A roadmap for implanting microelectrode arrays to evoke tactile sensations through intracortical microstimulation.

Intracortical microstimulation (ICMS) is a method for restoring sensation to people with paralysis as part of a bidirectional brain-computer interface to restore upper limb function. Evoking tactile sensations of the hand through ICMS requires precise targeting of implanted electrodes. Here we describe the presurgical imaging procedures used to generate functional maps of the hand area of the somatosensory cortex and subsequent planning that guided the implantation of intracortical microelectrode arrays. In five participants with cervical spinal cord injury, across two study locations, this procedure successfully enabled ICMS-evoked sensations localized to at least the first four digits of the hand. The imaging and planning procedures developed through this clinical trial provide a roadmap for other brain-computer interface studies to ensure successful placement of stimulation electrodes.

Microstimulation of human somatosensory cortex evokes task-dependent, spatially patterned responses in motor cortex.

The primary motor (M1) and somatosensory (S1) cortices play critical roles in motor control but the signaling between these structures is poorly understood. To fill this gap, we recorded - in three participants in an ongoing human clinical trial (NCT01894802) for people with paralyzed hands - the responses evoked in the hand and arm representations of M1 during intracortical microstimulation (ICMS) in the hand representation of S1. We found that ICMS of S1 activated some M1 neurons at short, fixed latencies consistent with monosynaptic activation. Additionally, most of the ICMS-evoked responses in M1 were more variable in time, suggesting indirect effects of stimulation. The spatial pattern of M1 activation varied systematically: S1 electrodes that elicited percepts in a finger preferentially activated M1 neurons excited during that finger's movement. Moreover, the indirect effects of S1 ICMS on M1 were context dependent, such that the magnitude and even sign relative to baseline varied across tasks. We tested the implications of these effects for brain-control of a virtual hand, in which ICMS conveyed tactile feedback. While ICMS-evoked activation of M1 disrupted decoder performance, this disruption was minimized using biomimetic stimulation, which emphasizes contact transients at the onset and offset of grasp, and reduces sustained stimulation.

Tessellation of artificial touch via microstimulation of human somatosensory cortex.

When we interact with objects, we rely on signals from the hand that convey information about the object and our interaction with it. A basic feature of these interactions, the locations of contacts between the hand and object, is often only available via the sense of touch. Information about locations of contact between a brain-controlled bionic hand and an object can be signaled via intracortical microstimulation (ICMS) of somatosensory cortex (S1), which evokes touch sensations that are localized to a specific patch of skin. To provide intuitive location information, tactile sensors on the robotic hand drive ICMS through electrodes that evoke sensations at skin locations matching sensor locations. This approach requires that ICMS-evoked sensations be focal, stable, and distributed over the hand. To systematically investigate the localization of ICMS-evoked sensations, we analyzed the projected fields (PFs) of ICMS-evoked sensations - their location and spatial extent - from reports obtained over multiple years from three participants implanted with microelectrode arrays in S1. First, we found that PFs vary widely in their size across electrodes, are highly stable within electrode, are distributed over large swaths of each participant's hand, and increase in size as the amplitude or frequency of ICMS increases. Second, while PF locations match the locations of the receptive fields (RFs) of the neurons near the stimulating electrode, PFs tend to be subsumed by the corresponding RFs. Third, multi-channel stimulation gives rise to a PF that reflects the conjunction of the PFs of the component channels. By stimulating through electrodes with largely overlapping PFs, then, we can evoke a sensation that is experienced primarily at the intersection of the component PFs. To assess the functional consequence of this phenomenon, we implemented multichannel ICMS-based feedback in a bionic hand and demonstrated that the resulting sensations are more localizable than are those evoked via single-channel ICMS.

Ambulatory Local Field Potential Recordings from the Thalamus in Epilepsy: A Feasibility Study.

INTRODUCTION: Stimulation of the thalamus is gaining favor in the treatment of medically refractory multifocal and generalized epilepsy. Implanted brain stimulators capable of recording ambulatory local field potentials (LFPs) have recently been introduced, but there is little information to guide their use in thalamic stimulation for epilepsy. This study sought to assess the feasibility of chronically recording ambulatory interictal LFP from the thalamus in patients with epilepsy. METHODS: In this pilot study, ambulatory LFP was recorded from patients who underwent sensing-enabled deep brain stimulation (DBS, 2 participants) or responsive neurostimulation (RNS, 3 participants) targeting the anterior nucleus of the thalamus (ANT, 2 electrodes), centromedian nucleus (CM, 7 electrodes), or medial pulvinar (PuM, 1 electrode) for multifocal or generalized epilepsy. Time-domain and frequency-domain LFP was investigated for epileptiform discharges, spectral peaks, circadian variation, and peri-ictal patterns. RESULTS: Thalamic interictal discharges were visible on ambulatory recordings from both DBS and RNS. At-home interictal frequency-domain data could be extracted from both devices. Spectral peaks were noted at 10-15 Hz in CM, 6-11 Hz in ANT, and 19-24 Hz in PuM but varied in prominence and were not visible in all electrodes. In CM, 10-15 Hz power exhibited circadian variation and was attenuated by eye opening. CONCLUSION: Chronic ambulatory recording of thalamic LFP is feasible. Common spectral peaks can be observed but vary between electrodes and across neural states. DBS and RNS devices provide a wealth of complementary data that have the potential to better inform thalamic stimulation for epilepsy.

Biomimetic multi-channel microstimulation of somatosensory cortex conveys high resolution force feedback for bionic hands.

Manual interactions with objects are supported by tactile signals from the hand. This tactile feedback can be restored in brain-controlled bionic hands via intracortical microstimulation (ICMS) of somatosensory cortex (S1). In ICMS-based tactile feedback, contact force can be signaled by modulating the stimulation intensity based on the output of force sensors on the bionic hand, which in turn modulates the perceived magnitude of the sensation. In the present study, we gauged the dynamic range and precision of ICMS-based force feedback in three human participants implanted with arrays of microelectrodes in S1. To this end, we measured the increases in sensation magnitude resulting from increases in ICMS amplitude and participant's ability to distinguish between different intensity levels. We then assessed whether we could improve the fidelity of this feedback by implementing "biomimetic" ICMS-trains, designed to evoke patterns of neuronal activity that more closely mimic those in natural touch, and by delivering ICMS through multiple channels at once. We found that multi-channel biomimetic ICMS gives rise to stronger and more distinguishable sensations than does its single-channel counterpart. Finally, we implemented biomimetic multi-channel feedback in a bionic hand and had the participant perform a compliance discrimination task. We found that biomimetic multi-channel tactile feedback yielded improved discrimination over its single-channel linear counterpart. We conclude that multi-channel biomimetic ICMS conveys finely graded force feedback that more closely approximates the sensitivity conferred by natural touch.

Tailored Hemispherotomy Using Tractography-Guided Laser Interstitial Thermal Therapy.

BACKGROUND: Medically refractory hemispheric epilepsy is a devastating disease with significant lifetime costs and social burden. Functional hemispherotomy is a highly effective treatment for hemispheric epilepsy but is associated with significant complication rates. Percutaneous hemispherotomy through laser interstitial thermal therapy (LITT) based on morphological MRI has been recently described in a single patient but not replicated in the literature. OBJECTIVE: To describe the first 2 cases of tractography-guided interstitial laser hemispherotomy and their short-term outcomes. METHODS: Two 11-year-old male patients with medically refractory epilepsy secondary to perinatal large vessel infarcts were referred for hemispherotomy. Both patients underwent multitrajectory LITT to disconnect the remaining pathological hemisphere, using tractography to define targets and assess structural outcomes. RESULTS: Both cases had minor complication of small intraventricular/subarachnoid hemorrhage not requiring additional intervention. Both patients remain seizure-free at all follow-up visits. CONCLUSION: LITT hemispherotomy can produce seizure freedom with short hospitalization and recovery. Tractography allows surgical planning to be tailored according to individual patient anatomy, which often is distorted in perinatal stroke. Minimally invasive procedures offer the greatest potential for seizure freedom without the risks of an open hemispherotomy.

Source localization of ictal SEEG to predict postoperative seizure outcome.

OBJECTIVE: Stereo-electroencephalography (SEEG) is inherently-three-dimensional and can be modeled using source localization. This study aimed to assess the validity of ictal SEEG source localization. METHODS: The dominant frequency at ictal onset was used for source localization in the time and frequency domains using rotating dipoles and current density maps. Validity was assessed by concordance with the epileptologist-defined seizure onset zone (conventional SOZ) and the surgical treatment volume (TV) of seizure-free versus non-seizure-free patients. RESULTS: Source localization was performed on 68 seizures from 27 patients. Median distance to nearest contact in the conventional SOZ was 7 (IQR 6-12) mm for time-domain dipoles. Current density predicted ictal activity with up to 86 % (60-87 %) accuracy. Distance from time-domain dipoles to the TV was smaller (P = 0.045) in seizure-free (2 [0-4] mm) versus non-seizure-free (12 [2-17] mm) patients, and predicted surgical outcome with 91 % sensitivity and 63 % specificity. Removing near-field data from contacts within the TV negated outcome prediction (P = 0.51). CONCLUSIONS: Source localization of SEEG accurately mapped ictal onset compared with conventional interpretation. Proximity of dipoles to the TV predicted seizure outcome when near-field recordings were analyzed. SIGNIFICANCE: Ictal SEEG source localization is useful in corroborating the epileptogenic zone, assuming near-field recordings are obtained.

SEEG in 3D: Interictal Source Localization From Intracerebral Recordings.

BACKGROUND: Stereo-electroencephalography (SEEG) uses a three-dimensional configuration of depth electrodes to localize epileptiform activity, but traditional analysis of SEEG is spatially restricted to the point locations of the electrode contacts. Interpolation of brain activity between contacts might allow for three-dimensional representation of epileptiform activity and avoid pitfalls of SEEG interpretation. OBJECTIVE: The goal of this study was to validate SEEG-based interictal source localization and assess the ability of this technique to monitor far-field activity in non-implanted brain regions. METHODS: Interictal epileptiform discharges were identified on SEEG in 26 patients who underwent resection, ablation, or disconnection of the suspected epileptogenic zone. Dipoles without (free) and with (scan) gray matter restriction, and current density (sLORETA and SWARM methods), were calculated using a finite element head model. Source localization results were compared to the conventional irritative zone (IZ) and the surgical treatment volumes (TV) of seizure-free vs. non-seizure-free patients. RESULTS: The median distance from dipole solutions to the nearest contact in the conventional IZ was 7 mm (interquartile range 4-15 mm for free dipoles and 4-14 mm for scan dipoles). The IZ modeled with SWARM predicted contacts within the conventional IZ with 83% (75-100%) sensitivity and 94% (88-100%) specificity. The proportion of current within the TV was greater in seizure-free patients (P = 0.04) and predicted surgical outcome with 45% sensitivity and 93% specificity. Dipole solutions and sLORETA results did not correlate with seizure outcome. Addition of scalp EEG led to more superficial modeled sources (P = 0.03) and negated the ability to predict seizure outcome (P = 0.23). Removal of near-field data from contacts within the TV resulted in smearing of the current distribution (P = 0.007) and precluded prediction of seizure freedom (P = 0.20). CONCLUSIONS: Source localization accurately represented interictal discharges from SEEG. The proportion of current within the TV distinguished between seizure-free and non-seizure-free patients when near-field recordings were obtained from the surgical target. The high prevalence of deep sources in this cohort likely obscured any benefit of concurrent scalp EEG. SEEG-based interictal source localization is useful in illustrating and corroborating the epileptogenic zone. Additional techniques are needed to localize far-field epileptiform activity from non-implanted brain regions.

Interstitial laser anterior capsulotomy for obsessive-compulsive disorder: lesion size and tractography correlate with outcome.

BACKGROUND: Anterior capsulotomy is a well-established treatment for refractory obsessive-compulsive disorder (OCD). MRI-guided laser interstitial thermal therapy (LITT) allows creation of large, sharply demarcated lesions with the safeguard of real-time imaging. OBJECTIVE: To characterise the outcomes of laser anterior capsulotomy, including radiographical predictors of improvement. METHODS: Patients with severe OCD refractory to pharmacotherapy and cognitive-behavioural therapy underwent bilateral anterior capsulotomy via LITT. The primary outcome was per cent reduction in Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score over time. Lesion size was measured on postablation MRI. Disconnection of the anterior limb of the internal capsule (ALIC) was assessed via individual and normative tractography. RESULTS: Eighteen patients underwent laser anterior capsulotomy. Median follow-up was 6 months (range 3-51 months). Time occupied by obsessions improved immediately (median Y-BOCS item 1 score 4-1, p=0.002). Mean (±SD) decrease in Y-BOCS score at last follow-up was 46%±32% (16±11 points, p<0.0001). Sixty-one per cent of patients were responders. Seven patients (39%) exhibited transient postoperative apathy. One patient had an asymptomatic intracerebral haemorrhage. Reduction in Y-BOCS score was positively associated with ablation volume (p=0.006). Individual tractography demonstrated durable ALIC disconnection. Normative tractography revealed a dorsal-ventral gradient, with disconnection of orbitofrontal streamlines most strongly associated with a positive response (p<0.0001). CONCLUSIONS: Laser anterior capsulotomy resulted in immediate, marked improvement in OCD symptom severity. Larger lesions permit greater disconnection of prefrontal-subcortical pathways involved in OCD. The importance of greater disconnection is presumably related to variation in ALIC structure and the complex role of the PFC in OCD.

Extent of parahippocampal ablation is associated with seizure freedom after laser amygdalohippocampotomy.

OBJECTIVE: The authors aimed to examine the relationship between mesial temporal subregion ablation volume and seizure outcome in a diverse cohort of patients who underwent stereotactic laser amygdalohippocampotomy (SLAH) for mesial temporal lobe epilepsy (MTLE). METHODS: Seizure outcomes and pre- and postoperative images were retrospectively reviewed in patients with MTLE who underwent SLAH at a single institution. Mesial temporal subregions and the contrast-enhancing ablation volume were manually segmented. Pre- and postoperative MR images were coregistered to assess anatomical ablation. Postoperative MRI and ablation volumes were also spatially normalized, enabling the assessment of seizure outcome with heat maps. RESULTS: Twenty-eight patients with MTLE underwent SLAH, 15 of whom had mesial temporal sclerosis (MTS). The rate of Engel class I outcome at 1 year after SLAH was 39% overall: 47% in patients with MTS and 31% in patients without MTS. The percentage of parahippocampal gyrus (PHG) ablated was higher in patients with an Engel class I outcome (40% vs 25%, p = 0.04). Subregion analysis revealed that extent of ablation in the parahippocampal cortex (35% vs 19%, p = 0.03) and angular bundle (64% vs 43%, p = 0.02) was positively associated with Engel class I outcome. The degree of amygdalohippocampal complex (AHC) ablated was not associated with seizure outcome (p = 0.30). CONCLUSIONS: Although the AHC was the described target of SLAH, seizure outcome in this cohort was associated with degree of ablation for the PHG, not the AHC. Complete coverage of both the AHC and PHG is technically challenging, and more work is needed to optimize seizure outcome after SLAH.

Surgical Outcomes and EEG Prognostic Factors After Stereotactic Laser Amygdalohippocampectomy for Mesial Temporal Lobe Epilepsy.

Objective: To assess the seizure outcomes of stereotactic laser amygdalohippocampectomy (SLAH) in consecutive patients with mesial temporal lobe epilepsy (mTLE) in a single center and identify scalp EEG and imaging factors in the presurgical evaluation that correlate with post-surgical seizure recurrence. Methods: We retrospectively reviewed the medical and EEG records of 30 patients with drug-resistant mTLE who underwent SLAH and had at least 1 year of follow-up. Surgical outcomes were classified using the Engel scale. Univariate hazard ratios were used to evaluate the risk factors associated with seizure recurrence after SLAH. Results: The overall Engel class I outcome after SLAH was 13/30 (43%), with a mean postoperative follow-up of 48.9 ± 17.6 months. Scalp EEG findings of interictal regional slow activity (IRSA) on the side of surgery (HR = 4.05, p = 0.005) and non-lateralizing or contra-lateralizing seizure onset (HR = 4.31, p = 0.006) were negatively correlated with postsurgical seizure freedom. Scalp EEG with either one of the above features strongly predicted seizure recurrence after surgery (HR = 7.13, p < 0.001) with 100% sensitivity and 71% specificity. Significance: Understanding the factors associated with good or poor surgical outcomes can help choose the best candidates for SLAH. Of the variables assessed, scalp EEG findings were the most clearly associated with seizure outcomes after SLAH.

Effect of Deep Brain Stimulation on Cerebellar Tremor Compared to Non-Cerebellar Tremor Using a Wearable Device in a Patient With Multiple Sclerosis: Case Report.

Tremor of the upper extremity is a significant cause of disability in some patients with multiple sclerosis (MS). The MS tremor is complex because it contains an ataxic intentional tremor component due to the involvement of the cerebellum and cerebellar outflow pathways by MS plaques, which makes the MS tremor, in general, less responsive to medications or deep brain stimulation (DBS) than those associated with essential tremor or Parkinson's disease. The cerebellar component has been thought to be the main reason for making DBS less effective, although it is not clear whether it is due to the lack of suppression of the ataxic tremor by DBS or else. The goal of this study was to clarify the effect of DBS on cerebellar tremor compared to non-cerebellar tremor in a patient with MS. By wearing an accelerometer on the index finger of each hand, we were able to quantitatively characterize kinetic tremor by frequency and amplitude, with cerebellar ataxia component on one hand and that without cerebellar component on the other hand, at the beginning and end of the hand movement approaching a target at DBS Off and On status. We found that cerebellar tremor surprisingly had as good a response to DBS as the tremor without a cerebellar component, but the function control on cerebellar tremor was not as good due to its distal oscillation, which made the amplitude of tremor increasingly greater as it approached the target. This explains why cerebellar tremor or MS tremor with cerebellar component has a poor functional transformation even with a good percentage of tremor control. This case study provides a better understanding of the effect of DBS on cerebellar tremor and MS tremor by using a wearable device, which could help future studies improve patient selection and outcome prediction for DBS treatment of this disabling tremor.

Deep Brain Stimulation Impedance Decreases Over Time Even When Stimulation Settings Are Held Constant.

Objectives: To study whether and to what extent the therapeutic impedance and current change under long-term deep brain stimulation (DBS) with constant stimulation settings, which could inform the role of constant current stimulation. Methods: Therapy impedance and current measurements were retrospectively collected from patients with Parkinson's disease (PD) undergoing DBS of the subthalamic nucleus (STN) or essential tremor (ET) undergoing ventral intermediate nucleus (VIM). Baseline and follow-up measurements were obtained for intervals of at least 6 months without changes in stimulation settings. The single longest interval of constant stimulation for each electrode was included. Temporal trends in impedance and current were analyzed as absolute and relative differences and as the rate of change. Results: Impedance and current data from 79 electrodes (60 in STN, 19 in VIM) in 44 patients (32 with PD, 12 with ET) met inclusion criteria. The duration between baseline and follow-up measurements with constant stimulation settings was 17 months (median, with an interquartile range of 12-26 months) in the mixed group. Therapy impedance decreased by 27 ± 12 Ω/year (mean ± 2 standard errors; p < 0.0001), and therapy current increased at a rate of 0.142 ± 0.063 mA/year (p < 0.0001). Similar results were observed in the STN and VIM subgroups. Conclusions: Impedance decreases gradually over time, even when stimulation settings are kept constant. The rate of decrease is smaller than previously reported, suggesting that changes in stimulation settings contribute to impedance drift. Stimulation-independent impedance drift is gradual but relevant to constant-current programming.

Stereotactic laser anterior corpus callosotomy for Lennox-Gastaut syndrome.

OBJECTIVE: Corpus callosotomy is an effective palliative treatment for drug-resistant Lennox-Gastaut syndrome (LGS). Laser interstitial thermal therapy has been increasingly used in the treatment of epilepsy. Here, we assess the safety and effectiveness of minimally invasive stereotactic laser anterior corpus callosotomy (SLACC) for drop attacks in LGS. METHODS: We reviewed sequential cases of patients with medically intractable LGS who underwent SLACC using a two-cannula technique between November 2014 and July 2019. Pre- and postoperative magnetic resonance imaging was used to measure the anteroposterior length of callosal ablation (contrast-enhancing lesion) and estimated disconnection (gap in tract projections on diffusion tensor imaging). Patients were followed longitudinally to assess clinical outcomes. RESULTS: Ten patients were included in this study. The median age was 33 (range = 11-52) years, median duration of epilepsy was 26 (range = 10-49) years, and median duration of postoperative follow-up was 19 (range = 6-40) months. In the anteroposterior direction, 53 ± 7% (mean ± SD) of the corpus callosum was ablated and 62 ± 19% of the corpus callosum was estimated to be disconnected. Six (60%) of 10 patients achieved >80% seizure reduction, two (20%) of whom became seizure-free. Eight (80%) patients had >80% reduction in drop attacks, five (50%) of whom became free of drop attacks. Three patients subsequently underwent laser posterior callosotomy with further improvement in drop attacks and/or overall seizure frequency. One patient had an asymptomatic intracerebral hemorrhage along the cannula tract. One patient developed significant aggression after becoming seizure-free. SIGNIFICANCE: Seizure outcomes following SLACC were comparable to previously reported outcomes of open callosotomy, with reasonable safety profile. SLACC appears to be an effective alternative to open anterior corpus callosotomy with minimal postoperative discomfort and a short recovery period.

Stereotactic laser interstitial thermal therapy for epilepsy associated with solitary and multiple cerebral cavernous malformations.

OBJECTIVE: The authors sought to perform a preliminary assessment of the safety and effectiveness of stereotactic laser interstitial thermal therapy (LITT) for patients with cerebral cavernous malformation (CCM)-related epilepsy. METHODS: The authors retrospectively analyzed 6 patients with CCM-related epilepsy who underwent LITT. Pre-, intra-, and postoperative brain MRI studies were used to characterize preoperative CCM volume, ablation volume, and postablation hemosiderin volume. Clinical outcomes were assessed postoperatively during clinic follow-up visits or phone interviews. RESULTS: LITT was performed in 7 CCMs in 6 patients. Two patients had familial CCM disease with multifocal lesions. Four treated CCMs were extratemporal, and 3 were in or near the visual pathways. The median follow-up was 25 (range 12-39) months. Five of 6 (83%) patients achieved seizure freedom (Engel I classification), of whom 4 (67%) were Engel IA and 1 was Engel IC after a single seizure on postoperative day 4. The remaining patient had rare seizures (Engel II). One patient had a nondisabling visual field deficit. There were no hemorrhagic complications. All patients were discharged within 24 hours postablation. MRI 3-11 months after ablation demonstrated expected focal necrosis and trace hemosiderin-related T2 hypointensity measuring 9%-44% (median 24%) of the original lesion volume, with significant (p = 0.04) volume reduction. CONCLUSIONS: LITT is a minimally invasive option for treating CCM-related epilepsy with seizure outcomes comparable to those achieved with open lesionectomy. The precision of LITT allows for the obliteration of eloquent, deep, small, and multifocal lesions with low complication rates, minimal postoperative discomfort, and short hospital stays. In this study the feasibility and benefits of this method were demonstrated in 2 patients with multifocal lesions.

Technical note: accuracy and precision in stereotactic stem cell transplantation.

BACKGROUND: While multiple trials have employed stereotactic stem cell transplantation, injection techniques have received little critical attention. Precise cell delivery is critical for certain applications, particularly when targeting deep nuclei. METHODS: Ten patients with a history of ischemic stroke underwent CT-guided stem cell transplantation. Cells were delivered along 3 tracts adjacent to the infarcted area. Intraoperative air deposits and postoperative T2-weighted MRI fluid signals were mapped in relation to calculated targets. RESULTS: The deepest air deposit was found 4.5 ± 1.0 mm (mean ± 2 SEM) from target. The apex of the T2-hyperintense tract was found 2.8 ± 0.8 mm from target. On average, air pockets were found anterior (1.2 ± 1.1 mm, p = 0.04) and superior (2.4 ± 1.0 mm, p < 0.001) to the target; no directional bias was noted for the apex of the T2-hyperintense tract. Location and distribution of air deposits were variable and were affected by the relationship of cannula trajectory to stroke cavity. CONCLUSIONS: Precise stereotactic cell transplantation is a little-studied technical challenge. Reflux of cell suspension and air, and the structure of the injection tract affect delivery of cell suspensions. Intraoperative CT allows assessment of delivery and potential trajectory correction.

Long-term effect of low frequency stimulation of STN on dysphagia, freezing of gait and other motor symptoms in PD.

OBJECTIVE: To evaluate the long-term effect of 60 Hz stimulation of the subthalamic nucleus (STN) on dysphagia, freezing of gait (FOG) and other motor symptoms in patients with Parkinson's disease (PD) who have FOG at the usual 130 Hz stimulation. METHODS: This is a prospective, sequence randomised, crossover, double-blind study. PD patients with medication refractory FOG at 130 Hz stimulation of the STN were randomised to the sequences of 130 Hz, 60 Hz or deep brain stimulation off to assess swallowing function (videofluoroscopic evaluation and swallowing questionnaire), FOG severity (stand-walk-sit test and FOG questionnaire) and motor function (Unified PD Rating Scale, Part III motor examination (UPDRS-III)) at initial visit (V1) and follow-up visit (V2, after being on 60 Hz stimulation for an average of 14.5 months), in their usual medications on state. The frequency of aspiration events, perceived swallowing difficulty and FOG severity at 60 Hz compared with 130 Hz stimulation at V2, and their corresponding changes at V2 compared with V1 at 60 Hz were set as primary outcomes, with similar comparisons in UPDRS-III and its subscores as secondary outcomes. RESULTS: All 11 enrolled participants completed V1 and 10 completed V2. We found the benefits of 60 Hz stimulation compared with 130 Hz in reducing aspiration frequency, perceived swallowing difficulty, FOG severity, bradykinesia and overall axial and motor symptoms at V1 and persistent benefits on all of them except dysphagia at V2, with overall decreasing efficacy when comparing V2 to V1. CONCLUSIONS: The 60 Hz stimulation, when compared with 130 Hz, has long-term benefits on reducing FOG, bradykinesia and overall axial and motor symptoms except dysphagia, although the overall benefits decrease with long-term use. CLINICAL TRIAL REGISTRATION: NCT02549859; Pre-results.

A role for glutamine 183 in the folate oxidative half-reaction of methylenetetrahydrofolate reductase from Escherichia coli.

The flavoprotein methylenetetrahydrofolate reductase (MTHFR) from Escherichia coli catalyzes a ping-pong reaction with NADH and 5,10-methylenetetrahydrofolate (CH2-H4folate) to produce NAD+ and 5-methyltetrahydrofolate (CH3-H4folate). This work focuses on the function of the invariant, active-site aminoacyl residue Gln183. X-ray structures of the enzyme complexes Ered(wild-type)•NADH and Eox(Glu28Gln)•CH3-H4folate indicate that Gln183 makes key hydrogen-bonding interactions with both NADH and folate in their respective half-reactions, suggesting roles in binding each substrate. We propose that the polarity of Gln183 may also aid in stabilizing the proposed 5-iminium cation intermediate during catalysis in the oxidative half-reaction with folate. We have prepared mutants Gln183Ala and Gln183Glu, which we hypothesize to have altered charge/polarity and hydrogen bonding properties. We have examined the enzymes by steady-state and stopped-flow kinetics and by measurement of the flavin redox potentials. In the reductive half-reaction, NADH binding affinity and the rate of flavin reduction have not been hindered by either mutation. By contrast, our results support a minor role for Gln183 in the oxidative half-reaction. The Gln183Ala variant exhibited a 6-10 fold lower rate of folate reduction and bound CH2-H4folate with 7-fold lower affinity, whereas the Gln183Glu mutant displayed catalytic constants within 3-fold of the wild-type enzyme.

Mania secondary to focal brain lesions: implications for understanding the functional neuroanatomy of bipolar disorder.

OBJECTIVES: Approximately 3.5 million Americans will experience a manic episode during their lifetimes. The most common causes are psychiatric illnesses such as bipolar I disorder and schizoaffective disorder, but mania can also occur secondary to neurological illnesses, brain injury, or neurosurgical procedures. METHODS: For this narrative review, we searched Medline for articles on the association of mania with stroke, brain tumors, traumatic brain injury, multiple sclerosis, neurodegenerative disorders, epilepsy, and neurosurgical interventions. We discuss the epidemiology, features, and treatment of these cases. We also review the anatomy of the lesions, in light of what is known about the neurobiology of bipolar disorder. RESULTS: The prevalence of mania in patients with brain lesions varies widely by condition, from <2% in stroke to 31% in basal ganglia calcification. Mania occurs most commonly with lesions affecting frontal, temporal, and subcortical limbic brain areas. Right-sided lesions causing hypo-functionality or disconnection (e.g., stroke; neoplasms) and left-sided excitatory lesions (e.g., epileptogenic foci) are frequently observed. CONCLUSIONS: Secondary mania should be suspected in patients with neurological deficits, histories atypical for classic bipolar disorder, and first manic episodes after the age of 40 years. Treatment with antimanic medications, along with specific treatment for the underlying neurologic condition, is typically required. Typical lesion locations fit with current models of bipolar disorder, which implicate hyperactivity of left-hemisphere reward-processing brain areas and hypoactivity of bilateral prefrontal emotion-modulating regions. Lesion studies complement these models by suggesting that right-hemisphere limbic-brain hypoactivity, or a left/right imbalance, may be relevant to the pathophysiology of mania.

Hearing loss in hydrocephalus: a review, with focus on mechanisms.

While neither hydrocephalus nor cerebrospinal fluid (CSF) shunt placement is traditionally considered in the differential diagnosis of hearing loss, there is substantial evidence that CSF circulation and pressure abnormalities can produce auditory dysfunction. Several indirect mechanisms may explain association between hydrocephalus and hearing loss, including mass effect, compromise of the auditory pathway, complications of prematurity, and genetically mediated hydrocephalus and hearing loss. Nevertheless, researchers have proposed a direct mechanism, which we term the hydrodynamic theory. In this hypothesis, the intimate relationship between CSF and inner ear fluids permits relative endolymphatic or perilymphatic hydrops in the setting of CSF pressure disturbances. CSF is continuous with perilymph, and CSF pressure changes are known to produce parallel perilymphatic pressure changes. In support of the hydrodynamic theory, some studies have found an independent association between hydrocephalus and hearing loss. Moreover, surgical shunting of CSF has been linked to both resolution and development of auditory dysfunction. The disease burden of hydrocephalus-associated hearing loss may be large, and because hydrocephalus and over-shunting are reversible, this relationship merits broader recognition. Hydrocephalic patients should be monitored for hearing loss, and hearing loss in a patient with shunted hydrocephalus should prompt further evaluation and possibly adjustment of shunt settings.