The Determining Factors for Outcome of Pediatric Intensive Care Admitted Children After Stem Cell Transplantation.

INTRODUCTION: Requiring pediatric intensive care unit (PICU) admission relates to high mortality and morbidity in patients who received hematopoietic stem cell transplantation (HSCT). In this study, we aimed to evaluate the indications for PICU admission, treatments, and the determining risk factors for morbidity and mortality in patients who had allogeneic HSCT from various donors. MATERIALS AND METHODS: In this retrospective study, we enrolled to patients who required the PICU after receiving allogeneic HSCT at our Pediatric Bone Marrow Transplantation Unit between 2005 and 2020. We evaluated to indication to PICU admission, applications, mortality rate, and the determining factors to outcomes. RESULTS: Thirty-three (7%) patients had 47 PICU admissions and 471 patients underwent bone marrow transplantation during 16-year study period. Also, 14 repeated episodes were registered in 9 different patients. The median age of PICU admitted patients was 4 (0.3 to 18) years and 29 (62%) were male. The main reasons for PICU admission were a respiratory failure, sepsis, and neurological event in 20, 8, and 7 patients, respectively. The average length of PICU stay was 14.5 (1 to 80) days, 14 (43%) of patients survived and the mortality rate was 57%. Multiple organ failure ( P =0.001), need for respiratory support ( P =0.007), inotrope agents ( P =0.001), and renal replacement therapy ( P =0.013) were found as significant risk factors for mortality. CONCLUSIONS: Allogeneic HSCT recipients need PICU admission because of its related different life-threatening complications. But there is a good chance of survival with quality PICU care and different advanced organ support methods.

An invisible cause of disability: stigma in migraine and epilepsy.

OBJECTIVE: Our purpose was to identify the ratio and severity of stigmatization in patients with migraine and epilepsy. We also collected demographic and clinical data to search for possible facilitators. METHODS: In total, 196 patients with migraine and 60 patients with epilepsy were enrolled. Neuro-QoL Stigma Scale was applied in an office setting by a neurologist in 3 different centers. Stigma scores were calculated as standardized T scores (total, enacted, and internalized). Demographics, clinical characteristics, and treatment status of the patients were also compared in terms of stigma scores. Kruskal-Wallis test or Mann-Whitney U tests were applied for comparisons. Spearman's correlation analysis was used for the evaluation of inter-parameter correlations. RESULTS: Eighty-one percent of the patients with epilepsy and 72% of the patients with migraine reported being stigmatized. Total T scores were significantly higher in the epilepsy group (50.78 ± 9.1) than the patients with migraine (44.9 ± 7.62), also than the chronic (45.86 ± 8.76) and episodic (44.7 ± 7.27) migraine subgroups (p < 0.05). T scores increased as the duration of disease increased; however, this correlation was significant for the epilepsy group only (p < 0.05). Migraine group with prophylactic treatment had significantly higher scores than the migraineurs without preventive therapy (p < 0.05). Enacted T scores were higher than internalized T scores in all analyzed groups and subgroups (p < 0.05). CONCLUSION: Patients with migraine and epilepsy are subjected to stigma. The ratio and intensity can change in different countries. We need to increase the awareness and search for better solutions. The standardized tests are important to compare results between studies.

Lymphopenia and tuberculous lymphadenitis under immunomodulatory agents in a multiple sclerosis patient: Follow-up of a challenging case.

Interferon-beta (IFN-ß) 1a and glatiramer acetate (GA) are first-line therapies for multiple sclerosis (MS) with immunomodulatory effects. We present a patient who developed lymphopenia and tuberculous lymphadenitis under treatment with these agents. The female patient who at present 65 year old is followed at our MS outpatient clinics had received GA (20 mg/day, subcutaneous injection) and later IFN-ß 1a (44 µg, thrice weekly, subcutaneous injection). During the course of her treatment, she developed mild to severe lymphopenia. A follow up thoracic spinal MRI (when lymphocyte count was 800/µl) showed multiple enlarged lymph nodes in the posterior mediastinum incidentally. Further investigation revealed tuberculous lymphadenitis. She received anti-tuberculosis (TB) treatment for nine months and her condition resolved. Although immunomodulatory treatments are considered safe with regard to opportunistic infections, and lymphopenia under these treatments are generally accepted as mild and asymptomatic, our experience was different with this patient. Further studies on the management of patients with lymphopenia and assessment of the risk of TB under immunomodulatory agents are needed.

[Assessment of serum MMP-9, TIMP-1 levels and MMP-9/TIMP-1 ratio in migraine patients with and without aura].

Background and purpose: Matrix metalloproteinases (MMP) are the enzymes responsible for proteolytic ac-tivity of extracellular matrix proteins. Tissue inhibitors of metalloproteinases (TIMPs) are their endogenous inhibitors. MMP-9 acts on the basal membrane of cerebellar epithe-lium and is antagonized by TIMP-1. MMP-9/TIMP-1 ratio exhibits the net activity of MMP-9. These enzymes are thought to have a role in migraine physio-pathogenesis. Methods: Total of 50 treatment-naive migraine patients (25 with aura and 25 without aura) with no other diseases, were included. 25 healthy control subjects of cor-responding age and gender were enrolled. For MMP-9 and TIMP-1 analysis, one serum sample from control group and two samples from patients were collected (during headache and headache-free periods). The enzyme levels were quantitatively analyzed by competitive ELISA method. Duration and severity of the pain and duration of the disease were recorded. Results: There was no significant difference in MMP-9 levels between patient and control groups during headache and headache-free periods (p: 0,746, p: 0,243). TIMP-1 levels were significantly lower and MMP-9/TIMP ratios were higher comparing with the control group (p: 0.001). Positive correlation was obtained between the duration of pain and MMP-9 levels in the headache-free period for both patient groups (p<0.05). There was also a positive correlation between MMP-9/TIMP-1 ratio and severity of pain (p<0.05). Conclusion: In our study, low TIMP-1 levels of patients in both headache and headache-free periods suggest that disturbance of proteolytic protection has a role in neuro-inflammation and pain in migraine. Therefore, these enzymes could be potential targets in migraine therapies.

Local field potentials of subthalamic nucleus contain electrophysiological footprints of motor subtypes of Parkinson's disease.

Although motor subtypes of Parkinson's disease (PD), such as tremor dominant (TD) and postural instability and gait difficulty (PIGD), have been defined based on symptoms since the mid-1990s, no underlying neural correlates of these clinical subtypes have yet been identified. Very limited data exist regarding the electrophysiological abnormalities within the subthalamic nucleus (STN) that likely accompany the symptom severity or the phenotype of PD. Here, we show that activity in subbands of local field potentials (LFPs) recorded with multiple microelectrodes from subterritories of STN provide distinguishing neurophysiological information about the motor subtypes of PD. We studied 24 patients with PD and found distinct patterns between TD (n = 13) and PIGD (n = 11) groups in high-frequency oscillations (HFOs) and their nonlinear interactions with beta band in the superior and inferior regions of the STN. Particularly, in the superior region of STN, the power of the slow HFO (sHFO) (200-260 Hz) and the coupling of its amplitude with beta-band phase were significantly stronger in the TD group. The inferior region of STN exhibited fast HFOs (fHFOs) (260-450 Hz), which have a significantly higher center frequency in the PIGD group. The cross-frequency coupling between fHFOs and beta band in the inferior region of STN was significantly stronger in the PIGD group. Our results indicate that the spatiospectral dynamics of STN-LFPs can be used as an objective method to distinguish these two motor subtypes of PD. These observations might lead to the development of sensing and stimulation strategies targeting the subterritories of STN for the personalization of deep-brain stimulation (DBS).

Matrix metalloproteinases and their tissue inhibitors in relapsing remitting multiple sclerosis: Possible markers and treatment agents.

BACKGROUND AND PURPOSE: Matrix metalloproteinases (MMPs), which are synthesized by many cell groups and responsible for the destruction of matrix proteins, and endogen tissue inhibitors of MMPs (TIMPs) have a role in the pathogenesis of Multiple Sclerosis (MS) by affecting the blood-brain barrier. We aimed to investigate the role of MMPs and TIMPs in the immunopathogenesis and in the course of multiple sclerosis (MS). METHODS: We enrolled 25 relapsing remitting MS patients, who had a definite MS diagnosis according to McDonald criteria and 25 healthy subjects similar for age and gender as control group. MMP-9- and TIMP-1 levels were measured twice in patient group (one time during an attack and one in remission) and once in healthy subjects. RESULTS: MMP-9- and TIMP-levels of patients during attack and remission period and MMP-9/TIMP-1 ratio were found significantly higher than in the control subjects. In patient group MMP-9 and TIMP-1 levels and MMP-9/TIMP-1 ratio during attacks were not significantly different than during remission period. However, when subdivided according to their number of attacks, patients with 2 attacks had significantly higher levels during attack period comparing to remission period (p<0.05); in case of patients with more than 2 attacks did not have a statistically significant difference in attack and remission periods. CONCLUSION: Matrix metalloproteinases are important actors in MS immunopathogenesis, particularly in the early period and inhibitor agents for these enzymes can be used as a treatment option.

Distinct subthalamic coupling in the ON state describes motor performance in Parkinson's disease.

OBJECTIVE: Cross-frequency coupling has been reported in the STN of patients with PD, but its significance and functional role are still not well understood. This study investigates pharmacological modulations of subthalamic oscillations and their nonlinear cross-frequency interactions across three consecutive cycles over unique 24-hour-long recordings. BACKGROUND: Identifying neurobiomarkers for PD can drive the development of novel personalized treatments by providing objective assessment of impairment. In particular, distinct frequency bands in LFP recordings and their interaction with one another have been shown to modulate with dopaminergic medication and thus, proposed as such biomarkers. METHODS: We recorded local field potentials 3 weeks postoperatively from externalized leads in 9 patients and correlated the neural patterns with improvements in motor signs over three medication intake cycles. We used two modalities to assess symptoms in the unmedicated OFF and the l-dopa-induced motor ON state: a subsection of the UPDRS and a keyboard tapping score measuring bradykinesia. RESULTS: In the OFF state, the amplitude of high-frequency oscillations in the 200- to 300-Hz range was coupled with the phase of low-beta (13-22 Hz) in all patients. After transition to the ON state, three distinct coupling patterns were observed among subjects. Among these, patients showing ON coupling between high-beta (22-30 Hz) and high-frequency oscillations in the 300- to 400-Hz range had significantly greater improvement in bradykinesia, according to the keyboard scores. CONCLUSION: Observing diminished coupling in the ON state, previous studies have hypothesized that the sole existence of coupling in STN has an "impeding" effect on normal processes, and thus it was considered to be pathological. In contrast, our observation of ON state coupling at distinct frequencies associated with the improvements in motor features suggest that the underlying mechanism of coupling might have impeding or enhancing effects depending on the coupled frequencies. © 2019 International Parkinson and Movement Disorder Society.

The changing resistance patterns of bacterial uropathogens in children.

BACKGROUND: Increased antimicrobial resistance is a problem in managing urinary tract infections (UTI). With this study we assessed the resistance patterns of urinary isolates in children with UTI between January 2017 and January 2018. METHODS: A retrospective cohort study was conducted. Among 5,443 isolates, a total of 776 UTI episodes in 698 patients were included. Patients' gender, age, voiding dysfunction, UTI history, prophylaxis status, and presence of vesicoureteral reflux were noted. Patients were divided into three age groups: group 1 for ages ≤12 months; group 2 for ages 13-60 months; and group 3 for ages >60 months. The susceptibilities of etiologic agents to different antimicrobials were explored. RESULTS: Median age was 54 months (range 1 month-21 years); male to female ratio was 1:5. The most common causative agent was Escherichia coli (83% of the cases), followed by Klebsiella pneumoniae (7.5%). Resistance to ampicillin (62.6%) and co-trimoxazole (39.8%) were remarkable in all isolates. Overall extended-spectrum beta-lactamase (ESBL) positivity was 23.5%. The highest resistance rates, higher ESBL positivity (28.6%), and K. pneumoniae frequency (13.5%) were observed in group 1. Ceftriaxone resistance was significantly low (0.5%) in the ESBL (-) group, which constituted the majority of the isolates. Higher resistance rates were observed among the patients on prophylaxis compared to those off prophylaxis (P < 0.001). CONCLUSION: Ceftriaxone can still be used for empirical treatment; however, initial urine culture results are crucial due to high ESBL positivity. Special consideration must be taken for patients under 1 year of age. Periodical surveillance studies are needed to explore the changing resistance patterns of uropathogens and modify treatment plans.

Sleep patterns in Parkinson's disease: direct recordings from the subthalamic nucleus.

Sleep is a fundamental homeostatic process, and disorders of sleep can greatly affect quality of life. Parkinson's disease (PD) is highly comorbid for a spectrum of sleep disorders and deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been reported to improve sleep architecture in PD. We studied local field potential (LFP) recordings in PD subjects undergoing STN-DBS over the course of a full-night's sleep. We examined the changes in oscillatory activity recorded from STN between ultradian sleep states to determine whether sleep-stage dependent spectral patterns might reflect underlying dysfunction. For this study, PD (n=10) subjects were assessed with concurrent polysomnography and LFP recordings from the DBS electrodes, for an average of 7.5 hours in 'off' dopaminergic medication state. Across subjects, we found conserved spectral patterns among the canonical frequency bands (delta 0-3 Hz, theta 3-7 Hz, alpha 7-13 Hz, beta 13-30 Hz, gamma 30-90 Hz and high frequency 90-350 Hz) that were associated with specific sleep cycles: delta (0-3 Hz) activity during non-rapid eye movement (NREM) associated stages was greater than during Awake, whereas beta (13-30 Hz) activity during NREM states was lower than Awake and rapid eye movement (REM). In addition, all frequency bands were significantly different between NREM states and REM. However, each individual subject exhibited a unique mosaic of spectral interrelationships between frequency bands. Our work suggests that LFP recordings from human STN differentiate between sleep cycle states, and sleep-state specific spectral mosaics may provide insight into mechanisms underlying sleep pathophysiology.

Exploring psychiatric comorbidities and their effects on quality of life in patients with temporal lobe epilepsy and juvenile myoclonic epilepsy.

AIM: The relation of epilepsy with psychiatric disorders is of great interest to researchers due to its behavioral, social, and cognitive outcomes. In this study, we explored psychiatric comorbidity and its effects on quality of life (QOL) in patients with mesial temporal lobe epilepsy (MTLE) and juvenile myoclonic epilepsy (JME). METHODS: Thirty patients with MTLE, 30 patients with JME, and 30 healthy controls underwent the Structured Clinical Interview for DSM-IV (SCID-I) to diagnose psychiatric disorders. None of the subjects had previously undergone psychiatric examination. The Quality of Life in Epilepsy Inventory-89 (QOLIE-89) was used to assess QOL. We compared psychiatric comorbidity among groups and evaluated its effects on QOL. RESULTS: We detected comorbid psychiatric disorders in 37% of patients with JME and in 57% of patients with MTLE. Comorbid psychiatric disorders were less frequent in healthy controls compared to the patient groups (P = 0.029). Comparing demographic and clinical features of patients with JME and MTLE and their mean QOL scores, there was no statistical difference. Furthermore, we compared QOLIE scores between patients with and without psychiatric comorbidity. JME patients with mood disorders had lower scores on the Attention/Concentration subscale (P = 0.013). MTLE patients with a psychotic disorder had lower scores on the Social Isolation, Energy, and Fatigue subscales (P = 0.045). Patients with somatoform disorders had higher Pain scores (P = 0.04). CONCLUSION: Our study suggests that comorbid psychiatric disorders negatively affect patients' QOL regardless of seizure syndrome. Comorbid psychiatric conditions should be determined to increase QOL in patients with epilepsy.

Evaluation of interictal autonomic function during attack and remission periods in cluster headaches.

OBJECTIVE: To investigate which part of the autonomic system is mainly involved and assess the sensitivity of face sympathetic skin response in cluster headache. MATERIAL AND METHODS: The study sample consisted of 19 drug-free cluster headache patients (16 males, three females) and 19 healthy volunteers. Demographic features and pain characteristics were thoroughly identified. Dysautonomic symptoms were evaluated during attack and remission periods of cluster headache patients. Orthostatic hypotension, R-R interval variation and sympathetic skin responses obtained from the face and four extremities were evaluated and the sensitivity of face sympathetic skin responses was assessed in contrast to extremity sympathetic skin responses. RESULTS: All sympathetic skin responses of face and extremities could be obtained during attack and remission periods. On the symptomatic side, mean latency of face sympathetic skin responses was longer compared to the asymptomatic side and controls (p = 0.02, p = 0.004). There were no differences in latency or amplitude of extremity sympathetic skin responses between symptomatic and asymptomatic sides and controls. No significant relationship was determined between sympathetic skin responses, R-R interval variation, orthostatic hypotension and cluster headache clinical features. CONCLUSION: Sympathetic hypoactivity of the face seems to predominate the pathophysiology of cluster headache. Face sympathetic skin responses might be more sensitive compared to extremity sympathetic skin response in demonstrating dysautonomic symptoms in cluster headache patients.

Evaluation of cognitive functions of juvenile myoclonic epileptic patients by magnetic resonance spectroscopy and neuropsychiatric cognitive tests concurrently.

Our aim in this research is investigating the hypothesis of biochemical changes in frontal cortex and thalamocortical pathways in juvenile myoclonic epilepsy (JME) and the interaction between the biochemical changes and cortical functions. Magnetic resonance spectroscopy (MRS) was applied to 20 JME patients and 20 controls for measuring N-acetyl aspartate (NAA), N-acetyl aspartate to creatine ratio (NAA/Cr), Glutamine and Glutamate (GLX), Glutamine-Glutamate to creatine (GLX/Cr), Choline containing compounds (Cho) and Choline to creatine (Cho/Cr) levels. Neuropsychological cognitive tests for linguistic and visual attention, linguistic and visual memory, visuospatial and executive functions were applied to all participants. NAA and NAA/Cr concentrations were found lower in bilateral frontal and thalamic regions in JME group as compared with the control group (p < 0.05). There was no difference in frontal and thalamic GLX, GLX/Cr, Cho, Cho/Cr levels in between JME patients and controls (p > 0.05). JME patients were found more unsuccessful than the controls in attention, memory, visuospatial function, verbal fluency, Trail B test and executive functions, stroop test, clock drawing test and Trail A test (p < 0.05). Prefrontal NAA/Cr level was positively related to visual attention, memory, stroop test and thalamic NAA/Cr level was positively related to linguistic memory and Wisconsin card sorting test in JME patients. This research highlights regional brain changes and cognitive decline in JME patients and suggests that MRS may be a sensitive technique for showing subclinical cognitive changes.

Gender influences headache characteristics with increasing age in migraine patients.

BACKGROUND AND AIMS: Migraine headache is one of the most common primary headache disorders and is three times more prevalent in women than in men, especially during the reproductive ages. The neurobiological basis of the female dominance has been partly established. The present study aimed to investigate the effect of gender on the headache manifestations in migraine patients. METHODS: The study group consisted of 2082 adult patients from five different hospitals' tertiary care-based headache clinics. The relationship between headache characteristics and gender was evaluated in migraine with aura (MwA) and migraine without aura (MwoA). The duration, severity, frequency of headache and associated symptoms were evaluated in both genders and age-dependent variations and analyzed in two subgroups. RESULTS: Women with migraine were prone to significantly longer duration and intensity of headache attacks. Nausea, phonophobia and photophobia were more prevalent in women. Median headache duration was also longer in women than in men in MwA (p = 0.013) and MwoA (p < 0.001). Median headache intensity was higher in women than in men in MwA (p = 0.010) and MwoA (p = 0.009). The frequency of nausea was significantly higher in women than in men in MwA (p = 0.049). Throbbing headache quality and associated features (nausea, photophobia, and phonophobia) were significantly more frequent in women than in men in MwoA. The gender impact varied across age groups and significant changes were seen in female migraineurs after age 30. No age-dependent variation was observed in male migraineurs. CONCLUSION: Gender has an influence on the characteristics of the headache as well as on the associated symptoms in migraine patients, and this impact varies across the age groups, particularly in women.

Time-varying causality between income inequality and ecological footprint in Turkey.

This paper investigates the relationship between income inequality and environmental degradation for the case of Turkey between 1987 and 2017 through the bootstrap causality method that changes over time. The study used the GINI coefficient to denote income inequality and ecological footprint (EFP) to represent environmental degradation. According to the analysis results, a causal relationship has been determined for Turkey from GINI to EFP between 2002 and 2015 and from EFP to GINI between 2002 and 2008. Thanks to the method used in the analysis, it was concluded that GINI-affected EFP positively between 2002 and 2005 and negatively between 2006 and 2015. Between 2002 and 2005, Turkey endured a difficult period of restructuring after two major banking crises in 1999 and 2001. The rapid development, especially in industry and urbanization, caused environmental degradation in this period. Between 2006 and 2015, the central dynamic of Turkey's growth trend was the finance sector, and rapid privatizations were realized. Nevertheless, the income justice improvement in this period negatively impacted the environment due to consumption and production habits. Policymakers should evaluate Turkey in its economic reality and produce policies accordingly. Environmental awareness should be increased in the production and consumption activities of all segments of society, benefiting from the developments in income distribution. The ecological impact of the income redistribution policy, along with its market and social consequences, needs to be evaluated.

A study of the relationship between serum uric acid levels and pain in patients with migraine.

Serum uric acid (SUA), the end product of purine metabolism acts as an antioxidant and is related to oxidative stress. It has been reported that SUA may be involved in the pathogenesis of neurodegenerative diseases including Alzheimer disease, Huntington disease, Parkinson disease, and multiple sclerosis. However, studies evaluating SUA levels in migraine are scarce. This study aimed to explore the relationship between pain characteristics and SUA levels in patients with migraine and compare SUA levels in migraine patients during a headache attack and headache-free period with those control groups. This prospective, cross-sectional study included 78 patients with migraine and 78 healthy subjects who were randomly selected from hospital personnel as the control group. Headache characteristics (duration of attack, pain intensity, and headache frequency) and sociodemographic features were recorded. The SUA level was measured once in the control group and twice in the migraine patients, during the migraine attack and headache-free periods. Although the SUA levels of the migraine group in the headache-free period were higher than those of the control group, the difference was not statistically significant. Gender was not significantly related to the change in SUA levels between the attack and headache-free period. When the correlation between age, duration of migraine, frequency, duration, and intensity of pain was evaluated; the difference between SUA levels in female migraine patients was weakly correlated with headache intensity, whereas male patients had a moderate correlation. ( P < .05; R > 0.250, and R > 0.516, respectively). The difference in SUA level in the migraine attack period compared to the headache-free period showing a positive correlation with pain intensity suggested that SUA may have a role in migraine due to its antioxidant role.

Frequency of epilepsies in family members of patients with different epileptic syndromes.

AIM: To determine the frequency of epilepsies in the family members of epileptic patients. METHODS: The records of 4,851 patients with epilepsy were reviewed. The frequency and patterns of different epilepsies and epileptic syndromes in the patients, number of affected relatives and consanguinity were studied. RESULTS: A total of 1,753 patients were excluded due to various reasons. Of the remaining patients, 296 (9.5% of 3,098) had first- or second-degree relatives affected with seizures. The incidence of family history in the localization-related cryptogenic epilepsies group was significantly higher than all other groups (246 patients). Juvenile myoclonic epilepsy was the most frequent epileptic syndrome (34 patients). Consanguinity was detected in 56 patients, and 33 (58.9%) of these subjects were in the localization-related cryptogenic epilepsies group. Of all subjects, 59 (19.9%) had more than 1 epileptic family member. The ratio of affected first- to second-degree relatives was 202/94. CONCLUSIONS: A considerable number of the relatives of epileptic patients have seizures. The risk of relatives being affected depends on their relationship with the proband. Genetic factors may play an almost equal role in the predisposition of relatives to epilepsy in families of probands with cryptogenic and idiopathic epileptic syndromes.

Electroceutically induced subthalamic high-frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson's disease.

Despite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by electrical stimulation of the subthalamic nucleus (STN) at therapeutic and non-therapeutic frequencies in Parkinson's disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130-180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20 Hz) stimulation, the HFOs were induced only with therapeutic frequencies, and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA. We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

Subthalamic Single Cell and Oscillatory Neural Dynamics of a Dyskinetic Medicated Patient With Parkinson's Disease.

Single cell neuronal activity (SUA) and local field potentials (LFP) in the subthalamic nucleus (STN) of unmedicated Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery have been well-characterized during microelectrode recordings (MER). However, there is limited knowledge about the changes in the firing patterns and oscillations above and within the territories of STN after the intake of dopaminergic medication. Here, for the first time, we report the STN single cell and oscillatory neural dynamics in a medicated patient with idiopathic PD using intraoperative MER. We recorded LFP and SUA with microelectrodes at various depths during bilateral STN-DBS electrode implantation. We isolated 26 neurons in total and observed that tonic and irregular firing patterns of individual neurons predominated throughout the territories of STN. While burst-type firings have been well-characterized in the dorsal territories of STN in unmedicated patients, interestingly, this activity was not observed in our medicated subject. LFP recordings lacked the excessive beta (8-30 Hz) activity, characteristic of the unmedicated state and signal energy was mainly dominated by slow oscillations below 8 Hz. We observed sharp gamma oscillations between 70 and 90 Hz within and above the STN. Despite the presence of a broadband high frequency activity in 200-400 Hz range, no cross-frequency interaction in the form of phase-amplitude coupling was noted between low and high frequency oscillations of LFPs. While our results are in agreement with the previously reported LFP recordings from the DBS lead in medicated PD patients, the sharp gamma peak present throughout the depth recordings and the lack of bursting firings after levodopa intake have not been reported before. The lack of bursting in SUA, the lack of excessive beta activity and cross frequency coupling between HFOs and lower rhythms further validate the link between bursting firing regime of neurons and pathological oscillatory neural activity in PD-STN. Overall, these observations not only validate the existing literature on the PD electrophysiology in healthy/medicated animal models but also provide insights regarding the underlying electro-pathophysiology of levodopa-induced dyskinesias in PD patients through demonstration of multiscale relationships between single cell firings and field potentials.

Unsupervised clustering reveals spatially varying single neuronal firing patterns in the subthalamic nucleus of patients with Parkinson's disease.

INTRODUCTION: Subthalamic nucleus (STN) is an effective target for deep brain stimulation (DBS) to reduce the motor symptoms of Parkinson's disease (PD). It is important to identify firing patterns within the structure for a better understanding of the electro-pathophysiology of the disease. Using recently established metrics, our study aims to autonomously identify the discharge patterns of individual cells and examine their spatial distribution within the STN. METHODS: We recorded single unit activity (SUA) from 12 awake PD patients undergoing a standard clinical DBS surgery. Three extracted features from raw SUA (local variation, bursting index and prominence of peak) were used with k-means clustering to achieve the aforementioned unsupervised grouping of firing patterns. RESULTS: 279 neurons were isolated and four distinct firing patterns were identified across patients: tonic (11%), irregular (55%), periodic (9%) and non-periodic bursts (25%). The mean firing rates for irregular discharges were significantly lower (p < 0.05) than the rest. Tonic firings were significantly ventral (p < 0.05) while periodic (p < 0.05) and non-periodic (p < 0.01) bursts were dorsal. The percentage of periodically bursting neurons in dorsal region and entire STN were significantly correlated with off state UPDRS tremor scores (r = 0.51, p = 0.04) and improvement in bradykinesia and rigidity (r = 0.57, p = 0.02) respectively. CONCLUSION: Strengthening the application of unsupervised clustering for firing patterns of individual cells, this study shows a unique spatial affinity of tonic activity towards the ventral and bursting activity towards the dorsal region of STN in PD patients. This spatial preference, together with the correlation of clinical scores, can provide a clue towards understanding Parkinsonian symptom generation.

Randomized, Double-Blind Assessment of LFP Versus SUA Guidance in STN-DBS Lead Implantation: A Pilot Study.

Background: The efficacy of deep brain stimulation (DBS) therapy in Parkinson's disease (PD) patients is highly dependent on the precise localization of the target structures such as subthalamic nucleus (STN). Most commonly, microelectrode single unit activity (SUA) recordings are performed to refine the target. This process is heavily experience based and can be technically challenging. Local field potentials (LFPs), representing the activity of a population of neurons, can be obtained from the same microelectrodes used for SUA recordings and allow flexible online processing with less computational complexity due to lower sampling rate requirements. Although LFPs have been shown to contain biomarkers capable of predicting patients' symptoms and differentiating various structures, their use in the localization of the STN in the clinical practice is not prevalent. Methods: Here we present, for the first time, a randomized and double-blinded pilot study with intraoperative online LFP processing in which we compare the clinical benefit from SUA- versus LFP-based implantation. Ten PD patients referred for bilateral STN-DBS were randomly implanted using either SUA or LFP guided targeting in each hemisphere. Although both SUA and LFP were recorded for each STN, the electrophysiologist was blinded to one at a time. Three months postoperatively, the patients were evaluated by a neurologist blinded to the intraoperative recordings to assess the performance of each modality. While SUA-based decisions relied on the visual and auditory inspection of the raw traces, LFP-based decisions were given through an online signal processing and machine learning pipeline. Results: We found a dramatic agreement between LFP- and SUA-based localization (16/20 STNs) providing adequate clinical improvement (51.8% decrease in 3-month contralateral motor assessment scores), with LFP-guided implantation resulting in greater average improvement in the discordant cases (74.9%, n = 3 STNs). The selected tracks were characterized by higher activity in beta (11-32 Hz) and high-frequency (200-400 Hz) bands (p < 0.01) of LFPs and stronger non-linear coupling between these bands (p < 0.05). Conclusion: Our pilot study shows equal or better clinical benefit with LFP-based targeting. Given the robustness of the electrode interface and lower computational cost, more centers can utilize LFP as a strategic feedback modality intraoperatively, in conjunction to the SUA-guided targeting.