Andrew L. Ko

Androgenic Suppression of ATP-binding Cassette Transporter A1 Expression in LNCaP Human Prostate Cancer Cells

Alteration of lipid metabolism is commonly observed in sex hormone-dependent cancer cells, yet its mechanistic involvement in cancer cell proliferation and progression is unclear. We have found that the expression of the cholesterol transporter, ATP-binding cassette transporter A1 (ABCA1), was 15- to 20-fold higher in androgen-dependent than in androgen-independent LNCaP human prostate cancer cells, indicating a possible relationship between the expression levels of ABCA1 and prostate cancer progression. On the basis of real-time quantitative PCR and Western blot analysis, expression of ABCA1 in androgen-dependent cells was inhibited by androgen. The antiandrogen Casodex blocked the effect of androgen, implicating the androgen receptor in regulation of ABCA1 expression by androgens. Using an ABCA1 promoter-reporter gene assay, androgenic suppression was observed at the transcriptional level in androgen-dependent but not in androgen-independent prostate cancer cells. ABCA1 appears to have a role in modulating cell proliferation because knockdown of ABCA1 expression by RNA interference in androgen-dependent cells increased their rate of proliferation. Therefore, a suppressive effect of androgen on ABCA1 expression may be one of the mechanisms by which androgens regulate proliferation in prostate cancer cells. Attenuated ABCA1 expression in androgen-independent cells thus may contribute, in part, to prostate cancer progression.

Quasi-periodic Fluctuations in Default Mode Network Electrophysiology

The study of human brain electrophysiology has extended beyond traditional frequency ranges identified by the classical EEG rhythms, encompassing both higher and lower frequencies. Changes in high-gamma-band (>70 Hz) power have been identified as markers of local cortical activity. Fluctuations at infra-slow (<0.1 Hz) frequencies have been associated with functionally significant cortical networks elucidated using fMRI studies. In this study, we examined infra-slow changes in band-limited power across a range of frequencies (1–120 Hz) in the default mode network (DMN). Measuring the coherence in band-limited power fluctuations between spatially separated electrodes makes it possible to detect small, spatially extended, and temporally coherent fluctuating components in the presence of much larger incoherent fluctuations. We show that the default network is characterized by significant high-gamma-band (65–110 Hz) coherence at infra-slow (<0.1 Hz) frequencies. This coherence occurs over a narrow frequency range, centered at 0.015 Hz, commensurate with the frequency of BOLD signal fluctuations seen by fMRI, suggesting that quasi-periodic, infra-slow changes in local cortical activity form the neurophysiological basis for this network.

Deep brain stimulation for psychiatric disorders: where we are now.

Fossil records showing trephination in the Stone Age provide evidence that humans have sought to influence the mind through physical means since before the historical record. Attempts to treat psychiatric disease via neurosurgical means in the 20th century provided some intriguing initial results. However, the indiscriminate application of these treatments, lack of rigorous evaluation of the results, and the side effects of ablative, irreversible procedures resulted in a backlash against brain surgery for psychiatric disorders that continues to this day. With the advent of psychotropic medications, interest in invasive procedures for organic brain disease waned. Diagnosis and classification of psychiatric diseases has improved, due to a better understanding of psychiatric patho-physiology and the development of disease and treatment biomarkers. Meanwhile, a significant percentage of patients remain refractory to multiple modes of treatment, and psychiatric disease remains the number one cause of disability in the world. These data, along with the safe and efficacious application of deep brain stimulation (DBS) for movement disorders, in principle a reversible process, is rekindling interest in the surgical treatment of psychiatric disorders with stimulation of deep brain sites involved in emotional and behavioral circuitry. This review presents a brief history of psychosurgery and summarizes the development of DBS for psychiatric disease, reviewing the available evidence for the current application of DBS for disorders of the mind.

Retrospective review of multilevel spinal fusion combined with spinal cord transection for treatment of kyphoscoliosis in pediatric myelomeningocele patients

Study Design. Retrospective review of cases at a single institution from 1998 to 2005. Objective. The authors present their surgical experience, complications, and learned insight in 9 myelomeningocele children with kyphoscoliosis treated with combined spinal cord transection and spinal fusion. Summary of Background Data. Complication rates in spinal fusion for treatment of kyphoscoliosis in myelomeningocele patients are high. Spinal cord transection in combination with fusion can be an appropriate strategy in selected patients, but changes in cerebrospinal fluid (CSF) dynamics that may accompany ligation of the distal CSF circulation are not well characterized. Methods. Demographic, clinical, and radiologic data were examined in 9 children with myelomeningocele level at or above T12 and no residual urologic function treated at our institution with spinal cord detethering and transection, and multilevel spinal fusion. Seven children underwent kyphectomy with posterior fusion only for severe gibbus deformities, while 2 had anterior and posterior fusions for severe kyphoscoliosis. Results. Follow-up of patients ranged from 4 to 92 months (mean, 37.8 months). Eight children (89%) experienced postoperative complications involving wound infection or skin breakdown. One child presented with a CSF leak. Two children (22%) required revision of their ventriculoperitoneal shunts. The average angle of kyphosis before surgery was 122.3 (range, 48°–180°), and the average postoperative angle was 38.2 (range, 4°–113°), with average correction being 81.9° (range, 29°–124). Average correction of scoliosis, if present, was 59.5° (range, 35°–92°). Conclusion. Combined spinal cord transection and spinal fusion allowed an average correction of kyphosis by 81.9°. The complication rate was 89%, with wound concerns being the most significant. Additionally, 22% of patients required shunt revision within 6 weeks of surgery. We attribute this to alteration of CSF dynamics resulting from loss of CSF absorption and flow-buffering capacity below the level of the spinal cord transection.

Identifying functional networks using endogenous connectivity in gamma band electrocorticography.

Correlations in spontaneous, infra-slow (<0.1 Hz) fluctuations in gamma band (70-100 Hz) signal recorded using electrocorticography (ECoG) reflect the functional organization of the brain, appearing in auditory and visual sensory cortex, motor cortex, and the default mode network (DMN). We have developed a data-driven method using co-modulation in spontaneous, infra-slow, and gamma band power fluctuations in ECoG to characterize the connectivity between cortical areas. A graph spectral clustering algorithm was used to identify networks that appear consistently. These networks were compared with clinical mapping results obtained using electrocortical stimulation (ECS). We identify networks corresponding to motor and visual cortex with good specificity. Anatomic and functional evidence indicates that other networks, such as the DMN, are also identified by this algorithm. These results indicate that it may be possible to map functional cortex using only spontaneous ECoG recordings. In addition, they support the hypothesis that infra-slow co-modulations of gamma band power represent the neurophysiological basis underlying resting-state networks. Methods examining infra-slow co-modulations in gamma band power will be useful for studying changes in brain connectivity in differing behavioral contexts. Our observations can be made in the absence of observable behavior, suggesting that the electrical mapping of functional cortex is feasible without the use of ECS or task-mediated evoked responses.

Trigeminal neuralgia without neurovascular compression presents earlier than trigeminal neuralgia with neurovascular compression.

OBJECT Trigeminal neuralgia (TN) occurs and recurs in the absence of neurovascular compression (NVC). To characterize what may be distinct patient populations, the authors examined age at onset in patients with TN with and without NVC. METHODS A retrospective review of patients undergoing posterior fossa surgery for Type I TN at Oregon Health & Science University from 2009 to 2013 was undertaken. Charts were reviewed, and imaging and operative data were collected for patients with and without NVC. Mean, median, and the empirical cumulative distribution of onset age were determined. Statistical analysis was performed using Student t-test, Wilcoxon and Kolmogorov-Smirnoff tests, and Kaplan-Meier analysis. Multivariate analysis was performed using a Cox proportional hazards model. RESULTS The charts of 219 patients with TN were reviewed. There were 156 patients who underwent posterior fossa exploration and microvascular decompression or internal neurolysis: 129 patients with NVC and 27 without NVC. Mean age at symptoms onset for patients with and without NVC was 51.1 and 42.6 years, respectively. This difference (8.4 years) was significant (t-test: p = 0.007), with sufficient power to detect an effect size of 8.2 years. Median age between groups with and without NVC was 53.25 and 41.2 years, respectively (p = 0.003). Histogram analysis revealed a bimodal age at onset in patients without NVC, and cumulative distribution of age at onset revealed an earlier presentation of symptoms (p = 0.003) in patients without NVC. Chi-square analysis revealed a trend toward female predominance in patients without NVC, which was not significant (p = 0.08). Multivariate analysis revealed that age at onset was related to NVC but not sex, symptom side or distribution, or patient response to medical treatment. CONCLUSIONS NVC is neither sufficient nor necessary for the development of TN. Patients with TN without NVC may represent a distinct population of younger, predominantly female patients. Further research into the pathophysiology underlying this debilitating disease is needed.

Chronic electrocorticography for sensing movement intention and closed-loop deep brain stimulation with wearable sensors in an essential tremor patient

Deep brain stimulation (DBS) has become a widespread and valuable treatment for patients with movement disorders such as essential tremor (ET). However, current DBS treatment constantly delivers stimulation in an open loop, which can be inefficient. Closing the loop with sensors to provide feedback may increase power efficiency and reduce side effects for patients. New implantable neuromodulation platforms, such as the Medtronic Activa PC+S DBS system, offer important data sources by providing chronic neural sensing capabilities and a means of investigating dynamic stimulation based on symptom measurements. The authors implanted in a single patient with ET an Activa PC+S system, a cortical strip of electrodes on the hand sensorimotor cortex, and therapeutic electrodes in the ventral intermediate nucleus of the thalamus. In this paper they describe the effectiveness of the platform when sensing cortical movement intentions while the patient actually performed and imagined performing movements. Additionally, they demonstrate dynamic closed-loop DBS based on several wearable sensor measurements of tremor intensity.

Transcriptional regulation of farnesyl pyrophosphate synthase by liver X receptors

Liver X receptors (LXRs) are members of the nuclear receptor superfamily that are involved in cholesterol and lipid metabolism. In addition to liver, the brain is another site where LXRs may control cholesterol homeostasis. In the brain, the regulation of cholesterol homeostasis is independent from other parts of the body, and its disturbance is associated with neurodegenerative disorders, such as Alzheimers disease. We have used PCR-based suppressive subtractive cloning to identify new LXR target genes in brain cells. In this report, we show that farnesyl pyrophosphate synthase (FPPS) is a new target gene for LXR in astrocytes and neurons. Farnesyl pyrophosphate is an obligate intermediate for de novo cholesterol synthesis and a substrate for protein farnesylation. Stimulation of FPPS mRNA synthesis by an LXR agonist, Hypocholamide, was observed in several cell lines from the central nervous system. We identified a single putative direct repeat 4 (DR4) LXR response element in the FPPS promoter. In a reporter gene assay, LXR transactivated a reporter gene bearing a truncated FPPS promoter containing this DR4 cis-element but not if the DR4 element was mutated. Using gel-mobility shift assay, we further demonstrated the direct interaction between the LXR/retinoid X receptor (RXR) heterodimer and the response element. Taken together, our results indicate that LXRs directly regulate FPPS gene expression, and thus may play a role in modulating cholesterol synthesis in the brain.

Directional patterns of cross frequency phase and amplitude coupling within the resting state mimic patterns of fMRI functional connectivity.

Functional imaging investigations into the brains resting state interactions have yielded a wealth of insight into the intrinsic and dynamic neural architecture supporting cognition and behavior. Electrophysiological studies however have highlighted the fact that synchrony across large-scale cortical systems is composed of spontaneous interactions occurring at timescales beyond the traditional resolution of fMRI, a feature that limits the capacity of fMRI to draw inference on the true directional relationship between network nodes. To approach the question of directionality in resting state signals, we recorded resting state functional MRI (rsfMRI) and electrocorticography (ECoG) from four human subjects undergoing invasive epilepsy monitoring. Using a seed-point based approach, we employed phase-amplitude coupling (PAC) and biPhase Locking Values (bPLV), two measures of cross-frequency coupling (CFC) to explore both outgoing and incoming connections between the seed and all non-seed, site electrodes. We observed robust PAC between a wide range of low-frequency phase and high frequency amplitude estimates. However, significant bPLV, a CFC measure of phase-phase synchrony, was only observed at specific narrow low and high frequency bandwidths. Furthermore, the spatial patterns of outgoing PAC connectivity were most closely associated with the rsfMRI connectivity maps. Our results support the hypothesis that PAC is relatively ubiquitous phenomenon serving as a mechanism for coordinating high-frequency amplitudes across distant neuronal assemblies even in absence of overt task structure. Additionally, we demonstrate that the spatial distribution of a seed-point rsfMRI sensorimotor network is strikingly similar to specific patterns of directional PAC. Specifically, the high frequency activities of distal patches of cortex owning membership in a rsfMRI sensorimotor network were most likely to be entrained to the phase of a low frequency rhythm engendered from the neural populations at the seed-point, suggestive of greater directional coupling from the seed out to the site electrodes.

Intracerebral abscess associated with the Camino intracranial pressure monitor: case report and review of the literature.

BACKGROUND AND IMPORTANCE Intracranial pressure (ICP) monitoring is a mainstay in the management of traumatic brain injury. Large investigations have validated the safety and efficacy of ICP monitors in comatose patients. Clinically relevant infections are extremely rare and cerebral abscess has never been reported with the Camino device. We describe an exceptional case of a life-threatening intracerebral abscess from an intraparenchymal ICP monitor. CLINICAL PRESENTATION A 35-month-old child required 7 days of ICP monitoring after a fall from a 2-story window. His hospital course was complicated by severe airway edema treated, in part, with high-dose corticosteroid therapy for a total of 10 days. Two weeks later, the patient deteriorated acutely owing to a large intracerebral abscess under the previous ICP monitor site. Urgent craniotomy with evacuation of the abscess was performed on 2 separate occasions. Cultures grew methicillin-sensitive Staphylococcus aureus, which was treated with long-term antibiotics. At the 3-month follow-up, the patient was meeting age-appropriate milestones without focal deficits. CONCLUSION To the best of our knowledge, this is the first report describing an intracerebral abscess as a complication from an intraparenchymal pressure monitor. Corticosteroid therapy may have constituted an independent risk factor for the ICP monitor--associated infection, as well as reinsertion of the ICP monitoring device at the same site. That this is the first reported parenchymal infectious complication underscores the safety of this device with respect to infection. When reinsertion of a parenchymal monitor is considered, a new site should be chosen.