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Objective: Subthalamic nucleus (STN) and globus pallidus internus (GPI) deep brain stimulation (DBS) effectively treat motor symptoms in Parkinson's disease (PD) but may be associated with cognitive and psychiatric changes in some patients. Evaluation of changes in cognitive and psychiatric symptoms following DBS is complicated by changes in these symptoms that occur as part of the natural disease course. The aim of this study was to evaluate whether electrode position was associated with changes in neurocognitive symptoms in patients who underwent STN and GPI DBS., Methods: A single-institution retrospective cohort study was conducted on patients with PD who underwent DBS from 2008 to 2019. Cognitive and psychiatric outcomes included Beck Depression Inventory II (BDI-II) score, presence of impulsive-compulsive behavior (ICB), Mini-Mental State Examination (MMSE) score, and overall cognitive status grade determined by comprehensive neuropsychology testing (normal, mild impairment, moderate impairment, and dementia). Pre- and postoperative comparisons were performed using a Wilcoxon signed-rank test or paired t-test. Patients with and without cognitive decline were compared using a Mann-Whitney U-test or unpaired t-test. A chi-square test was used for categorical comparisons., Results: One hundred thirty patients were included (mean age 62.5 ± 7.9 years). At a mean postoperative follow-up from DBS of 13.0 ± 12.7 (range 6-66) months, there was an improvement in ICB (26.3% preoperatively vs 15.0% postoperatively, p = 0.017), but a decline in MMSE score (28.6 ± 1.6 vs 27.6 ± 2.0, p < 0.001) and overall cognitive status (normal: 66.2% vs 39.2%; mild: 12.3% vs 17.7%; moderate: 21.5% vs 33.1%; dementia: 0.0% vs 10.0%; p < 0.001). Patients undergoing STN DBS had a worse decline in overall cognitive status than patients who underwent GPI DBS (p = 0.006). Postoperative cognitive decline was associated with a more medial electrode position only for patients who underwent STN DBS., Conclusions: Cognitive change was observed in some patients with PD who underwent both GPI and STN DBS, likely due partly to underlying disease progression. Compared with GPI DBS, STN DBS was associated with a greater likelihood of cognitive decline. In STN but not GPI DBS, cognitive decline was associated with medialized electrode position, suggesting modulation of nonmotor STN divisions may contribute to cognitive changes following STN DBS.

Objective: MRI-guided low-intensity focused ultrasound (FUS) has been shown to reversibly open the blood-brain barrier (BBB), with the potential to deliver therapeutic agents noninvasively to target brain regions in patients with Alzheimer's disease (AD) and other neurodegenerative conditions. Previously, the authors reported the short-term safety and feasibility of FUS BBB opening of the hippocampus and entorhinal cortex (EC) in patients with AD. Given the need to treat larger brain regions beyond the hippocampus and EC, brain volumes and locations treated with FUS have now expanded. To evaluate any potential adverse consequences of BBB opening on disease progression, the authors report safety, imaging, and clinical outcomes among participants with mild AD at 6-12 months after FUS treatment targeted to the hippocampus, frontal lobe, and parietal lobe., Methods: In this open-label trial, participants with mild AD underwent MRI-guided FUS sonication to open the BBB in β-amyloid positive regions of the hippocampus, EC, frontal lobe, and parietal lobe. Participants underwent 3 separate FUS treatment sessions performed 2 weeks apart. Outcome assessments included safety, imaging, neurological, cognitive, and florbetaben β-amyloid PET., Results: Ten participants (range 55-76 years old) completed 30 separate FUS treatments at 2 participating institutions, with 6-12 months of follow-up. All participants had immediate BBB opening after FUS and BBB closure within 24-48 hours. All FUS treatments were well tolerated, with no serious adverse events related to the procedure. All 10 participants had a minimum of 6 months of follow-up, and 7 participants had a follow-up out to 1 year. Changes in the Alzheimer's Disease Assessment Scale-cognitive and Mini-Mental State Examination scores were comparable to those in controls from the Alzheimer's Disease Neuroimaging Initiative. PET scans demonstrated an average β-amyloid plaque of 14% in the Centiloid scale in the FUS-treated regions., Conclusions: This study is the largest cohort of participants with mild AD who received FUS treatment, and has the longest follow-up to date. Safety was demonstrated in conjunction with reversible and repeated BBB opening in multiple cortical and deep brain locations, with a concomitant reduction of β-amyloid. There was no apparent cognitive worsening beyond expectations up to 1 year after FUS treatment, suggesting that the BBB opening treatment in multiple brain regions did not adversely influence AD progression. Further studies are needed to determine the clinical significance of these findings. FUS offers a unique opportunity to decrease amyloid plaque burden as well as the potential to deliver targeted therapeutics to multiple brain regions in patients with neurodegenerative disorders.

Object: Traumatic brain injury (TBI) often causes an encephalopathic state, corresponding amplitude suppression, and disorganization of electroencephalographic activity. Clinical recovery in patients who have suffered TBI varies, and identification of patients with a poor likelihood of functional recovery is not always straightforward. The authors sought to investigate temporal patterns of electrophysiological recovery of neuronal networks in an animal model of TBI. Because thalamocortical circuit function is a critical determinant of arousal state, as well as electroencephalography organization, these studies were performed using a thalamocortical brain slice preparation., Methods: Adult rats received a moderate parietal fluid-percussion injury and were allowed to survive for 1 hour, 2 days, 7 days, or 15 days prior to in vitro electrophysiological recording. Thalamocortical brain slices, 450-μm thick, were prepared using a cutting angle that preserved reciprocal connections between the somatosensory cortex and the ventrobasal thalamic complex., Results: Extracellular recordings in the cortex of uninjured control brain slices revealed spontaneous slow cortical oscillations (SCOs) that are blocked by (2R)-amino-5-phosphonovaleric acid (50 μM) and augmented in low [Mg2+]o. These oscillations have been shown to involve simultaneous bursts of activity in both the cortex and thalamus and are used here as a metric of thalamocortical circuit integrity. They were absent in 84% of slices recorded at 1 hour postinjury, and activity slowly recovered to approximate control levels by Day 15. The authors next used electrically evoked SCO-like potentials to determine neuronal excitability and found that the maximum depression occurred slightly later, on Day 2 following TBI, with only 28% of slices showing evoked activity. In addition, stimulus intensities needed to create evoked SCO activity were elevated at 1 hour, 2 days, and 7 days following TBI, and eventually returned to control levels by Day 15. The SCO frequency remained low throughout the 15 days following TBI (40% of control by Day 15)., Conclusions: The suppression of cortical oscillatory activity following TBI observed in the rat model suggests an injury-induced functional disruption of thalamocortical networks that gradually recovers to baseline at approximately 15 days postinjury. The authors speculate that understanding the processes underlying disrupted thalamocortical circuit function may provide important insights into the biological basis of altered consciousness following severe head injury. Moreover, understanding the physiological basis for this process may allow us to develop new therapies to enhance the rate and extent of neurological recovery following TBI.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a clinically effective neurosurgical treatment for Parkinson disease. Tissue reaction to chronic DBS therapy and the definitive location of active stimulation contacts are best studied on a postmortem basis in patients who have undergone DBS. The authors report the postmortem analysis of STN DBS following 5 years and 11 months of effective chronic stimulation including the histologically verified location of the active contacts associated with bilateral implants. They also describe tissue response to intraoperative test passes with recording microelectrodes and stimulating semimacroelectrodes. The results indicated that 1) the neural tissue surrounding active and nonactive contacts responds similarly, with a thin glial capsule and foreign-body giant cell reaction surrounding the leads as well as piloid gliosis, hemosiderin-laden macrophages, scattered lymphocytes, and Rosenthal fibers; 2) there was evidence of separate tracts in the adjacent tissue for intraoperative microelectrode and semimacroelectrode passes together with reactive gliosis, microcystic degeneration, and scattered hemosiderin deposition; and 3) the active contacts used for approximately 6 years of effective bilateral DBS therapy lie in the zona incerta, just dorsal to the rostral STN. To the authors' knowledge, the period of STN DBS therapy herein described for Parkinson disease and subjected to postmortem analysis is the longest to date.