Transition of Topical Therapy Formulation in Psoriasis: Insights from a Canadian Practice Reflective.

Patient preferences for psoriasis treatment may affect treatment adherence and disease control; changing topical formulation may improve adherence and patient acceptance of treatment. This study explored dermatologists' reasons for transitioning psoriasis patients from an ointment or gel (Dovobet®) formulation to an aerosol foam (Enstilar®) formulation of calcipotriol and betamethasone dipropionate (Cal/BD), and to assess the success of this transition. Medical records of 81 Canadian patients from 9 dermatologists were retrospectively reviewed for symptoms affecting quality of life, reasons for transitioning treatment, and whether transition was successful. Reasons for transition included efficacy, quality of life, and patient adherence. At follow-up, median psoriasis severity and body surface area affected had decreased from baseline, and patients experienced improved quality of life. Itch and itch-related sleep loss, which were identified as burdensome in 63% of patients at baseline, had resolved in 33% and improved in 54% of patients at follow-up. Dermatologists deemed the transition successful in 85% of patients, with the most common reasons being patient-reported success, clearance of signs/symptoms, and continued prescription refills. Transition from Cal/BD ointment or gel to aerosol foam was generally deemed successful by patients and dermatologists, and was associated with improved quality of life and improved itch control.

Spatiotemporal dynamics of cortical perfusion in response to thalamic deep brain stimulation.

Deep brain stimulation (DBS) has revolutionized the treatment of movement disorders. The parameters of electrical stimulation are important to its therapeutic effect and remain a source of clinical controversy. DBS exerts its actions not only locally at the site of stimulation but also remotely through afferent and efferent connections, which are vital to its clinical effects. Yet, only a few studies have examined how cortical activity changes in response to various electrical parameters. Here, we investigated how the parameters of thalamic DBS alter cortical perfusion in rats using intrinsic optical imaging. We hypothesized that thalamic DBS will increase perfusion in primary motor cortex (M1), proportional to amplitude, pulse width, or frequency of the stimulation applied. We applied 45 different combinations of amplitude, pulse width and frequency in the ventro-lateral (VL) nucleus of the thalamus in anesthetized rats while measuring perfusion in M1. VL thalamic DBS reduced cortical reflectance, which corresponds to an increase in cortical perfusion. We computed the maximum change in reflectance (MCR) as well as the spatial spread of MCR in each trial. Both MCR and spatial spread increased linearly with increases in current amplitude or pulse width of stimulation; however, the effect of frequency was non-linear. Stimulation at 20 Hz was significantly different from that at higher frequencies while stimulation at higher frequencies did not differ significantly from each other. Moreover, the effect of pulse width on MCR was larger than the effect of amplitude. The proportional increase in M1 perfusion due to increase in amplitude or pulse width suggests that both activate more neural elements and increase the volume of tissue activated. These results should help clinicians set parameters of DBS. The use of optical imaging to monitor effects of DBS on M1 may not only help understand DBS mechanisms, but may also provide feedback for closed loop DBS devices.

CMOS Image Sensor and System for Imaging Hemodynamic Changes in Response to Deep Brain Stimulation.

Deep brain stimulation (DBS) is a therapeutic intervention used for a variety of neurological and psychiatric disorders, but its mechanism of action is not well understood. It is known that DBS modulates neural activity which changes metabolic demands and thus the cerebral circulation state. However, it is unclear whether there are correlations between electrophysiological, hemodynamic and behavioral changes and whether they have any implications for clinical benefits. In order to investigate these questions, we present a miniaturized system for spectroscopic imaging of brain hemodynamics. The system consists of a 144 ×144, [Formula: see text] pixel pitch, high-sensitivity, analog-output CMOS imager fabricated in a standard 0.35 µm CMOS process, along with a miniaturized imaging system comprising illumination, focusing, analog-to-digital conversion and µSD card based data storage. This enables stand alone operation without a computer, nor electrical or fiberoptic tethers. To achieve high sensitivity, the pixel uses a capacitive transimpedance amplifier (CTIA). The nMOS transistors are in the pixel while pMOS transistors are column-parallel, resulting in a fill factor (FF) of 26%. Running at 60 fps and exposed to 470 nm light, the CMOS imager has a minimum detectable intensity of 2.3 nW/cm(2) , a maximum signal-to-noise ratio (SNR) of 49 dB at 2.45 µW/cm(2) leading to a dynamic range (DR) of 61 dB while consuming 167 µA from a 3.3 V supply. In anesthetized rats, the system was able to detect temporal, spatial and spectral hemodynamic changes in response to DBS.

Time and frequency-dependent modulation of local field potential synchronization by deep brain stimulation.

High-frequency electrical stimulation of specific brain structures, known as deep brain stimulation (DBS), is an effective treatment for movement disorders, but mechanisms of action remain unclear. We examined the time-dependent effects of DBS applied to the entopeduncular nucleus (EP), the rat homolog of the internal globus pallidus, a target used for treatment of both dystonia and Parkinson's disease (PD). We performed simultaneous multi-site local field potential (LFP) recordings in urethane-anesthetized rats to assess the effects of high-frequency (HF, 130 Hz; clinically effective), low-frequency (LF, 15 Hz; ineffective) and sham DBS delivered to EP. LFP activity was recorded from dorsal striatum (STR), ventroanterior thalamus (VA), primary motor cortex (M1), and the stimulation site in EP. Spontaneous and acute stimulation-induced LFP oscillation power and functional connectivity were assessed at baseline, and after 30, 60, and 90 minutes of stimulation. HF EP DBS produced widespread alterations in spontaneous and stimulus-induced LFP oscillations, with some effects similar across regions and others occurring in a region- and frequency band-specific manner. Many of these changes evolved over time. HF EP DBS produced an initial transient reduction in power in the low beta band in M1 and STR; however, phase synchronization between these regions in the low beta band was markedly suppressed at all time points. DBS also enhanced low gamma synchronization throughout the circuit. With sustained stimulation, there were significant reductions in low beta synchronization between M1-VA and STR-VA, and increases in power within regions in the faster frequency bands. HF DBS also suppressed the ability of acute EP stimulation to induce beta oscillations in all regions along the circuit. This dynamic pattern of synchronizing and desynchronizing effects of EP DBS suggests a complex modulation of activity along cortico-BG-thalamic circuits underlying the therapeutic effects of GPi DBS for conditions such as PD and dystonia.

Persistent cocaine-induced reversal learning deficits are associated with altered limbic cortico-striatal local field potential synchronization.

Repeated exposure to cocaine is known to produce persistent deficits in behavioral flexibility. Evidence suggests that these deficits are mediated in part by a circuit involving the medial prefrontal and orbitofrontal cortices (PFC and OFC), nucleus accumbens (NAC), and basolateral amygdala (BLA). To assess the effects of cocaine on this circuit, we treated rats with cocaine daily for 14 d, followed by 4 weeks of abstinence. Animals were then tested on a cross-maze-based reversal learning and set-shifting task, after which they were anesthetized to allow for recording of spontaneous local field potential (LFP) activity simultaneously from all four regions, in addition to activity evoked from acute BLA stimulation. Cocaine-treated (COC) animals showed specific deficits in reversal learning; furthermore, spontaneous LFP oscillation power was reduced and BLA-induced oscillation power was increased in all regions compared with saline-treated (SAL) rats. Theta-burst stimulation of BLA potentiated BLA-evoked responses in all regions and cocaine challenge reduced spontaneous oscillation power and evoked response amplitude, with no COC/SAL group differences. Notably, cocaine challenge produced differential changes in coherence between OFC-BLA, BLA-NAC, and OFC-NAC in COC and SAL groups. These data indicate that repeated exposure to cocaine can produce changes in oscillatory LFP synchronization along limbic cortico-striatal circuits that persist long into abstinence. Furthermore, the regional specificity of these changes strongly correlates with the observed behavioral deficits. Aberrant synchronization within and between regions and consequent dysregulation of the neurocircuitry involved in executive control may contribute to the long-lasting maladaptive decision making seen in cocaine abusers.

Motivation on the Mediterranean: reward, compulsions and habit formation.

The 2007 Motivational Neuronal Networks meeting, held in Porquerolles, France was organized to generate debate and discussion on issues relating to reward, compulsion, and habit formation. The conference consisted primarily of four workshops that brought researchers from a wide variety of fields together in an informal atmosphere designed to facilitate interaction. This report is based on the detailed notes taken during the wide-ranging discussions, and summarizes major areas of both consensus and disagreement, as well research topics that are likely to be high priorities in the years to come.

Nucleus accumbens deep brain stimulation produces region-specific alterations in local field potential oscillations and evoked responses in vivo.

Deep brain stimulation of the nucleus accumbens (NAC) region is an effective therapeutic avenue for several psychiatric disorders that are not responsive to traditional treatment strategies. Nonetheless, the mechanisms by which DBS achieves therapeutic effects remain unclear. We showed previously that high-frequency (HF) NAC DBS suppressed pyramidal cell firing and enhanced slow local field potential (LFP) oscillations in the orbitofrontal cortex (OFC) via antidromic activation of corticostriatal recurrent inhibition. Using simultaneous multisite LFP recordings in urethane-anesthetized rats, we now show that NAC DBS delivered for 90 min at high or low frequency (LF) selectively affects spontaneous and evoked LFP oscillatory power and coherence within and between the medial prefrontal cortex (mPFC), lateral OFC, mediodorsal thalamus (MD), and NAC. Compared with LF or sham DBS, HF DBS enhanced spontaneous slow oscillations and potentiated evoked LFP responses only in OFC. HF DBS also produced widespread increases in spontaneous beta and gamma power and enhanced coherent beta activity between MD and all other regions. In contrast, LF DBS elevated theta power in MD and NAC. Analysis of acute NAC-induced oscillations showed that HF DBS increased and LF DBS decreased induced relative gamma coherence compared with sham DBS. These data suggest that HF (therapeutic) and LF (possibly deleterious) NAC DBS produce distinct region-specific and frequency band-specific changes in LFP oscillations. NAC DBS may achieve therapeutic effects by enhancing rhythmicity and synchronous inhibition within and between afferent structures, thereby normalizing function of a neural circuit that shows aberrant activity in obsessive-compulsive disorder and depression.

High-frequency deep brain stimulation of the nucleus accumbens region suppresses neuronal activity and selectively modulates afferent drive in rat orbitofrontal cortex in vivo.

High-frequency deep-brain stimulation (DBS) of the nucleus accumbens (NAc) region is an effective therapeutic avenue for patients with treatment-resistant obsessive-compulsive disorder (OCD). Imaging studies suggest that DBS acts by suppressing the aberrant metabolism in the orbitofrontal cortex (OFC) that is a hallmark of OCD; however, little is known about the mechanisms by which this occurs. We examined the effects of 30 min NAc DBS at 130 Hz on spontaneously active OFC neurons and local field potentials (LFPs) in addition to evoked responses elicited by single-pulse stimulation of the NAc or mediodorsal thalamus (MD) in urethane-anesthetized rats. NAc DBS reduced the mean firing rate of OFC neurons, although neurons receiving monosynaptic input from MD were less affected and some putative interneurons were excited by DBS. Single-pulse stimulation of the NAc produced a robust inhibition in OFC neurons that was attenuated after DBS, whereas excitatory responses were unchanged. In contrast, after DBS inhibitory responses evoked from MD were unchanged, whereas excitatory responses were enhanced. NAc-evoked LFP responses were potentiated after DBS, whereas MD-evoked LFP responses were unchanged. NAc DBS also enhanced OFC spontaneous LFP oscillatory activity in the slow (0.5-4 Hz) frequency band. These results suggest that DBS of the NAc region may alleviate OCD symptoms by reducing activity in subsets of OFC neurons, potentially by driving recurrent inhibition though antidromic activation of corticostriatal axon collaterals. Moreover, selective potentiation of input to these inhibitory circuits may also contribute to the therapeutic effects produced by DBS in OCD patients.

A single evoked afterdischarge produces rapid time-dependent changes in connexin36 protein expression in adult rat dorsal hippocampus.

Gap junctions between neurons contribute to synchronous neuronal firing and may play a role in the pathophysiology of epilepsy. We examined the expression of a number of gap junction subunits, including the neuronal gap junction forming protein connexin36 (Cx36), in the hippocampus at various time points following an electrically stimulated afterdischarge (AD) in freely-moving animals. Once recovered from electrode implantation, animals were tested with an escalating series of stimulations until an AD was evoked. Suprathreshold stimulation produced a brief AD with no convulsion. Groups of animals were sacrificed at 3, 12, and 24h post-stimulation, and connexin expression was assessed via semiquantitative immunoblotting. Compared to implanted non-stimulated controls, a significant decrease in Cx36 expression was observed in the stimulated dorsal hippocampus at 3h post-stimulation, which returned to control levels by 24h. No changes were seen in the ventral hippocampus. As well, no changes were seen in other selected connexin proteins including Cx26, Cx32, and Cx43, thought to be expressed primarily in glia, in either dorsal or ventral hippocampus. These data suggest that a relatively brief hypersynchronous neuronal discharge can produce rapid and specific changes in Cx36 expression, which may have implications for both normal brain function and the pathophysiology of epilepsy.

Extended cocaine self-administration and deprivation produces region-specific and time-dependent changes in connexin36 expression in rat brain.

Cocaine addiction is a disease that develops over time, and it is thought that drug-induced neuro-adaptations underlie the changes in behavior seen across the addictive process. While a number of alterations in synaptic transmission have been identified, little is currently known regarding cocaine's effects on gap junctional communication between neurons. Here we examine the effects of a cocaine self-administration regimen, previously shown to increase the reinforcing efficacy of cocaine, on the expression of the neuron-specific gap junction-forming protein connexin36 (C x 36). Using real-time RT-PCR and immunoblotting, we show that binge cocaine self-administration produces region-specific and time-dependent changes in C x 36 mRNA and protein expression in the nucleus accumbens, prefrontal cortex, and hippocampus. A number of changes in C x 36 were present 1 day and 7 days following self-administration, and C x 36 mRNA and protein appeared to be differentially regulated in a region-specific manner. C x 36 protein was significantly decreased in the prefrontal cortex 7 days following self-administration, a time point when behavioral sensitization to the reinforcing effects of cocaine is observed. These results suggest that changes in neuronal gap junction expression may be one mechanism by which cocaine self-administration produces enduring changes in behavior.

Amphetamine withdrawal produces region-specific and time-dependent changes in connexin36 expression in rat brain.

Repeated amphetamine treatment produces a long-lasting augmentation of locomotor behavior in rats, a phenomenon known as behavioral sensitization. This process is thought to be a correlate of the addictive process in humans, and it is believed that there are drug-induced neuroadaptations that underlie these behavioral changes. One mechanism by which amphetamine can alter brain function is by affecting direct intercellular communication between neurons via gap junctions. The purpose of the present study was to examine the effect of an amphetamine treatment regimen known to produce changes in dye coupling between neurons, a functional correlate of gap junction function, on the expression of the neuronal gap junction-forming protein, connexin36. Here we report that withdrawal from an extended amphetamine regimen produces region-specific and time-dependent changes in connexin36 expression in rat nucleus accumbens and prefrontal cortex, brain regions known play roles in sensitization and addiction. This is, to our knowledge, the first demonstration of pharmacological manipulation of connexin36 in vivo.