Intraoperative neural signals predict rapid antidepressant effects of deep brain stimulation.

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is a promising intervention for treatment-resistant depression (TRD). Despite the failure of a clinical trial, multiple case series have described encouraging results, especially with the introduction of improved surgical protocols. Recent evidence further suggests that tractography targeting and intraoperative exposure to stimulation enhances early antidepressant effects that further evolve with ongoing chronic DBS. Accelerating treatment gains is critical to the care of this at-risk population, and identification of intraoperative electrophysiological biomarkers of early antidepressant effects will help guide future treatment protocols. Eight patients underwent intraoperative electrophysiological recording when bilateral DBS leads were implanted in the SCC using a connectomic approach at the site previously shown to optimize 6-month treatment outcomes. A machine learning classification method was used to discriminate between intracranial local field potentials (LFPs) recorded at baseline (stimulation-naïve) and after the first exposure to SCC DBS during surgical procedures. Spectral inputs (theta, 4-8 Hz; alpha, 9-12 Hz; beta, 13-30 Hz) to the model were then evaluated for importance to classifier success and tested as predictors of the antidepressant response. A decline in depression scores by 45.6% was observed after 1 week and this early antidepressant response correlated with a decrease in SCC LFP beta power, which most contributed to classifier success. Intraoperative exposure to therapeutic stimulation may result in an acute decrease in symptoms of depression following SCC DBS surgery. The correlation of symptom improvement with an intraoperative reduction in SCC beta power suggests this electrophysiological finding as a biomarker for treatment optimization.

Clinical outcomes of globus pallidus deep brain stimulation for Parkinson disease: a comparison of intraoperative MRI- and MER-guided lead placement.

OBJECTIVE: Deep brain stimulation (DBS) lead placement is increasingly performed with the patient under general anesthesia by surgeons using intraoperative MRI (iMRI) guidance without microelectrode recording (MER) or macrostimulation. The authors assessed the accuracy of lead placement, safety, and motor outcomes in patients with Parkinson disease (PD) undergoing DBS lead placement into the globus pallidus internus (GPi) using iMRI or MER guidance. METHODS: The authors identified all patients with PD who underwent either MER- or iMRI-guided GPi-DBS lead placement at Emory University between July 2007 and August 2016. Lead placement accuracy and adverse events were determined for all patients. Clinical outcomes were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores for patients completing 12 months of follow-up. The authors also assessed the levodopa-equivalent daily dose (LEDD) and stimulation parameters. RESULTS: Seventy-seven patients were identified (MER, n = 28; iMRI, n = 49), in whom 131 leads were placed. The stereotactic accuracy of the surgical procedure with respect to the planned lead location was 1.94 ± 0.21 mm (mean ± SEM) (95% CI 1.54-2.34) with frame-based MER and 0.84 ± 0.007 mm (95% CI 0.69-0.98) with iMRI. The rate of serious complications was similar, at 6.9% for MER-guided DBS lead placement and 9.4% for iMRI-guided DBS lead placement (RR 0.71 [95% CI 0.13%-3.9%]; p = 0.695). Fifty-seven patients were included in clinical outcome analyses (MER, n = 16; iMRI, n = 41). Both groups had similar characteristics at baseline, although patients undergoing MER-guided DBS had a lower response on their baseline levodopa challenge (44.8% ± 5.4% [95% CI 33.2%-56.4%] vs 61.6% ± 2.1% [95% CI 57.4%-65.8%]; t = 3.558, p = 0.001). Greater improvement was seen following iMRI-guided lead placement (43.2% ± 3.5% [95% CI 36.2%-50.3%]) versus MER-guided lead placement (25.5% ± 6.7% [95% CI 11.1%-39.8%]; F = 5.835, p = 0.019). When UPDRS III motor scores were assessed only in the contralateral hemibody (per-lead analyses), the improvements remained significantly different (37.1% ± 7.2% [95% CI 22.2%-51.9%] and 50.0% ± 3.5% [95% CI 43.1%-56.9%] for MER- and iMRI-guided DBS lead placement, respectively). Both groups exhibited similar reductions in LEDDs (21.2% and 20.9%, respectively; F = 0.221, p = 0.640). The locations of all active contacts and the 2D radial distance from these to consensus coordinates for GPi-DBS lead placement (x, ±20; y, +2; and z, -4) did not differ statistically by type of surgery. CONCLUSIONS: iMRI-guided GPi-DBS lead placement in PD patients was associated with significant improvement in clinical outcomes, comparable to those observed following MER-guided DBS lead placement. Furthermore, iMRI-guided DBS implantation produced a similar safety profile to that of the MER-guided procedure. As such, iMRI guidance is an alternative to MER guidance for patients undergoing GPi-DBS implantation for PD.

Underlying Cortical Dysplasia as Risk Factor for Traumatic Epilepsy: An Animal Study.

Traumatic brain injury (TBI) is a significant risk factor for development of epilepsy in humans. It is unclear, however, why some persons are at an increased risk of becoming epileptic, while others recover from the TBI seizure-free. We previously showed that the presence of a proepileptic pathology increases the risk of epilepsy in an animal model of cortical dysplasia (CD) after a secondary insult, which we described as the "second hit". Here we sought to evaluate the prevalence of epileptic activity and seizures in CD after a moderate TBI to determine the influence of dysplastic pathology on TBI-induced epileptogenesis. CD was generated in rats through in utero irradiation (the "first hit"). Nondysplastic and CD rats were surgically implanted with EEG electrodes. Craniotomies were performed over the pre-central cortex, and rats were given a moderate TBI using the lateral fluid percussion injury device. Rats were monitored with chronic EEG and video. EEG data were analyzed for the occurrence of interictal spikes and epileptic EEG seizure patterns. Brains were harvested and evaluated histologically. Spontaneous seizures are more prominent and occur earlier in rats with CD after a moderate TBI compared with nondysplastic control rats. All of the CD animals exhibited interictal spiking after TBI, while only a portion of nondysplastic animals produced spikes. These results suggest that the presence of a proepileptic pathology may increase the risk for the development of epilepsy after TBI. Diagnosis and treatment of TBI may depend on underlying pathologies contributing to epilepsy after a brain injury.

A systematic approach to selecting task relevant neurons.

BACKGROUND: Since task related neurons cannot be specifically targeted during surgery, a critical decision to make is to select which neurons are task-related when performing data analysis. Including neurons unrelated to the task degrade decoding accuracy and confound neurophysiological results. Traditionally, task-related neurons are selected as those with significant changes in firing rate when a stimulus is applied. However, this assumes that neurons' encoding of stimuli are dominated by their firing rate with little regard to temporal dynamics. NEW METHOD: This paper proposes a systematic approach for neuron selection, which uses a likelihood ratio test to capture the contribution of stimulus to spiking activity while taking into account task-irrelevant intrinsic dynamics that affect firing rates. This approach is denoted as the model deterioration excluding stimulus (MDES) test. RESULTS: MDES is compared to firing rate selection in four case studies: a simulation, a decoding example, and two neurophysiology examples. COMPARISON WITH EXISTING METHODS: The MDES rankings in the simulation match closely with ideal rankings, while firing rate rankings are skewed by task-irrelevant parameters. For decoding, 95% accuracy is achieved using the top 8 MDES-ranked neurons, while the top 12 firing-rate ranked neurons are needed. In the neurophysiological examples, MDES matches published results when firing rates do encode salient stimulus information, and uncovers oscillatory modulations in task-related neurons that are not captured when neurons are selected using firing rates. CONCLUSIONS: These case studies illustrate the importance of accounting for intrinsic dynamics when selecting task-related neurons and following the MDES approach accomplishes that. MDES selects neurons that encode task-related information irrespective of these intrinsic dynamics which can bias firing rate based selection.

Chronic deep cerebellar stimulation promotes long-term potentiation, microstructural plasticity, and reorganization of perilesional cortical representation in a rodent model.

Control over postinjury CNS plasticity is a major frontier of science that, if conquered, would open new avenues for treatment of neurological disorders. Here we investigate the functional, physiological, and structural changes in the cerebral cortex associated with chronic deep brain stimulation of the cerebellar output, a treatment approach that has been shown to improve postischemia motor recovery in a rodent model of cortical infarcts. Long-Evans rats were pretrained on the pasta-matrix retrieval task, followed by induction of focal cortical ischemia and implantation of a macroelectrode in the contralesional lateral cerebellar nucleus. Animals were assigned to one of three treatment groups pseudorandomly to balance severity of poststroke motor deficits: REGULAR stimulation, BURST stimulation, or SHAM. Treatment initiated 2 weeks post surgery and continued for 5 weeks. At the end, animals were randomly selected for perilesional intracortical microstimulation mapping and tissue sampling for Western blot analysis or contributed tissue for 3D electron microscopy. Evidence of enhanced cortical plasticity with therapeutically effective stimulation is shown, marked by greater perilesional reorganization in stimulation- treated animals versus SHAM. BURST stimulation was significantly effective for promoting distal forepaw cortical representation. Stimulation-treated animals showed a twofold increase in synaptic density compared with SHAM. In addition, treated animals demonstrated increased expression of synaptic markers of long-term potentiation and plasticity, including synaptophysin, NMDAR1, CaMKII, and PSD95. These findings provide a critical foundation of how deep cerebellar stimulation may guide plastic reparative reorganization after nonprogressive brain injury and indicate strong translational potential.

Intra-operative behavioral tasks in awake humans undergoing deep brain stimulation surgery.

Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through implanted electrodes. Deep brain stimulation was first implemented as a therapeutic modality by Benabid et al. in the late 1980s, when he used this technique to stimulate the ventral intermediate nucleus of the thalamus for the treatment of tremor. Currently, the procedure is used to treat patients who fail to respond adequately to medical management for diseases such as Parkinson's, dystonia, and essential tremor. The efficacy of this procedure for the treatment of Parkinson's disease has been demonstrated in well-powered, randomized controlled trials. Presently, the U.S. Food and Drug Administration has approved DBS as a treatment for patients with medically refractory essential tremor, Parkinson's disease, and dystonia. Additionally, DBS is currently being evaluated for the treatment of other psychiatric and neurological disorders, such as obsessive compulsive disorder, major depressive disorder, and epilepsy. DBS has not only been shown to help people by improving their quality of life, it also provides researchers with the unique opportunity to study and understand the human brain. Microelectrode recordings are routinely performed during DBS surgery in order to enhance the precision of anatomical targeting. Firing patterns of individual neurons can therefore be recorded while the subject performs a behavioral task. Early studies using these data focused on descriptive aspects, including firing and burst rates, and frequency modulation. More recent studies have focused on cognitive aspects of behavior in relation to neuronal activity. This article will provide a description of the intra-operative methods used to perform behavioral tasks and record neuronal data with awake patients during DBS cases. Our exposition of the process of acquiring electrophysiological data will illuminate the current scope and limitations of intra-operative human experiments.

Recombinant adeno-associated virus type 2 pseudotypes: comparing safety, specificity, and transduction efficiency in the primate striatum. Laboratory investigation.

OBJECT: Although several clinical trials utilizing the adeno-associated virus (AAV) type 2 serotype 2 (2/2) are now underway, it is unclear whether this particular serotype offers any advantage over others in terms of safety or efficiency when delivered directly to the CNS. METHODS: Recombinant AAV2-green fluorescent protein (GFP) serotypes 2/1, 2/2, 2/5, and 2/8 were generated following standard triple transfection protocols (final yield 5.4 × 10(12) particles/ml). A total of 180 µl of each solution was stereotactically infused, covering the entire rostrocaudal extent of the caudoputamen in 4 rhesus monkeys (Macaca mulatta) (3.0 ± 0.5 kg). After 6 weeks' survival, the brain was formalin fixed, cut at 40 µm, and stained with standard immunohistochemistry for anti-GFP, anticaspase-2, and cell-specific markers (anti-microtubule-associated protein-2 for neurons and anti-glial fibrillary acidic protein for glia). Unbiased stereological counting methods were used to determine cell number and striatal volume. RESULTS: The entire striatum of each animal contained GFP-positive cells with significant labeling extending beyond the borders of the basal ganglia. No ischemic/necrotic, hemorrhagic, or neoplastic change was observed in any brain. Total infusate volumes were similar across the 4 serotypes. However, GFP-labeled cell density was markedly different. Adeno-associated virus 2/1, 2/2, and 2/5 each labeled < 8000 cells/mm(3), whereas serotype 8 labeled > 21,000 cells, a 3- to 4-fold higher transduction efficiency. On the other hand, serotype 8 also labeled neurons and glia with equal affinity compared with neuronal specificities > 89% for the other serotypes. Moderate caspase-2 colabeling was noted in neurons immediately around the AAV2/1 injection tracts, but was not seen above the background anywhere in the brain following injections with serotypes 2, 5, or 8. CONCLUSIONS: Intrastriatal delivery of AAV2 yields the highest cell transduction efficiencies but lowest neuronal specificity for serotype 8 when compared with serotypes 1, 2, and 5. Only AAV2/1 revealed significant caspase-2 activation. Careful consideration of serotype-specific differences in AAV2 neurotropism, transduction efficiency, and potential toxicity may affect future human trials.

Risk factors for hemorrhage during microelectrode-guided deep brain stimulation and the introduction of an improved microelectrode design.

OBJECTIVE: Hemorrhage is an infrequent but potentially devastating complication of deep brain stimulation (DBS) surgery. We examined the factors associated with hemorrhage after DBS surgery and evaluated a modified microelectrode design that may improve the safety of this procedure. METHODS: All microelectrode-guided DBS procedures performed at our institution between January 2000 and March 2008 were included in this study. A new microelectrode design with decreased diameter was introduced in May 2004, and data from the 2 types of electrodes were compared. RESULTS: We examined 246 microelectrode-guided lead implantations in 130 patients. Postoperative imaging revealed 7 hemorrhages (2.8%). Five of the 7 (2.0%) resulted in focal neurological deficits, all of which resolved within 1 month with the exception of 1 patient lost to follow-up. The new microelectrode design significantly decreased the number of hemorrhages (P = 0.04). A surgical trajectory traversing the ventricle also contributed significantly to the overall hemorrhage rate (P = 0.02) and specifically to the intraventricular hemorrhage rate (P = 0.01). In addition, the new microelectrode design significantly decreased the rate of intraventricular hemorrhage, given a ventricular penetration (P = 0.01). The mean age of patients with hemorrhage was significantly higher than that of patients without hemorrhage (P = 0.02). Hypertension, sex, and number of microelectrodes passed did not significantly contribute to hemorrhage rates in our population. CONCLUSION: The rate of complications after DBS surgery is not uniformly distributed across all cases. In particular, the rates of hemorrhage were increased in older patients. Importantly, transventricular electrode trajectories appeared to increase the risk of hemorrhage. A new microelectrode design minimizing the volume of brain parenchyma penetrated during microelectrode recording leads to decreased rates of hemorrhage, particularly if the ventricles are breached.

From symphony to cacophony: pathophysiology of the human basal ganglia in Parkinson disease.

Despite remarkable advances, the relationship between abnormal neuronal activity and the clinical manifestations of Parkinson disease (PD) remains unclear. Numerous hypotheses have emerged to explain the relationship between neuronal activity and symptoms such as tremor, rigidity and akinesia. Among these are the antagonist balance hypothesis wherein increased firing rates in the indirect pathway inhibits movement; the selectivity hypothesis wherein loss of neuronal selectivity leads to an inability to select or initiate movements; the firing pattern hypothesis wherein increased oscillation and synchronization contribute to tremor and disrupt information flow; and the learning hypothesis, wherein the basal ganglia are conceived as playing an important role in learning sensory-motor associations which is disrupted by the loss of dopamine. Deep brain stimulation (DBS) surgery provides a unique opportunity to assess these different ideas since neuronal activity can be directly recorded from PD patients. The emerging data suggest that the pathophysiologic changes include derangements in the overall firing rates, decreased neuronal selectivity, and increased neuronal oscillation and synchronization. Thus, elements of all hypotheses are present, emphasizing that the loss of dopamine results in a profound and multifaceted disruption of normal information flow through the basal ganglia that ultimately leads to the signs and symptoms of PD.