Aperiodic subthalamic activity predicts motor severity and stimulation response in Parkinson disease.

INTRODUCTION: Rhythmic beta activity in the subthalamic nucleus (STN) local field potential (LFP) is associated with Parkinson disease (PD) severity, though not all studies have found this relationship. We investigated whether aperiodic 'noise' elements of LFP, specifically slope of the 1/f broadband, predict PD motor symptoms and outcomes of STN-DBS. METHODS: We studied micro-LFP from 19 PD patients undergoing STN-DBS, relating the aperiodic 1/f slope and the periodic beta oscillation components to motor severity using the UPDRS-III and improvement with DBS at 1 year. RESULTS: Beta power, not 1/f slope, independently predicted baseline UPDRS-III (r = 0.425, p = 0.020; r = -0.434, p = 0.032, respectively), but multiple regression using both predicted better (F (2, 16) = 6.621, p = 0.008, R2 = 0.453). Only multiple regression using both slope and beta power predicted improvement in UPDRS-III at 1 year post-operatively (F (2, 15) = 6.049, R2 = 0.446, p = 0.012). CONCLUSIONS: Both beta synchronization and slope of the 1/f broadband are informative of motor symptoms in PD and predict response to STN-DBS.

Cholinergics contribute to the cellular mechanisms of deep brain stimulation applied in rat infralimbic cortex but not white matter.

Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) is a promising therapy for treatment-resistant depression. Pre-clinical models have been widely used to investigate the neural mechanisms underlying its antidepressant benefit. The ventral division of the medial prefrontal cortex (vmPFC), particularly the infralimbic cortex (IL), is the homologous region in rat and DBS applied to vmPFC shows antidepressant-like effects in the forced swim test. Therefore we investigated the cellular mechanisms of simulated DBS (sDBS) in layer 5 IL neurons, using in vitro whole-cell patch clamp recordings. sDBS in IL layer 5 induced a prolonged after-depolarization (ADP) in both pyramidal and fast spiking neurons, which was dependent on current amplitude and pulse width. In contrast, sDBS applied in the forebrain white matter fibers, although delivered at a higher intensity, failed to induce any persistent depolarization in layer 5 IL pyramidal neurons. Cholinergic blockade (atropine, 2.0 µM) decreased both the ADP amplitude and duration in pyramidal neurons, but left those in fast spiking neurons unchanged. These data suggest that: (i) sDBS in IL gray and white matter produced different cellular effects on pyramidal neurons; (ii) sDBS-induced ADP in pyramidal, but not fast spiking neurons, was mediated by acetylcholine; and (iii) different neuromodulators may contribute to sDBS-induced ADP in IL. In summary, cholinergic mediated ADP in pyramidal neurons may contribute to the antidepressant effects of DBS in IL.

Outcomes of Occipital Nerve Stimulation for Craniofacial Pain Syndromes.

OBJECTIVES: Occipital nerve regional stimulation (ONS) is reported to improve pain in several studies. We examined long-term pain and functional outcomes of ONS in an open-label prospective study. METHODS: Patients with medically refractory and disabling craniofacial pain were prospectively selected for ONS. Primary outcome was a change in mean daily pain intensity on the numeric pain rating scale (NPRS) at 6 months. Secondary outcomes included changes in NPRS, Headache Impact Test-6 (HIT-6), Migraine Disability Assessment (MIDAS), Pain Disability Index (PDI), Center for Epidemiologic Studies Depression Scale - Revised (CESD-R), and Short Form-36 version 2 (SF36) at last follow-up. RESULTS: Thirteen patients (mean age 49.7 ± 8.4) diagnosed with occipital neuralgia (6), hemicrania continua (2), persistent idiopathic facial pain (2), post-traumatic facial pain (1), cluster headache (1), and chronic migraine (1) were enrolled. Mean NPRS improved by 2.1 ± 2.1 at 6 months and 2.1 ± 1.9 at last follow-up (23.5 ± 18.1 months). HIT-6 decreased by 8.7 ± 8.8, MIDAS decreased by 61.3 ± 71.6, and PDI decreased by 17.9 ± 18. SF36 physical functioning, bodily pain, and social functioning improved by 16.4 ± 19.6, 18.0 ± 31.6, and 26.1 ± 37.3, respectively. Moderate to severe headache days (defined as ≥50% of baseline mean NPRS) were reduced by 8.9 ± 10.2 days per month with ONS. CONCLUSION: ONS reduced the long-term NPRS and moderate-severe monthly headache days by 30% and improved functional outcomes and quality of life. A prospective registry for ONS would be helpful in accumulating a larger cohort with longer follow-up in order to improve the use of ONS.

Neurovascular coupling during deep brain stimulation.

BACKGROUND: Deep brain stimulation (DBS) is an effective treatment for movement disorders, yet its mechanisms of action remain unclear. One method used to study its circuit-wide neuromodulatory effects is functional magnetic resonance imaging (fMRI) which measures hemodynamics as a proxy of neural activity. To interpret functional imaging data, we must understand the relationship between neural and vascular responses, which has never been studied with the high frequencies used for DBS. OBJECTIVE: To measure neurovascular coupling in the rat motor cortex during thalamic DBS. METHOD: Simultaneous intrinsic optical imaging and extracellular electrophysiology was performed in the motor cortex of urethane-anesthetized rats during thalamic DBS at 7 different frequencies. We related Maximum Change in Reflectance (MCR) from the imaging data to Integrated Evoked Potential (IEP) and change in broadband power of multi-unit (MU) activity, computing Spearman's correlation to determine the strength of these relationships. To determine the source of these effects, we studied the contributions of antidromic versus orthodromic activation in motor cortex perfusion using synaptic blockers. RESULTS: MCR, IEP and change in MU power increased linearly to 60 Hz and saturated at higher frequencies of stimulation. Blocking orthodromic transmission only reduced the DBS-induced change in optical signal by ∼25%, suggesting that activation of corticofugal fibers have a major contribution in thalamic-induced cortical activation. CONCLUSION: DBS-evoked vascular response is related to both evoked field potentials as well as multi-unit activity.

Long versus short pulse width subcallosal cingulate stimulation for treatment-resistant depression: a randomised, double-blind, crossover trial.

BACKGROUND: Stimulation adjustment is required to optimise outcomes of deep brain stimulation (DBS) for treatment-resistant depression, but controlled data for ideal stimulation parameters are poor or insufficient. We aimed to establish the efficacy and safety of short pulse width (SPW) and long pulse width (LPW) subcallosal cingulate DBS in depression. METHODS: We did a double-blind, randomised, crossover trial in an academic hospital in Calgary, AB, Canada. Patients had DSM IV-defined major depressive disorder and bipolar depression (20-70 years old, both sexes) and did not respond to treatment for more than 1 year, with a score of 20 or more on the 17-item Hamilton Depression Rating Scale (HDRS) at recruitment. Patients underwent bilateral DBS implantation into the subcallosal cingulate white matter using diffusion tensor imaging tractography. Patients were randomly assigned 1:1 without stratification using a computerised list generator to receive either SPW (90 µs) or LPW (210-450 µs) stimulation for 6 months. Patients and the clinician assessing outcomes were masked to the stimulation group. Keeping frequency constant (130 Hz), either pulse width or voltage was increased monthly, based on response using the HDRS. Patients who did not respond to treatment (<50% reduction in HDRS from baseline) at 6 months crossed over to the opposite stimulation for another 6 months. All patients received individualised cognitive behavioural therapy (CBT) for 12 weeks. The primary outcome was change in HDRS at 6 months and 12 months using intention-to-treat analysis. This study is registered with ClinicalTrials.gov, NCT01983904. FINDINGS: Between Dec 5, 2013, and Sept 30, 2016, of 225 patients screened for eligibility, 23 patients were selected for DBS surgery. After one patient withdrew, 22 (mean age 46·4 years, SEM 3·1; 10 [45%] female, 12 [55%] male) were randomly assigned, ten (45%) to LPW stimulation and 12 (55%) to SPW stimulation. Patients were followed up at 6 months and 12 months. There was a significant reduction in HDRS scores (p<0·0001) with no difference between SPW and LPW groups (p=0·54) in the randomisation phase at 6 months. Crossover groups did not show a significant decrease in HDRS within groups (p=0·15) and between groups (p=0·21) from 6-12 months. Adverse events were equal between groups. Worsening anxiety and depression were the most common psychological adverse events. One patient in the SPW group died by suicide. INTERPRETATION: Both LPW and SPW stimulation of subcallosal cingulate white matter tracts carried similar risks and were equally effective in reducing depressive symptoms, suggesting a role for both pulse width and amplitude titration in optimising clinical outcomes in patients with treatment-resistant depression. FUNDING: Alberta Innovates Health Solutions.