Transient increased thalamic-sensory connectivity and decreased whole-brain dynamism in autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with social communication deficits and restricted/repetitive behaviors and is characterized by large-scale atypical subcortical-cortical connectivity, including impaired resting-state functional connectivity between thalamic and sensory regions. Previous studies have typically focused on the abnormal static connectivity in ASD and overlooked potential valuable dynamic patterns in brain connectivity. However, resting-state brain connectivity is indeed highly dynamic, and abnormalities in dynamic brain connectivity have been widely identified in psychiatric disorders. In this study, we investigated the dynamic functional network connectivity (dFNC) between 51 intrinsic connectivity networks in 170 individuals with ASD and 195 age-matched typically developing (TD) controls using independent component analysis and a sliding window approach. A hard clustering state analysis and a fuzzy meta-state analysis were conducted respectively, for the exploration of local and global aberrant dynamic connectivity patterns in ASD. We examined the group difference in dFNC between thalamic and sensory networks in each functional state and group differences in four high-dimensional dynamic measures. The results showed that compared with TD controls, individuals with ASD show an increase in transient connectivity between hypothalamus/subthalamus and some sensory networks (right postcentral gyrus, bi paracentral lobule, and lingual gyrus) in certain functional states, and diminished global meta-state dynamics of the whole-brain functional network. In addition, these atypical dynamic patterns are significantly associated with autistic symptoms indexed by the Autism Diagnostic Observation Schedule. These converging results support and extend previous observations regarding hyperconnectivity between thalamic and sensory regions and stable whole-brain functional configuration in ASD. Dynamic brain connectivity may serve as a potential biomarker of ASD and further investigation of these dynamic patterns might help to advance our understanding of behavioral differences in this complex neurodevelopmental disorder.

Biophysical basis of subthalamic local field potentials recorded from deep brain stimulation electrodes.

Clinical deep brain stimulation (DBS) technology is evolving to enable chronic recording of local field potentials (LFPs) that represent electrophysiological biomarkers of the underlying disease state. However, little is known about the biophysical basis of LFPs, or how the patient's unique brain anatomy and electrode placement impact the recordings. Therefore, we developed a patient-specific computational framework to analyze LFP recordings within a clinical DBS context. We selected a subject with Parkinson's disease implanted with a Medtronic Activa PC+S DBS system and reconstructed their subthalamic nucleus (STN) and DBS electrode location using medical imaging data. The patient-specific STN volume was populated with 235,280 multicompartment STN neuron models, providing a neuron density consistent with histological measurements. Each neuron received time-varying synaptic inputs and generated transmembrane currents that gave rise to the LFP signal recorded at DBS electrode contacts residing in a finite element volume conductor model. We then used the model to study the role of synchronous beta-band inputs to the STN neurons on the recorded power spectrum. Three bipolar pairs of simultaneous clinical LFP recordings were used in combination with an optimization algorithm to customize the neural activity parameters in the model to the patient. The optimized model predicted a 2.4-mm radius of beta-synchronous neurons located in the dorsolateral STN. These theoretical results enable biophysical dissection of the LFP signal at the cellular level with direct comparison to the clinical recordings, and the model system provides a scientific platform to help guide the design of DBS technology focused on the use of subthalamic beta activity in closed-loop algorithms. NEW & NOTEWORTHY The analysis of deep brain stimulation of local field potential (LFP) data is rapidly expanding from scientific curiosity to the basis for clinical biomarkers capable of improving the therapeutic efficacy of stimulation. With this growing clinical importance comes a growing need to understand the underlying electrophysiological fundamentals of the signals and the factors contributing to their modulation. Our model reconstructs the clinical LFP from first principles and highlights the importance of patient-specific factors in dictating the signals recorded.

Long-Term Results of Deep Brain Stimulation of the Mamillotegmental Fasciculus in Chronic Cluster Headache.

BACKGROUND: Deep brain stimulation (DBS) and the proper target for chronic cluster headache (CCH) are still subjects of controversy. OBJECTIVES: We present our long-term results of analysis of the target and its structural connectivity. METHODS: Fifteen patients with drug-resistant CCH underwent DBS in coordinates 4 mm lateral to the III ventricular wall and 2 mm behind and 5 mm below the intercommissural point. The clinical parameters recorded were the number of weekly attacks, pain intensity, and duration of the headache. Structural connectivity was studied using 3-T MR diffusion tensor imaging (DTI). RESULTS: All of our patients improved from a mean of 39 attacks/week to 2; pain intensity decreased from 9 to 3 out of 10, and the mean cephalalgia duration decreased from 53 to 8 min. The mean stereotactic coordinates of the effective contact location were 6.1 mm lateral to the midcommissural point and 1.2 mm behind and 4.0 mm below the intercommissural point. DTI analysis showed that this target was connected to tracts and nuclei of the posterior mesencephalic tegmentum, specifically the dorsal longitudinal and mamillotegmental fasciculi. CONCLUSIONS: Our data showed DBS to be a safe and useful procedure for the treatment of drug-resistant CCH; the rate of improvement was higher than those found in other series. Although these are promising results, larger series targeting those fasciculi with a longer follow-up are needed.

Somnolence Preceded the Development of a Subthalamic Lesion in Neuromyelitis Optica Spectrum Disorder.

A 67-year-old woman with neuromyelitis optica spectrum disorder (NMOSD) developed severe somnolence. Ten days after admission, fluid-attenuated inversion-recovery magnetic resonance imaging (MRI) revealed hyperintense areas around the bilateral hypothalamus, which were not present on MRI at admission. The orexin level, which is decreased in idiopathic narcolepsy, was slightly decreased in her cerebrospinal fluid. Immunosuppressive treatment and methylphenidate markedly improved her somnolence. This case shows that NMOSD in the acute phase can cause somnolence in a patient without apparent lesions in the hypothalamus.

Microstructural Injury to Left-Sided Perisylvian White Matter Predicts Language Decline After Brain Radiation Therapy.

PURPOSE: Our purpose was to investigate the association between imaging biomarkers of radiation-induced white matter (WM) injury within perisylvian regions and longitudinal language decline in patients with brain tumors. METHODS AND MATERIALS: Patients with primary brain tumors (n = 44) on a prospective trial underwent brain magnetic resonance imaging, diffusion-weighted imaging, and language assessments of naming (Boston Naming Test [BNT]) and fluency (Delis-Kaplan Executive Function System Category Fluency [DKEFS-CF]) at baseline and 3, 6, and 12 months after fractionated radiation therapy (RT). Reliable change indices of language function (0-6 months), accounting for practice effects (RCI-PE), evaluated decline. Bilateral perisylvian WM regions (superficial WM subadjacent to Broca's area and the superior temporal gyrus [STG], inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus [IFOF], and arcuate fasciculus) were autosegmented. We quantified volume and diffusion measures of WM microstructure: fractional anisotropy (FA; lower values indicate disruption) and mean diffusivity (MD; higher values indicate injury). Linear mixed-effects models assessed mean dose as predictor of imaging biomarker change and imaging biomarkers as longitudinal predictors of language scores. RESULTS: DKEFS-CF scores declined at 6 months post-RT (RCI-PE, -0.483; P = .01), whereas BNT scores improved (RCI-PE, 0.262; P = .04). Higher mean dose to left and right regions was predictive of decreased volume (left-STG, P = .02; right-ILF and IFOF, P = .03), decreased FA (left-WM tracts, all P < .01; right-STG and IFOF, P < .02), and increased MD of left-WM tracts (all P < .03). Volume loss within left-Broca's area (P = .01), left-ILF (P = .01), left-IFOF (P = .01), and left-arcuate fasciculus (P = .04) was associated with lower BNT scores. Lower FA correlated with poorer DKEFS-CF and BNT scores within left-ILF (P = .02, not significant), left-IFOF (P = .02, .04), and left-arcuate fasciculus (P = .01, .01), respectively. Poorer DKEFS-CF scores correlated with increased MD values within the left-arcuate fasciculus (P = .03). Right-sided biomarkers did not correlate with language scores. CONCLUSIONS: Patients with primary brain tumors experience language fluency decline post-RT. Poorer fluency and naming function may be explained by microstructural injury to left-sided perisylvian WM, representing potential dose-avoidance targets for language preservation.

Free-water metrics in medial temporal lobe white matter tract projections relate to longitudinal cognitive decline.

Although hippocampal volume has served as a long-standing predictor of cognitive decline, diffusion magnetic resonance imaging studies of white matter have shown similar relationships. Still, it remains unclear if gray matter and white matter interact to predict cognitive impairment and longitudinal decline. Here, we investigate whether free-water (FW) and FW-corrected fractional anisotropy (FAT) within medial temporal lobe white matter tracts provides meaningful contribution to cognition and cognitive decline beyond hippocampal volume. Using data from the Vanderbilt Memory & Aging Project (n = 319), we found that FW was associated with baseline memory and executive function beyond that of hippocampal volume and other comorbidities. Longitudinal analyses demonstrated significant interactions of hippocampal volume and inferior longitudinal fasciculus (p = 0.043) and cingulum bundle (p = 0.025) FAT on memory decline and with fornix FAT (p = 0.025) on decline in executive function. Results suggest that FW metrics of white matter have a unique role in cognitive decline and should be included in theoretical models of aging, cerebrovascular disease, and Alzheimer's disease.

Subthalamic deep brain stimulation in patients with primary dystonia: A ten-year follow-up study.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) is a promising intervention for primary dystonia; however, evidence regarding its efficacy is lacking. Thus, a long-term follow-up is indispensable. OBJECTIVE: This trial was designed to examine the efficacy and consistency of subthalamic deep brain stimulation in patients with primary dystonia over the long term. METHOD: This was a retrospective study involving 14 patients with primary dystonia who underwent STN-DBS and consented to a follow-up of at least 10 years. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and 36-item Short-Form General Health Survey were employed, at five time points (pre-operation [baseline], 1 month post-operation, 1 year post-operation, 5 years post-operation, and last follow-up), to assess improvement of dystonic symptoms and changes in quality of life. OUTCOMES: All patients gained extensive clinical benefits from STN-DBS therapy, without experiencing serious adverse effects. Improvements of 59.0% at 1 month, 85.0% at 1 year, and 90.8% at 5 years after the operation, and up to 91.4% at the last follow-up, were demonstrated by movement evaluation with the BFMDRS. All patients achieved a substantial improvement in quality of life. CONCLUSION: Subthalamic deep brain stimulation is an effective and persisting alternative to pallidal deep brain stimulation, and importantly, it is very safe even with extremely long-term chronic stimulation.

Evolving metabolic changes during the first postoperative year after subthalamotomy.

OBJECT: Short-term benefit from unilateral subthalamotomy for advanced Parkinson disease (PD) is associated with metabolic alterations in key targets of subthalamic nucleus (STN) and globus pallidus (GP) output. In this study positron emission tomography (PET) scanning was used to assess these changes and their relation to long-term benefits of subthalamotomy. METHODS: To determine whether the early postoperative changes persisted at longer-term follow up, the authors assessed six patients with advanced PD by using [18F]fluorodeoxyglucose-PET at 3 and 12 months postsurgery. The authors compared each of the postoperative images with baseline studies, and assessed interval changes between the short- and long-term follow-up scans. Clinical improvement at 3 and 12 months was associated with sustained metabolic decreases in the midbrain GP internus (GPi), thalamus, and pons of the lesioned side (p < 0.01). The activity of a PD-related multiregional brain network, which correlated with bradykinesia and rigidity, was reduced at both postoperative time points (p < 0.05). Comparisons of 3- and 12-month images revealed a relative metabolic increase in the GP externus (GPe) (p < 0.001), which was associated with worsening gait, postural stability, and tremor at long-term follow up. CONCLUSIONS: These findings indicate that subthalamotomy may have differential effects on each of the functional pathways that mediate parkinsonian symptomatology. Sustained relief of akinesia and rigidity is associated with suppression of a pathological network involving the GPi and its output. In contrast, the recurrence of tremor may relate to changes in the function of an STN-GPe oscillatory network.

Individual fiber anatomy of the subthalamic region revealed with diffusion tensor imaging: a concept to identify the deep brain stimulation target for tremor suppression.

BACKGROUND: Deep brain stimulation (DBS) has been proven to alleviate tremor of various origins. Distinct regions have been targeted. One explanation for good clinical tremor control might be the involvement of the dentatorubrothalamic tract (DRT) as has been suggested in superficial (thalamic) and inferior (posterior subthalamic) target regions. Beyond a correlation with atlas data and the postmortem evaluation of patients treated with lesion surgery, proof for the involvement of DRT in tremor reduction in the living, the scope of this work, is elusive. OBJECTIVE: To report a case of unilateral refractory tremor in tremor-dominant Parkinson disease treated with thalamic DBS. METHODS: Preoperative diffusion tensor imaging (DTI) was performed. Correlation with individual DBS electrode contact locations was obtained through postoperative fusion of helical computed tomography (CT) data with DTI fiber tracking. RESULTS: Tremor was alleviated effectively. An evaluation of the active electrode contact position revealed clear involvement of the DRT in tremor control. A closer evaluation of clinical effects and side effects revealed a highly detailed individual fiber map of the subthalamic region with DTI fiber tracking. CONCLUSION: This is the first time the involvement of the DRT in tremor reduction through DBS has been shown in the living. The combination of DTI with postoperative CT and the evaluation of the electrophysiological environment of distinct electrode contacts led to an individual detailed fiber map and might be extrapolated to refined DTI-based targeting strategies in the future. Data acquisition for a larger study group is the topic of our ongoing research.