicated in behavioral disorders. Better understanding of the amygdala circuitry is crucial to develop new therapies for these disorders. We used data from 200 healthy-subjects from the human connectome project. Using probabilistic tractography, we created population statistical maps of amygdala connectivity to brain regions involved in limbic, associative, memory, and reward circuits. Based on the amygdala connectivity with these regions, we applied k-means clustering to parcellate the amygdala into three clusters. The resultant clusters were averaged across all subjects and the main white-matter pathways of the amygdala from each averaged cluster were generated. Amygdala parcellation into three clusters showed a medial-to-lateral pattern. The medial cluster corresponded with the centromedial and cortical nuclei, the basal cluster with the basal nuclei and the lateral cluster with the lateral nuclei. The connectivity analysis revealed different white-matter pathways consistent with the anatomy of the amygdala circuit. This in vivo connectivity-based parcellation of the amygdala delineates three clusters of the amygdala in a mediolateral pattern based on its connectivity with brain areas involved in cognition, memory, emotion, and reward. The human amygdala circuit presented in this work provides the first step for personalized amygdala circuit mapping for patients with behavioral disorders.

Introduction: This study intended to evaluate the safety and possible therapeutic effect of transcranial infrared laser stimulation (TILS) based on photobiomodulation (PBM) among patients with traumatic brain injury (TBI). Methods: Eleven participants who were diagnosed with TBI after full neurological examination and MRI evaluation by a board-certified neurologist completed five to eight 20-minute TILS sessions using the Cytonsys CytonPro-5000 apparatus (pilot laser control, focused wavelength of 1064 nm, maximum output power of 10W, maximum optical power density of 500 mW/cm2, effective area 4.5 cm2 in diameter). Per TILS session, participants underwent a laser dose of 250 mW/cm2 continuous laser wave to each hemisphere using predetermined patient-specific coordinates. Structural imaging was used to neuronavigate individual treatment targets in the frontal cortex (Brodmann area 10). The primary safety measure for this study was the occurrence of adverse events (AEs) or serious adverse events (SAEs). The primary efficacy outcome measure was the participant-rated global rating of change (GRC) post-intervention. Secondary outcome measures included a battery of neuropsychological testing and mood questionnaires done both pre- and post-intervention. Results: All patients enrolled in this study protocol were able to tolerate the study procedures without any AEs or SAEs. Nine out of eleven participants had clinically significant improvements in GRC score (≥ +2). Neuropsychological testing and mood questionnaire outcomes also suggested a positive therapeutic effect. Conclusion: This study provides preliminary evidence supporting the safety and potential efficacy of TILS as a non-invasive clinical intervention for individuals with TBI.

OBJECTIVE: Cognitive impairment is common among individuals with Parkinsons disease (PD). Intraindividual variability (IIV) is a measure of variability across multiple tasks of cognitive functioning. Due to the limited amount of research, particularly among individuals with PD, IIV has been an underutilized metric of cognitive functioning both in research and clinical practice. Previous research demonstrated that individuals with PD have greater variability in cognitive performance relative to controls, and that IIV is predictive of future cognitive impairments. The aim of this study is to investigate the association between baseline IIV and change in cortical and subcortical volumes among individuals with PD. METHOD: The present study used data from 80 newly diagnosed PD patients who were part of a longitudinal cohort study (Parkinson progression marker initiative [PPMI]). Participants completed neuropsychological measures and underwent T1 structural magnetic resonance imaging (MRI) at baseline and the first annual follow-up. Neuropsychological tests assessed attention, processing speed, visuospatial functioning, verbal fluency learning, and memory. T1 scans were processed using standard Freesurfer protocols for extraction of regional volumes. RESULTS: Greater IIV at baseline was predictive of change in cortical volume in posterior temporal/parietal regions over the 1-year period. Baseline IIV predicted cortical volume changes above and beyond the main effect of motor severity and the baseline statistical mean/global cognition score. CONCLUSION: Our results provide initial evidence that IIV is a marker of longitudinal cortical volume loss. Evidence is building that IIV is a sensitive marker of cognitive impairment and the underlying neurodegeneration among individuals with PD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

BACKGROUND: Understanding the structural connectivity of key brainstem nuclei with limbic cortical regions is essential to the development of therapeutic neuromodulation for depression, chronic pain, addiction, anxiety and movement disorders. Several brainstem nuclei have been identified as the primary central nervous system (CNS) source of important monoaminergic ascending fibers including the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, and dopaminergic ventral tegmental area. However, due to practical challenges to their study, there is limited data regarding their in vivo anatomic connectivity in humans. OBJECTIVE: To evaluate the structural connectivity of the following brainstem nuclei with limbic cortical areas: locus coeruleus, ventral tegmental area, periaqueductal grey, dorsal raphe nucleus, and nucleus tractus solitarius. Additionally, to develop a group average atlas of these limbic brainstem structures to facilitate future analyses. METHODS: Each nucleus was manually masked from 197 Human Connectome Project (HCP) structural MRI images using FSL software. Probabilistic tractography was performed using FSLs FMRIB Diffusion Toolbox. Connectivity with limbic cortical regions was calculated and compared between brainstem nuclei. Results were aggregated to produce a freely available MNI structural atlas of limbic brainstem structures. RESULTS: A general trend was observed for a high probability of connectivity to the amygdala, hippocampus and DLPFC with relatively lower connectivity to the orbitofrontal cortex, NAc, hippocampus and insula. The locus coeruleus and nucleus tractus solitarius demonstrated significantly greater connectivity to the DLPFC than amygdala while the periaqueductal grey, dorsal raphe nucleus, and ventral tegmental area did not demonstrate a significant difference between these two structures. CONCLUSION: Monoaminergic and other modulatory nuclei in the brainstem project widely to cortical limbic regions. We describe the structural connectivity across the several key brainstem nuclei theorized to influence emotion, reward, and cognitive functions. An increased understanding of the anatomic basis of the brainstems role in emotion and other reward-related processing will support targeted neuromodulatary therapies aimed at alleviating the symptoms of neuropsychiatric disorders.

IntroductionStudying neuro-structural markers of intellectual giftedness (IG) will inform scientific understanding of the processes helping children excel academically.MethodsStructural and diffusion-weighted MRI was used to compare regional brain shape and connectivity of 12 children with average to high average IQ and 18 IG children, defined as having IQ greater than 145.ResultsIG had larger subcortical structures and more robust white matter microstructural organization between those structures in regions associated with explicit memory. TD had more connected, larger subcortical structures in regions associated with implicit memory.ConclusionsIt was found that the memory systems within brains of children with exceptional intellectual abilities are differently sized and connected compared to the brains of typically developing children. These different neurodevelopmental trajectories suggest different learning strategies. A spectrum of intelligence types is envisioned, facilitated by different ratios of implicit and explicit system, which was validated using a large external dataset.

BackgroundThis study sought to validate the clinical utility of multimodal magnetic resonance imaging (MRI) techniques in the assessment of neurodegenerative disorders. We intended to demonstrate that advanced neuroimaging techniques commonly used in research can effectively be employed in clinical practice to accurately differentiate heathy aging and dementia subtypes.MethodsTwenty patients with dementia of the Alzheimer's type (DAT) and 18 patients with Parkinson's disease dementia (PDD) were identified using gold-standard techniques. Twenty-three healthy, age and sex matched control participants were also recruited. All participants underwent multimodal MRI including T1 structural, diffusion tensor imaging (DTI), arterial spin labeling (ASL), and magnetic resonance spectroscopy (MRS). MRI modalities were evaluated by trained neuroimaging readers and were separately assessed using cross-validated, iterative discriminant function analyses with subsequent feature reduction techniques. In this way, each modality was evaluated for its ability to differentiate patients with dementia from healthy controls as well as to differentiate dementia subtypes.ResultsFollowing individual and group feature reduction, each of the multimodal MRI metrics except MRS successfully differentiated healthy aging from dementia and also demonstrated distinct dementia subtypes. Using the following ten metrics, excellent separation (95.5% accuracy, 92.3% sensitivity; 100.0% specificity) was achieved between healthy aging and neurodegenerative conditions: volume of the left frontal pole, left occipital pole, right posterior superior temporal gyrus, left posterior cingulate gyrus, right planum temporale; perfusion of the left hippocampus and left occipital lobe; fractional anisotropy (FA) of the forceps major and bilateral anterior thalamic radiation. Using volume of the left frontal pole, right posterior superior temporal gyrus, left posterior cingulate gyrus, perfusion of the left hippocampus and left occipital lobe; FA of the forceps major and bilateral anterior thalamic radiation, neurodegenerative subtypes were accurately differentiated as well (87.8% accuracy, 95.2% sensitivity; 85.0% specificity).ConclusionsRegional volumetrics, DTI metrics, and ASL successfully differentiated dementia patients from controls with sufficient sensitivity to differentiate dementia subtypes. Similarly, feature reduction results suggest that advanced analyses can meaningfully identify brain regions with the most positive predictive value and discriminant validity. Together, these advanced neuroimaging techniques can contribute significantly to diagnosis and treatment planning for individual patients.

ObjectiveTranscranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing.MethodsNeuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm2. Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others.ResultsWith respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS.SignificanceThis study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits.

ObjectiveThe pursuit of an effective therapeutic intervention for dementia has inspired interest in the class of medications known as tyrosine kinase inhibitors such as bosutinib.MethodsThirty-one patients with probable Alzheimer dementia or Parkinson spectrum disorder with dementia completed 12 months of bosutinib therapy and an additional 12 months of follow-up. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Repeatable Battery Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment. Cox regression methods were used to compare results with population-based estimates of cognitive decline.ResultsThe present article reports on cognitive outcomes obtained at 12 months for 31 participants and up to 24 months for a 16-participant subset. Safety and tolerability of bosutinib were confirmed among the study population (Mage = 73.7 years, SDage = 14 years). Bosutinib was associated with less worsening in Clinical Dementia Rating (CDR) scores (hazard ratio = -0.62, p < 0.001, 95% confidence interval [CI]: -1.02 to -0.30) and less decline in RBANS performance (hazard ratio = -3.42, p < 0.001, 95% CI: -3.59 to -3.72) during the year of treatment than population-based estimates of decline. In the 24-month follow-up, wherein 16 patients were observed after 1 year postintervention, 31.2% of participants exhibited worsened CDR levels compared with their 12-month performances.ConclusionsResults support an overall positive outcome after 1 year of bosutinib. Future studies should explore the relationship between tyrosine kinases and neurodegenerative pathology as well as related avenues of treatment.

ObjectiveBrain tumors located close to the language cortex may distort functional MRI (fMRI)-based estimates of language dominance. The nature of this distortion, and whether this is an artifact of numerous confounders, remains unknown. The authors hypothesized tumor bias based on laterality estimates independent of confounders and that the effects are the greatest for tumors proximal to Broca's area.MethodsTo answer this question, the authors reviewed more than 1113 patients who underwent preoperative fMRI to match samples on 11 known confounders (tumor location, size, type, and grade; seizure history; prior neurosurgery; aphasia presence and severity; and patient age, sex, and handedness). The samples included 30 patients with left hemisphere tumors (15 anterior and 15 posterior) and 30 with right hemisphere tumors (15 anterior and 15 posterior), thus totaling 60 patients (25 women; 18 left-handed and 4 ambidextrous; mean age 47 [SD 14.1] years). Importantly, the authors matched not only patients with left and right hemisphere tumors but also those with anterior and posterior tumors. Standard fMRI laterality indices (LIs) were calculated using whole-brain and region of interest (ROI) approaches (Broca's and Wernicke's areas).ResultsTumors close to Broca's area in the left hemisphere decreased LIs independently of known confounders. At the whole-brain level, this appeared to reflect a decrease in LI values in patients with left anterior tumors compared with patients with right anterior tumors. ROI analysis replicated these findings. Broca's area LIs were significantly lower (p = 0.02) in patients with left anterior tumors (mean LI 0.28) when compared with patients with right anterior tumors (mean LI 0.70). Changes in Wernicke's area-based LIs did not differ as a function of the tumor hemisphere. Therefore, in patients with left anterior tumors, it is essential to assess language laterality using left posterior ROIs. In all remaining tumor groups (left posterior tumors and right hemisphere tumors), language laterality derived from the anterior language ROI was the most robust measure of language dominance.ConclusionsPatients with tumors close to Broca's area showed more bilateral fMRI language maps independent of known confounders. The authors caution against the assumption that this reduced language laterality suggests no or little risk to language function following tumor resection in the left inferior frontal gyrus. Their results address how to interpret fMRI data for neurosurgical purposes, along with theoretical questions of contralesional functional compensation and disinhibition.

IntroductionNonmotor symptoms, including depression, anxiety, apathy, and cognitive dysfunction, are common in Parkinson's disease (PD). Although a link between mood symptoms and cognitive impairment in PD has been theorized vis-à-vis striatal dopamine depletion, studies have been inconsistent regarding the relationship between mood symptoms and cognitive function. Inconsistencies may reflect the cross-sectional nature of previous studies. The current study examined the bidirectional longitudinal relationship between mood and cognition.MethodData were obtained from 310 individuals newly diagnosed with PD, who were followed up to 4 years (baseline, 1st, 2nd, 3rd, and 4th annual follow-ups). Apathy, anxiety, depressive symptoms, motor severity, and neurocognitive functioning were assessed at each annual assessment. The longitudinal relationship between apathy, anxiety, depressive symptoms, and cognition was analyzed with multilevel models.ResultsOver the 4-year period, more severe depressive symptoms were related to worse performance on tasks of processing speed, verbal learning, and verbal delayed recall. Additionally, there was a significant Depression × Time interaction, suggesting that individuals with more severe depressive symptoms experience more rapid declines in global cognitive functioning and verbal learning. Apathy and anxiety were not significantly related to performance in any cognitive test. Lagged models revealed that changes in depression precede declines in working memory, verbal learning, delayed verbal recall, and global cognition.ConclusionFindings suggest depressive symptoms may be a harbinger for future cognitive decline among individuals with PD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Recent evidence suggests the aging process is accelerated by HIV. Degradation of white matter (WM) has been independently associated with HIV and healthy aging. Thus, WM may be vulnerable to joint effects of HIV and aging. Diffusion-weighted imaging (DWI) was conducted with HIV-seropositive (n = 72) and HIV-seronegative (n = 34) adults. DWI data underwent tractography, which was parcellated into 18 WM tracts of interest (TOIs). Functional Analysis of Diffusion Tensor Tract Statistics (FADTTS) regression was conducted assessing the joint effect of advanced age and HIV on fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) along TOI fibers. In addition to main effects of age and HIV on WM microstructure, the interactive effect of age and HIV was significantly related to lower FA and higher MD, AD, and RD across all TOIs. The location of findings was consistent with the clinical presentation of HIV-associated neurocognitive disorders. While older age is related to poorer WM microstructure, its detrimental effect on WM is stronger among HIV+ relative to HIV- individuals. Loss of WM integrity in the context of advancing age may place HIV+ individuals at increased risk for brain and cognitive compromise.

ObjectivesDespite treatment-related improvements in morbidity and mortality, HIV-1-infected (HIV+) individuals continue to face a wide range of HIV-associated medical and HIV-associated neurocognitive disorders. Little is known about the impact of cognitive impairment on patients' health-related quality of life (HRQoL). To address this, the current study examined the longitudinal relationship between cognitive functioning and HRQoL among HIV+ individuals.MethodThe sample consisted of 1,306 HIV+ men enrolled in the Multicenter AIDS Cohort Study. Participants received biannual assessments of cognitive functioning (including tests of processing speed, executive functioning, attention/working memory, motor functioning, learning, and memory) and completed questionnaires assessing HRQoL and depression. Multilevel models were used to examine the longitudinal and cross-lagged relationship between HRQoL and cognition, independent of depression and HIV disease severity.ResultsThere was a significant relationship between HRQoL and cognitive functioning both between and within subjects. Specifically, individuals who reported better HRQoL reported better cognitive functioning, and longitudinal change in cognition was positively related to change in HRQoL. There was a significant unidirectional-lagged relationship; cognition predicted HRQoL at subsequent visits, but HRQoL did not predict cognitive functioning at subsequent visits. Furthermore, analyses of severity of neurocognitive impairment revealed that transition to a more severe stage of cognitive impairment was associated with a decline in HRQoL.ConclusionsOverall, the current study suggests that changes in HRQoL are partially driven by changes in cognitive functioning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The original Human Connectome Project yielded a rich data set on structural and functional connectivity in a large sample of healthy young adults using improved methods of data acquisition, analysis, and sharing. More recent efforts are extending this approach to include infants, children, older adults, and brain disorders. This paper introduces and describes the Human Connectome Project in Aging (HCP-A), which is currently recruiting 1200 + healthy adults aged 36 to 100+, with a subset of 600 + participants returning for longitudinal assessment. Four acquisition sites using matched Siemens Prisma 3T MRI scanners with centralized quality control and data analysis are enrolling participants. Data are acquired across multimodal imaging and behavioral domains with a focus on factors known to be altered in advanced aging. MRI acquisitions include structural (whole brain and high resolution hippocampal) plus multiband resting state functional (rfMRI), task fMRI (tfMRI), diffusion MRI (dMRI), and arterial spin labeling (ASL). Behavioral characterization includes cognitive (such as processing speed and episodic memory), psychiatric, metabolic, and socioeconomic measures as well as assessment of systemic health (with a focus on menopause via hormonal assays). This dataset will provide a unique resource for examining how brain organization and connectivity changes across typical aging, and how these differences relate to key characteristics of aging including alterations in hormonal status and declining memory and general cognition. A primary goal of the HCP-A is to make these data freely available to the scientific community, supported by the Connectome Coordination Facility (CCF) platform for data quality assurance, preprocessing and basic analysis, and shared via the NIMH Data Archive (NDA). Here we provide the rationale for our study design and sufficient details of the resource for scientists to plan future analyses of these data. A companion paper describes the related Human Connectome Project in Development (HCP-D, Somerville et al., 2018), and the image acquisition protocol common to both studies (Harms et al., 2018).

IntroductionPreclinical studies support investigation of focused ultrasound for breakdown of cerebral pathologies in neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD).MethodsA focused transcranial Doppler device with probes (2 MHz, 520 mW/cm2) affixed bilaterally was used to target the hippocampus (AD) or substantia nigra (PD) with functional magnetic resonance imaging navigation for enhanced plaque removal. A total of 22 patients (n = 11 AD, n = 11 PD) underwent 8 consecutive, weekly, 1-hour treatments wherein sleep was encouraged naturally or pharmacologically. Cognitive and motor functioning assessment was carried out using standardized evaluations at baseline and conclusion.ResultsOf all, 62.5% of patients had one or more improved cognitive scores without data incongruence, 87% had stable or improved fine motor scores, and 87.5% had stable or improved gross motor scores. No adverse events were reported.DiscussionThe safety of focused transcranial Doppler and possible enhancement in patient functioning were suggested by outcome data.

ObjectiveHIV-associated neurocognitive disorder (HAND) occurs in a significant percentage of HIV-infected (HIV+) adults. Increased intraindividual variability (IIV) in cognitive function may be an early marker of emerging neurocognitive disorder, which suggests that IIV may be a sensitive measure of neurologic compromise in HIV. In the current study, we hypothesize that increased IIV may predict impending morbidity, including future cognitive decline and death.MethodIn 708 HIV+ participants followed longitudinally for up to 14 years, we assessed the role of dispersion in forecasting death and cognitive decline. Incident neurocognitive impairment was predicted in a mixed-effects ordinal logistic regression model using age, gender, baseline mean cognitive functioning, CD4+, time followed, years of education, and dispersion at the previous visit. Death before the next visit was predicted in a binomial mixed-effects regression model using age, gender, baseline mean cognitive functioning, CD4+, time followed, years of education, and dispersion.ResultsPoint-in-time dispersion and change in dispersion between visits predict future cognitive decline and death in HIV+ individuals. Individuals with greater dispersion at a visit or who had larger changes in dispersion between visits were more likely to demonstrate greater neurocognitive impairment at the subsequent visit. Greater IIV was also associated with an increased risk of death prior to the subsequent visit, even after controlling for HAND severity and global cognitive functioning.ConclusionsWe conclude that the IIV in cognitive functioning may be more predictive of future disease consequence than mean level of cognitive functioning. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

ObjectiveHIV infection and aging are both associated with neurodegeneration. However, whether the aging process alone or other factors associated with advanced age account for the progression of neurodegeneration in the aging HIV-positive (HIV+) population remains unclear.MethodsHIV+ (n = 70) and HIV-negative (HIV-, n = 34) participants underwent diffusion tensor imaging (DTI) and metrics of microstructural properties were extracted from regions of interest (ROIs). A support vector regression model was trained on two independent datasets of healthy adults across the adult life-span (n = 765, Cam-CAN = 588; UiO = 177) to predict participant age from DTI metrics, and applied to the HIV dataset. Predicted brain age gap (BAG) was computed as the difference between predicted age and chronological age, and statistically compared between HIV groups. Regressions assessed the relationship between BAG and HIV severity/medical comorbidities. Finally, correlation analyses tested for associations between BAG and cognitive performance.ResultsBAG was significantly higher in the HIV+ group than the HIV- group F (1, 103) = 12.408, p = .001). HIV RNA viral load was significantly associated with BAG, particularly in older HIV+ individuals (R2  = 0.29, F(7, 70) = 2.66, p = .021). Further, BAG was negatively correlated with domain-level cognitive function (learning: r = -0.26, p = .008; memory: r = -0.21, p = .034).ConclusionsHIV infection is associated with augmented white matter aging, and greater brain aging is associated with worse cognitive performance in multiple domains.

INTRODUCTION:Past studies have shown that a large portion of individuals with Parkinson's disease (PD) and mild cognitive impairment (MCI) will revert to a cognitively intact (CI) status in the future. Aging studies have shown that individuals who revert from MCI to CI are at increased risk for reconverting to MCI or dementia in the future. The current study examined if individuals who revert from PD-mild cognitive impairment (PD-MCI) to CI will be at increased risk for future PD-MCI and Parkinson's disease dementia (PDD). METHOD:The study utilized data from the Parkinson's Progression Markers Initiative (PPMI). The sample included 364 newly diagnosed PD participants who were followed annually for up to 4 years. Based on the first and second assessments, we identified individuals who were CI at each assessment (CI-Stable) and individuals who were PD-MCI at baseline but then reverted to CI (Reversion). Analyses examined if participants in the Reversion group were at greater risk, relative to the CI-Stable group, for cognitive impairment at future assessments. RESULTS:Participants in the Reversion group were at greater risk for future cognitive impairment (PD-MCI or PDD) at the 2nd, 3rd and 4th annual follow-up, relative to the CI-Stable group. The Reversion group continued to be at increased risk for future cognitive impairment when adjusting for age, gender, education, depressive symptoms, and motor severity. CONCLUSION:A large proportion of individuals with PD-MCI will not show evidence of cognitive impairment within a year. However, these "reverters" continue to be at risk for future development of cognitive impairment.

ObjectivesRecent studies suggest that intraindividual variability (IIV) of neuropsychological performance may be sensitive to HIV-associated neurologic compromise. IIV may be particularly dependent upon the integrity of frontal-subcortical systems, and therefore may be a meaningful phenotype in HIV. We examined the relationship between change in IIV and white matter integrity among HIV seropositive (HIV+) and HIV seronegative (HIV-) individuals.MethodThe sample consisted of 38 HIV+ participants and 26 HIV- control participants who underwent neuroimaging and a neuropsychological evaluation at baseline and at 2-year follow-up evaluation.ResultsAmong HIV+ participants, increases in IIV (greater dispersion) were related to lower fractional anisotropy (FA) values in the anterior thalamic radiations (ATR) and the superior longitudinal fasciculus (SLF). Changes in mean-level global cognitive functioning were not significantly related to white matter integrity. Additionally, there was a significant Group × IIV interaction effect in the SLF demonstrating that the relationship between IIV and white matter integrity was specific to HIV.ConclusionsOverall, findings suggest that IIV may be more sensitive, relative to mean-level global cognitive functioning, in the detection of neurologic compromise among HIV+ individuals. (PsycINFO Database Record

The purpose of the current study was to examine the independent and interactive effects of social adversity (SA) and HIV infection on subcortical shape alterations and cognitive functions. Participants included HIV+ (n = 70) and HIV- (n = 23) individuals who underwent MRI, neurocognitive and clinical assessment, in addition to completing questionnaires from which responses were used to create an SA score. Bilateral amygdalae and hippocampi were extracted from T1-weighted images. Parametric statistical analyses were used to compare the radial distance of the structure surface to a median curve to determine the presence of localized shape differences as a function of HIV, SA and their interaction. Next, multiple regression was used to examine the interactive association between HIV and SA with cognitive performance data. An HIV*SA interactive effect was found on the shape of the right amygdala and left hippocampus. Specifically, HIV-infected participants (but not HIV-uninfected controls) who evidenced higher levels of SA displayed an inward deformation of the surface consistent with reduced volume of these structures. We found interactive effects of HIV and SA on learning/memory performance. These results suggest that HIV+ individuals may be more vulnerable to neurological and cognitive changes in the hippocampus and amygdala as a function of SA than HIV- individuals, and that SA indicators of childhood SES and perceived racial discrimination are important components of adversity that are associated with cognitive performance.

Despite recent advances in treatment, hepatitis C remains a significant public health problem. The hepatitis C virus (HCV) is known to infiltrate the brain, yet findings from studies on associated neurocognitive and neuropathological changes are mixed. Furthermore, it remains unclear if HCV eradication improves HCV-associated neurological compromise. This study examined the longitudinal relationship between neurocognitive and neurophysiologic markers among healthy HCV- controls and HCV+ adults following successful HCV eradication. We hypothesized that neurocognitive outcomes following treatment would be related to both improved cognition and white matter integrity. Participants included 57 HCV+ participants who successfully cleared the virus at the end of treatment (sustained virologic responders [SVRs]) and 22 HCV- controls. Participants underwent neuropsychological testing and, for a nested subset of participants, neuroimaging (diffusion tensor imaging) at baseline and 12 weeks following completion of HCV therapy. Contrary to expectation, group-level longitudinal analyses did not reveal significant improvement in neurocognitive performance in the SVRs compared to the control group. However, a subgroup of SVRs demonstrated a significant improvement in cognition relative to controls, which was related to improved white matter integrity. Indeed, neuroimaging data revealed beneficial effects associated with clearing the virus, particularly in the posterior corona radiata and the superior longitudinal fasciculus. Findings suggest that a subgroup of HCV+ patients experienced improvements in cognitive functioning following eradication of HCV, which appears related to positive changes in white matter integrity. Future research should examine whether any additional improvements in neurocognition and white matter integrity among SVRs occur with longer follow-up periods.

Standard volumetric neuroimaging studies have demonstrated preferential atrophy of subcortical structures among individuals with HIV. However, to our knowledge, no study has investigated subcortical shape alterations secondary to HIV and whether advancing age impacts that relationship. This study employed 3D morphometry to examine the independent and interactive effects of HIV and age on shape differences in nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus in 81 participants ranging in age from 24 to 76 including 59 HIV+ individuals and 22 HIV-seronegative controls. T1-weighted MRI underwent a preprocessing pipeline followed by automated subcortical segmentation. Parametric statistical analyses were used to determine independent effects of HIV infection and age on volume and shape in each region of interest (ROI) and the interaction between age and HIV serostatus in predicting volume/shape in each ROI. Significant main effects for HIV were found in the shape of right caudate and nucleus accumbens, left pallidum, and hippocampus. Age was associated with differences in shape in left pallidum, right nucleus accumbens and putamen, and bilateral caudate, hippocampus, and thalamus. Of greatest interest, an age × HIV interaction effect was found in the shape of bilateral nucleus accumbens, amygdala, caudate, and thalamus as well as right pallidum and putamen such that increasing age in HIV participants was associated with greater shape alterations. Traditional volumemetric analyses revealed main effects for both HIV and age but no age × HIV interaction. These findings may suggest that age and HIV infection conferred additional deleterious effects on subcortical shape abnormalities beyond the independent effects of these factors. Hum Brain Mapp 38:1025-1037, 2017. © 2016 Wiley Periodicals, Inc.

IntroductionBrain surgery in the language dominant hemisphere remains challenging due to unintended post-surgical language deficits, despite using pre-surgical functional magnetic resonance (fMRI) and intraoperative cortical stimulation. Moreover, patients are often recommended not to undergo surgery if the accompanying risk to language appears to be too high. While standard fMRI language mapping protocols may have relatively good predictive value at the group level, they remain sub-optimal on an individual level. The standard tests used typically assess lexico-semantic aspects of language, and they do not accurately reflect the complexity of language either in comprehension or production at the sentence level. Among patients who had left hemisphere language dominance we assessed which tests are best at activating language areas in the brain.MethodWe compared grammar tests (items testing word order in actives and passives, wh-subject and object questions, relativized subject and object clauses and past tense marking) with standard tests (object naming, auditory and visual responsive naming), using pre-operative fMRI. Twenty-five surgical candidates (13 females) participated in this study. Sixteen patients presented with a brain tumor, and nine with epilepsy. All participants underwent two pre-operative fMRI protocols: one including CYCLE-N grammar tests (items testing word order in actives and passives, wh-subject and object questions, relativized subject and object clauses and past tense marking); and a second one with standard fMRI tests (object naming, auditory and visual responsive naming). fMRI activations during performance in both protocols were compared at the group level, as well as in individual candidates.ResultsThe grammar tests generated more volume of activation in the left hemisphere (left/right angular gyrus, right anterior/posterior superior temporal gyrus) and identified additional language regions not shown by the standard tests (e.g., left anterior/posterior supramarginal gyrus). The standard tests produced more activation in left BA 47. Ten participants had more robust activations in the left hemisphere in the grammar tests and two in the standard tests. The grammar tests also elicited substantial activations in the right hemisphere and thus turned out to be superior at identifying both right and left hemisphere contribution to language processing.ConclusionThe grammar tests may be an important addition to the standard pre-operative fMRI testing.

The current study examined the independent and combined effects of HIV and marijuana (MJ) use (no use, light use, and moderate-to-heavy use) on neurocognitive functioning among a convenience sample of HIV-positive (HIV+) and HIV-negative (HIV-) individuals recruited from HIV community care clinics and advertisements in the Greater Los Angeles area. MJ users consisted of individuals who reported regular use of MJ for at least 12 months, with last reported use within the past month. Participants included 89 HIV+ (n = 55) and HIV- (n = 34) individuals who were grouped into non-users, light users, and moderate-to-heavy users based on self-reported MJ use. Participants were administered a brief cognitive test battery and underwent laboratory testing for CD4 count and viral load. HIV+ individuals demonstrated lower performance on neurocognitive testing than controls, and moderate-to-heavy MJ users performed more poorly on neurocognitive testing than light users or non-users. Moderate-to-heavy HIV+ users performed significantly lower on learning/memory than HIV- moderate-to-heavy users (MD = -8.34; 95% CI: -16.11 to -0.56) as well as all other comparison groups. In the domain of verbal fluency, HIV+ light users outperformed HIV- light users (MD = 7.28; 95% CI: 1.62-12.39), but no HIV group differences were observed at other MJ use levels. HIV+ MJ users demonstrated lower viral load (MD = -0.58; 95% CI: -1.30 to 0.14) and higher CD4 count than non-users (MD = 137.67; 95% CI: 9.48-265.85). The current study findings extend the literature by demonstrating the complex relationship between HIV status and MJ use on neurocognitive and clinical outcomes.

We examined how two critical constructs, health beliefs and sensation seeking, influence combination antiretroviral therapy adherence in HIV+ African Americans, and whether these factors mediate the association between age and adherence. Two-hundred-and-eighty-six HIV+ African Americans participated in this observational study. Path analyses revealed that higher levels of a specific health belief, perceived utility of treatment, and lower levels of a sensation-seeking component, Thrill and Adventure Seeking, directly predicted optimal adherence. The influence of age on adherence was partially mediated by lower Thrill and Adventure Seeking levels. Depression predicted adherence via perceived utility of treatment and Thrill and Adventure Seeking, whereas current substance abuse and dependence did via Thrill and Adventure Seeking. Poorer neurocognitive function had a direct, adverse effect on adherence. Our findings suggest that supporting the development of more positive perceptions about HIV treatment utility may help increase medication adherence among African Americans. This may be particularly relevant for those with higher levels of depression symptoms, which was directly associated with negative perceptions about treatment. Additionally, clinicians can assess sensation-seeking tendencies to help identify HIV+ African Americans at risk for suboptimal adherence. Compensatory strategies for medication management may help improve adherence among HIV+ individuals with poorer neurocognitive function.

Background: Understanding the structural connectivity of key brainstem nuclei with limbic cortical regions is essential to the development of therapeutic neuromodulation for depression, chronic pain, addiction, anxiety and movement disorders. Several brainstem nuclei have been identified as the primary central nervous system (CNS) source of important monoaminergic ascending fibers including the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, and dopaminergic ventral tegmental area. However, due to practical challenges to their study, there is limited data regarding their in vivo anatomic connectivity in humans. Objective: To evaluate the structural connectivity of the following brainstem nuclei with limbic cortical areas: locus coeruleus, ventral tegmental area, periaqueductal grey, dorsal raphe nucleus, and nucleus tractus solitarius. Additionally, to develop a group average atlas of these limbic brainstem structures to facilitate future analyses. Methods: Each nucleus was manually masked from 197 Human Connectome Project (HCP) structural MRI images using FSL software. Probabilistic tractography was performed using FSL's FMRIB Diffusion Toolbox. Connectivity with limbic cortical regions was calculated and compared between brainstem nuclei. Results were aggregated to produce a freely available MNI structural atlas of limbic brainstem structures. Results: A general trend was observed for a high probability of connectivity to the amygdala, hippocampus and DLPFC with relatively lower connectivity to the orbitofrontal cortex, NAc, hippocampus and insula. The locus coeruleus and nucleus tractus solitarius demonstrated significantly greater connectivity to the DLPFC than amygdala while the periaqueductal grey, dorsal raphe nucleus, and ventral tegmental area did not demonstrate a significant difference between these two structures. Conclusion: Monoaminergic and other modulatory nuclei in the brainstem project widely to cortical limbic regions. We describe the structural connectivity across the several key brainstem nuclei theorized to influence emotion, reward, and cognitive functions. An increased understanding of the anatomic basis of the brainstem's role in emotion and other reward-related processing will support targeted neuromodulatary therapies aimed at alleviating the symptoms of neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]