Case Studies in Neuroscience: The electrophysiology of a human obsession in nucleus accumbens.

Microelectrode recordings were performed during awake deep brain stimulation surgery for obsessive-compulsive disorder, revealing robust brain oscillations that were plainly visible throughout the ventral striatum. There was an elegant topological correspondence between each oscillation and the underlying brain anatomy, most prominently a ~35-Hz gamma-oscillation specific to the nucleus accumbens. Direct provocation of the patient's contamination obsession modulated both firing rate and gamma-oscillation amplitude within the nucleus accumbens. NEW & NOTEWORTHY Surgical implantation of deep brain stimulating electrodes (DBS) to treat obsessive-compulsive disorder (OCD) is an option for patients who have not fully responded to medical intervention or cognitive behavioral therapy. We measured the electrophysiology of a collection of deep brain structures during awake DBS surgery for an OCD patient with an obsession about cleanliness and contamination. The anatomic delineation of these deep brain structures was revealed by distinct brain rhythms, most notably a ~35 Hz oscillation specific to the nucleus accumbens. In the first ever measurement of a human obsessive thought, we found that this ~35-Hz biomarker, as well as the local neuronal action potential rate, were modulated by handing the patient a toothbrush to bring to his face and instructing him to "imagine brushing your teeth with this dirty toothbrush."

Subthalamic neural entropy is a feature of freezing of gait in freely moving people with Parkinson's disease.

The goal of this study was to investigate subthalamic (STN) neural features of Freezers and Non-Freezers with Parkinson's disease (PD), while freely walking without freezing of gait (FOG) and during periods of FOG, which were better elicited during a novel turning and barrier gait task than during forward walking. METHODS: Synchronous STN local field potentials (LFPs), shank angular velocities, and ground reaction forces were measured in fourteen PD subjects (eight Freezers) off medication, OFF deep brain stimulation (DBS), using an investigative, implanted, sensing neurostimulator (Activa® PC+S, Medtronic, Inc.). Tasks included standing still, instrumented forward walking, stepping in place on dual forceplates, and instrumented walking through a turning and barrier course. RESULTS: During locomotion without FOG, Freezers showed lower beta (13-30Hz) power (P=0.036) and greater beta Sample Entropy (P=0.032), than Non-Freezers, as well as greater gait asymmetry and arrhythmicity (P<0.05 for both). No differences in alpha/beta power and/or entropy were evident at rest. During periods of FOG, Freezers showed greater alpha (8-12Hz) Sample Entropy (P<0.001) than during walking without FOG. CONCLUSIONS: A novel turning and barrier course was superior to FW in eliciting FOG. Greater unpredictability in subthalamic beta rhythms was evident during stepping without freezing episodes in Freezers compared to Non-Freezers, whereas greater unpredictability in alpha rhythms was evident in Freezers during FOG. Non-linear analysis of dynamic neural signals during gait in freely moving people with PD may yield greater insight into the pathophysiology of FOG; whether the increases in STN entropy are causative or compensatory remains to be determined. Some beta LFP power may be useful for rhythmic, symmetric gait and DBS parameters, which completely attenuate STN beta power may worsen rather than improve FOG.

Sixty-hertz stimulation improves bradykinesia and amplifies subthalamic low-frequency oscillations.

BACKGROUND: The objective of this study was to investigate the hypothesis that attenuation of subthalamic nucleus (STN) alpha-/beta-band oscillations is causal to improvement in bradykinesia. METHODS: STN local field potentials from a sensing neurostimulator (Activa® PC+S; Medtronic, Inc.) and kinematics from wearable sensors were recorded simultaneously during 60- and 140-Hz deep brain stimulation (DBS) in 9 freely moving PD subjects (15 STNs) performing repetitive wrist flexion-extension. Kinematics were recorded during 20-Hz DBS in a subgroup. RESULTS: Both 60- and 140-Hz DBS improved the angular velocity and frequency of movement (P = 0.002 and P = 0.029, respectively, for 60 Hz; P < 0.001 and P < 0.001, respectively, for 140 Hz), but 60-Hz DBS did not attenuate beta-band power (13-30 Hz). In fact, 60-Hz DBS amplified alpha/low-beta (11-15 Hz, P = 0.007) and attenuated high-beta power (19-27 Hz, P < 0.001), whereas 140-Hz DBS broadly attenuated beta power (15-30 Hz, P < 0.001). Only 60-Hz DBS improved the regularity of angular range (P = 0.046) and 20-Hz DBS did not worsen bradykinesia. There was no correlation between beta-power modulation and bradykinesia. CONCLUSIONS: These novel results obtained from freely moving PD subjects demonstrated that both 140- and 60-Hz DBS improved bradykinesia and attenuated high beta oscillations; however, 60-Hz DBS amplified a subband of alpha/low-beta oscillations, and DBS at a beta-band frequency did not worsen bradykinesia. Based on recent literature, we suggest that both 140- and 60-Hz DBS decouple the cortico-STN hyperdirect pathway, whereas 60-Hz DBS increases coupling within striato-STN circuitry. These results inform future algorithms for closed-loop DBS in PD. © 2016 International Parkinson and Movement Disorder Society.

Sleep disorders in patients with postural tachycardia syndrome.

OBJECTIVE: Patients with postural tachycardia syndrome (POTS) often describe symptoms of fatigue, sleepiness, and lack of refreshing sleep. We aimed to provide further objective measures of sleep in patients with POTS. METHODS: POTS patients (n = 18) were selected based on autonomic testing and evaluation at our center. Controls (n = 16) of similar age, gender, and BMI were selected from new patients referred to the Stanford Sleep Disorders Clinic for any sleep-related complaint. All patients underwent polysomnography and completed several sleep questionnaires and a 2-week sleep diary. RESULTS: POTS patients and control subjects were of similar age (27 ± 10.2 vs. 29 ± 5.4 years, p = 0.92) and Body Mass Index (21 ± 3.8 vs. 24 ± 4.1, p = 0.14). The majority of subjects in both groups were females (72 % POTS vs. 81 % controls). POTS patients scored higher on subjective fatigue scales but not sleepiness scales. POTS patients scored in the normal range on the BDI and the "evening" category on the MEQ. Their sleep diaries were not different from controls. With the exception of mild OSA, slightly reduced %REM and prolonged REM latency, their PSG data were normal and no different from controls. CONCLUSIONS: It is unlikely that the sleep-related complaints of POTS patients are the result of a primary sleep disorder unique to POTS. We propose that a combination of factors such as body fatigue, chronic pain, and other somatic symptoms common in POTS patients might be the underlying reason for sleep-related symptoms in POTS.

Lower urinary tract dysfunction in patients with dysautonomia.

OBJECTIVE: With the goal of better defining the types of bladder dysfunction observed in this population, we present the chief urologic complaints, results of urodynamic studies, and treatments of patients with dysautonomia-related urinary symptoms. METHODS: All patients with dysautonomia referred to our neurourology clinic between 2005 and 2015 for management of lower urinary tract dysfunction were retrospectively reviewed. Each patient's chief urologic complaint was recorded and used to initially characterize the bladder storage or voiding symptoms. Patient evaluation included history and physical examination, urinalysis, post void bladder ultrasound, and urodynamic studies. Successful treatment modalities that subjectively or objectively improved symptoms were recorded. RESULTS: Of 815 patients with the diagnosis of dysautonomia, 82 (10 %) were referred for evaluation of lower urinary tract dysfunction. Mean age was 47 years (range 12-83) and 84 % were female. The chief complaint was urinary urgency ± incontinence in 61 % and hesitancy in 23 % of patients. Urodynamic findings demonstrated detrusor overactivity ± incontinence in 50 % of patients, although chief complaint did not reliably predict objective findings. Successful objective and subjective treatments were multimodal and typically non-operative. INTERPRETATION: Lower urinary tract dysfunction may develop in at least 10 % of patients with dysautonomia, predominantly females. Bladder storage or voiding complaints do not reliably predict urodynamic findings. Urodynamically, most patients exhibited detrusor overactivity. The majority of patients were successfully managed with medical or physical therapy.

Prevention of motion-induced signal loss in diffusion-weighted echo-planar imaging by dynamic restoration of gradient moments.

PURPOSE: Head motion is a significant problem in diffusion-weighted imaging as it may cause signal attenuation due to residual dephasing during strong diffusion encoding gradients even in single-shot acquisitions. Here, we present a new real-time method to prevent motion-induced signal loss in DWI of the brain. METHODS: The method requires a fast motion tracking system (optical in the current implementation). Two alterations were made to a standard diffusion-weighted echo-planar imaging sequence: first, real-time motion correction ensures that slices are correctly aligned relative to the moving brain. Second, the tracking data are used to calculate the motion-induced gradient moment imbalance which occurs during the diffusion encoding periods, and a brief gradient blip is inserted immediately prior to the signal readout to restore the gradient moment balance. RESULTS: Phantom experiments show that the direction as well as magnitude of the gradient moment imbalance affects the characteristics of unwanted signal attenuation. In human subjects, the addition of a moment-restoring blip prevented signal loss and improved the reproducibility and reliability of diffusion tensor measures even in the presence of substantial head movements. CONCLUSION: The method presented can improve robustness for clinical routine scanning in populations that are prone to head movements, such as children and uncooperative adult patients.

Autonomic dysfunction, vasomotor rhinitis, and extraesophageal manifestations of gastroesophageal reflux.

OBJECTIVE: Several recent reports suggest there may be a relationship between chronic rhinitis and extraesophageal manifestations of gastroesophageal reflux (EER). It is hypothesized that this relationship is a result of autonomic nervous system (ANS) dysfunction. STUDY DESIGN: Patients with isolated vasomotor rhinitis (VR), both VR and EER, and a control group were studied by a battery of tests designed to objectively evaluate ANS function. In addition all 3 groups underwent barium esophagogram and 4-site (proximal pharynx, distal pharynx, proximal esophagus, and distal esophagus) ambulatory pH monitoring. Adult patients fulfilling diagnostic criteria for VR, and with both VR and EER underwent objective ANS testing in a recently developed ANS testing laboratory. The control group consisted of age- and sex-matched adults without diagnostic criteria for VR or EER. RESULTS: In patients with VR only (n = 9), 2 patients had a positive esophagogram, whereas a positive pharyngeal reflux probe was found in 1 and an abnormal composite autonomic scoring scale (CASS) was found in 8 (mean VR CASS = 1.750 vs control CASS 0.556, P =.02). The group with VR and EER (n = 12) had a positive esophagogram in 10 patients, positive pharyngeal reflux by probe in 9, and all 12 had an abnormal CASS (mean CASS VR/EER = 2.909 vs CASS control = 0.556, P =.001 and vs VR CASS = 1.750, P =.05). The control patients (n = 9) had normal transesophageal gastroduodenoscopy in 8, 1 had a positive pharyngeal probe study, and all 9 had a normal CASS. In addition ANS testing in patients with diagnostic criteria for both VR/EER revealed statistically significant evidence of an adrenergic deficit as compared with control patients on the basis of mean phase II blood pressure response to Valsalva maneuver (mean phase II VR/EER = -16.730 vs control = -7.780, P =.05). In the VR only group, the phase II blood pressure decrease was greater than in control patients, but did not reach statistical significance (mean phase II VR = -9.370 vs control = -7.780, P = 0.672). CONCLUSION: Patients with VR and VR/EER have objective evidence of ANS dysfunction when compared with a group of age- and sex-matched control patients. Patients with both VR/EER demonstrate a significantly greater degree of ANS dysfunction than patients with isolated VR. The mechanism by which VR and EER interact is not entirely clear, but ANS dysfunction is objectively associated with both disorders. In addition, patients with VR/EER seem to demonstrate hypofunction of the adrenergic component of the ANS, in contrast to the generally held hypothesis that VR results from increased cholinergic activity. Further characterization of the type of ANS abnormality may allow the development of novel pharmacologic therapies for these disorders.

Evaluation of the autonomic nervous system.

This article has reviewed the laboratory evaluation of autonomic disorders. Autonomic testing can be divided into the assessment of three functional domains: sudomotor (assessed best by the thermoregulatory sweat test or QSART), cardiovagal (assessed by the Valsalva ratio and heart rate response to deep breathing or standing up), and adrenergic (assessed by the blood pressure response to the Valsalva maneuver or head-upright tilt). Tables 2 and 3 summarize the test findings in a variety of clinical disorders affecting autonomic nervous system function.

Surface-evoked laryngeal sensory action potential evaluation in neurogenic chronic cough.

OBJECTIVES: Neurogenic chronic cough is currently a diagnosis of exclusion. We hypothesized that surface-evoked laryngeal sensory action potential (SELSAP) testing could be used to help establish a diagnosis of laryngeal sensory neuropathy as a cause of chronic cough, based on altered SELSAP waveform morphology. STUDY DESIGN: Retrospective cohort study. METHODS: Laryngeal electromyographic (EMG) data including SELSAP waveform testing from patients with chronic cough were directly compared with a control population without significant laryngeal symptoms, and statistical analysis of unilateral and bilateral neuropathy injury subgroups was performed. RESULTS: Thirty patients with a chief complaint of chronic cough underwent laryngeal EMG testing since January 2000 with needle EMG and surface nerve conduction studies. SELSAP waveform analysis of unilateral and bilateral laryngeal neuropathy demonstrated significantly lowered median SELSAP peak amplitude compared with controls (P < 0.01). CONCLUSIONS: Patients with suspected neurogenic chronic cough demonstrate statistically significant alterations in SELSAP waveform that can support a diagnosis of laryngeal sensory neuropathy.

Measurement and correction of microscopic head motion during magnetic resonance imaging of the brain.

Magnetic resonance imaging (MRI) is a widely used method for non-invasive study of the structure and function of the human brain. Increasing magnetic field strengths enable higher resolution imaging; however, long scan times and high motion sensitivity mean that image quality is often limited by the involuntary motion of the subject. Prospective motion correction is a technique that addresses this problem by tracking head motion and continuously updating the imaging pulse sequence, locking the imaging volume position and orientation relative to the moving brain. The accuracy and precision of current MR-compatible tracking systems and navigator methods allows the quantification and correction of large-scale motion, but not the correction of very small involuntary movements in six degrees of freedom. In this work, we present an MR-compatible tracking system comprising a single camera and a single 15 mm marker that provides tracking precision in the order of 10 m and 0.01 degrees. We show preliminary results, which indicate that when used for prospective motion correction, the system enables improvement in image quality at both 3 T and 7 T, even in experienced and cooperative subjects trained to remain motionless during imaging. We also report direct observation and quantification of the mechanical ballistocardiogram (BCG) during simultaneous MR imaging. This is particularly apparent in the head-feet direction, with a peak-to-peak displacement of 140 m.

A new noninvasive method for determination of laryngeal sensory function.

OBJECTIVES/HYPOTHESIS: We report a new surface technique for studying sensory conduction in the superior laryngeal nerve (SLN). STUDY DESIGN: Prospective controlled cohort study at an academic tertiary care hospital. METHODS: Surface stimulation of the vagus nerve 7-10 cm proximal to a surface electrode placed over the cricothyroid muscle was performed in controls and in subjects with needle electromyographic-confirmed laryngeal neuropathy. Cathodal stimulation was applied below the mastoid process behind the sternocleidomastoid muscle. Nerve conduction parameters were determined. RESULTS: Noninvasive SLN evoked potential studies were performed on healthy volunteers (n = 28) as well as neuropathic subjects (n = 27). Compared to controls, the neuropathic subjects had statistically significant differences in baseline-to-peak amplitude, conduction velocity, and intrasubject side-to-side amplitude ratio (P <.01) of their surface evoked laryngeal sensory action potential (SELSAP). CONCLUSIONS: Laryngeal sensory nerve conduction can be determined noninvasively by evaluating SELSAP waveform. This study provides a reproducible method for electrophysiologic evaluation of a sensory branch of the SLN.

Simultaneous ERP and fMRI of the auditory cortex in a passive oddball paradigm.

Infrequent occurrences of a deviant sound within a sequence of repetitive standard sounds elicit the automatic mismatch negativity (MMN) event-related potential (ERP). The main MMN generators are located in the superior temporal cortex, but their number, precise location, and temporal sequence of activation remain unclear. In this study, ERP and functional magnetic resonance imaging (fMRI) data were obtained simultaneously during a passive frequency oddball paradigm. There were three conditions, a STANDARD, a SMALL deviant, and a LARGE deviant. A clustered image acquisition technique was applied to prevent contamination of the fMRI data by the acoustic noise of the scanner and to limit contamination of the electroencephalogram (EEG) by the gradient-switching artifact. The ERP data were used to identify areas in which the blood oxygenation (BOLD) signal varied with the magnitude of the negativity in each condition. A significant ERP MMN was obtained, with larger peaks to LARGE deviants and with frontocentral scalp distribution, consistent with the MMN reported outside the magnetic field. This result validates the experimental procedures for simultaneous ERP/fMRI of the auditory cortex. Main foci of increased BOLD signal were observed in the right superior temporal gyrus [STG; Brodmann area (BA) 22] and right superior temporal plane (STP; BA 41 and 42). The imaging results provide new information supporting the idea that generators in the right lateral aspect of the STG are implicated in processes of frequency deviant detection, in addition to generators in the right and left STP.