Cognitive-behavioral therapy for anxiety in Parkinson's disease

Parkinson's disease (PD) is characterized by motor symptoms, but nonmotor symptoms also significantly impair daily functioning and reduce quality of life. Anxiety is prevalent and debilitating in PD, but remains understudied and undertreated. Much affective research in PD focuses on depression rather than anxiety, and as such, there are no evidence-based treatments for anxiety in this population. Cognitive-behavioral therapy (CBT) has shown promise for treating depression in PD and may be efficacious for anxiety. This exploratory study implemented a multiple-baseline single-case experimental design to evaluate the utility and feasibility of CBT for individuals with PD who also met criteria for a DSM-5 anxiety disorder ( n = 9). Participants were randomized to a 2-, 4-, or 6-week baseline phase, followed by 12 CBT sessions, and two post treatment assessments (immediately post treatment and 6-week follow-up). Multiple outcome measures of anxiety and depression were administered weekly during baseline and intervention. Weekly CBT sessions were conducted in-person ( n = 5) or via secure videoconferencing ( n = 4). At post treatment, seven of the nine participants showed significant reductions in anxiety and/or depression, with changes functionally related to treatment and most improvements maintained at 6-week follow-up. Effects of CBT on secondary outcomes varied across participants, with preliminary evidence for reduction in fear of falling. Adherence and retention were high, as were treatment satisfaction and acceptability. The findings of this pilot study provide preliminary evidence for the utility of CBT as a feasible treatment for anxiety and comorbid depressive symptoms in PD and highlight the potential of telehealth interventions for mood in this population.Accepted manuscrip

The potential of cognitive-behavioral intervention for anxiety in Parkinson's disease

OBJECTIVES: Anxiety is a prevalent but understudied non-motor symptom of Parkinson’s disease (PD), for which pharmacological treatments yield mixed results. Cognitive-behavioral therapy (CBT) has shown promise in improving depression in PD, and case studies suggest that it may also alleviate anxiety. Because of the deleterious effects of anxiety on cognition and quality of life, there is need for evidence-based psychological interventions. METHODS: This study explores the utility and feasibility of a transdiagnostic intervention to improve anxiety in PD using a multiple-baseline, single-case experimental design. Following a two-, four-, or six-week baseline phase, five individuals with PD who met DSM-5 criteria for an anxiety disorder received/are receiving 12 weekly sessions of CBT1, followed by a post-intervention assessment and a 6-week no-contact follow-up. Weekly levels of anxiety and depression are measured throughout the study, with measures of cognition, quality of life, sleep, and motor function completed at all pre- and post-intervention assessments. RESULTS: Results to date (2 completers, 3 currently enrolled) suggest that CBT may produce clinically meaningful changes in anxiety, depression, quality of life, and fear of falling (Figure 01). Results are mixed regarding effects on cognition, sleep, and motor function. Treatment satisfaction has been high. CONCLUSIONS: CBT may improve anxiety, depression, quality of life, and fear of falling among adults with PD and clinical anxiety. These findings warrant further exploration of CBT for anxiety across various stages of PD.Accepted manuscrip

Functional correlates of optic flow motion processing in Parkinson’s disease

The visual input created by the relative motion between an individual and the environment, also called optic flow, influences the sense of self-motion, postural orientation, veering of gait, and visuospatial cognition. An optic flow network comprising visual motion areas V6, V3A, and MT+, as well as visuo-vestibular areas including posterior insula vestibular cortex (PIVC) and cingulate sulcus visual area (CSv), has been described as uniquely selective for parsing egomotion depth cues in humans. Individuals with Parkinson’s disease (PD) have known behavioral deficits in optic flow perception and visuospatial cognition compared to age- and education-matched control adults (MC). The present study used functional magnetic resonance imaging (fMRI) to investigate neural correlates related to impaired optic flow perception in PD. We conducted fMRI on 40 non-demented participants (23 PD and 17 MC) during passive viewing of simulated optic flow motion and random motion. We hypothesized that compared to the MC group, PD participants would show abnormal neural activity in regions comprising this optic flow network. MC participants showed robust activation across all regions in the optic flow network, consistent with studies in young adults, suggesting intact optic flow perception at the neural level in healthy aging. PD participants showed diminished activity compared to MC particularly within visual motion area MT+ and the visuo-vestibular region CSv. Further, activation in visuo-vestibular region CSv was associated with disease severity. These findings suggest that behavioral reports of impaired optic flow perception and visuospatial performance may be a result of impaired neural processing within visual motion and visuo-vestibular regions in PD.Published versio

LTS and FS Inhibitory Interneurons, Short-Term Synaptic Plasticity, and Cortical Circuit Dynamics

Somatostatin-expressing, low threshold-spiking (LTS) cells and fast-spiking (FS) cells are two common subtypes of inhibitory neocortical interneuron. Excitatory synapses from regular-spiking (RS) pyramidal neurons to LTS cells strongly facilitate when activated repetitively, whereas RS-to-FS synapses depress. This suggests that LTS neurons may be especially relevant at high rate regimes and protect cortical circuits against over-excitation and seizures. However, the inhibitory synapses from LTS cells usually depress, which may reduce their effectiveness at high rates. We ask: by which mechanisms and at what firing rates do LTS neurons control the activity of cortical circuits responding to thalamic input, and how is control by LTS neurons different from that of FS neurons? We study rate models of circuits that include RS cells and LTS and FS inhibitory cells with short-term synaptic plasticity. LTS neurons shift the RS firing-rate vs. current curve to the right at high rates and reduce its slope at low rates; the LTS effect is delayed and prolonged. FS neurons always shift the curve to the right and affect RS firing transiently. In an RS-LTS-FS network, FS neurons reach a quiescent state if they receive weak input, LTS neurons are quiescent if RS neurons receive weak input, and both FS and RS populations are active if they both receive large inputs. In general, FS neurons tend to follow the spiking of RS neurons much more closely than LTS neurons. A novel type of facilitation-induced slow oscillations is observed above the LTS firing threshold with a frequency determined by the time scale of recovery from facilitation. To conclude, contrary to earlier proposals, LTS neurons affect the transient and steady state responses of cortical circuits over a range of firing rates, not only during the high rate regime; LTS neurons protect against over-activation about as well as FS neurons

Mechanisms of Firing Patterns in Fast-Spiking Cortical Interneurons

Cortical fast-spiking (FS) interneurons display highly variable electrophysiological properties. Their spike responses to step currents occur almost immediately following the step onset or after a substantial delay, during which subthreshold oscillations are frequently observed. Their firing patterns include high-frequency tonic firing and rhythmic or irregular bursting (stuttering). What is the origin of this variability? In the present paper, we hypothesize that it emerges naturally if one assumes a continuous distribution of properties in a small set of active channels. To test this hypothesis, we construct a minimal, single-compartment conductance-based model of FS cells that includes transient Na+, delayed-rectifier K+, and slowly inactivating d-type K+ conductances. The model is analyzed using nonlinear dynamical system theory. For small Na+ window current, the neuron exhibits high-frequency tonic firing. At current threshold, the spike response is almost instantaneous for small d-current conductance, gd, and it is delayed for larger gd. As gd further increases, the neuron stutters. Noise substantially reduces the delay duration and induces subthreshold oscillations. In contrast, when the Na+ window current is large, the neuron always fires tonically. Near threshold, the firing rates are low, and the delay to firing is only weakly sensitive to noise; subthreshold oscillations are not observed. We propose that the variability in the response of cortical FS neurons is a consequence of heterogeneities in their gd and in the strength of their Na+ window current. We predict the existence of two types of firing patterns in FS neurons, differing in the sensitivity of the delay duration to noise, in the minimal firing rate of the tonic discharge, and in the existence of subthreshold oscillations. We report experimental results from intracellular recordings supporting this prediction

How well can we estimate the information carried in neuronal responses from limited samples?

It is difficult to extract the information carried by neuronal responses about a set of stimuli because limited data samples result in biased estimates. Recently two improved procedures have been developed to calculate information from experimental results: a binning-and-correcting procedure and a neural network procedure. We have used data produced from a model of the spatiotemporal receptive fields of parvocellular and magnocellular lateral geniculate neurons to study the performance of these methods as a function of the number of trials used. Both procedures yield accurate results for one-dimensional neuronal codes. They can also be used to produce a reasonable estimate of the extra information in a three-dimensional code, in this instance, within 0.05-0.1 bit of the asymptotically calculated value - about 10% of the total transmitted information. We believe that this performance is much more accurate than previous procedures

Osteoblastic differentiation and stress response of human mesenchymal stem cells exposed to alternating current electric fields

<p>Abstract</p> <p>Background</p> <p>Electric fields are integral to many biological events, from maintaining cellular homeostasis to embryonic development to healing. The application of electric fields offers substantial therapeutic potential, while optimal dosing regimens and the underlying mechanisms responsible for the positive clinical impact are poorly understood.</p> <p>Methods</p> <p>The purpose of this study was to track the differentiation profile and stress response of human bone marrow derived mesenchymal stem cells (hMSCs) undergoing osteogenic differentiation during exposure to a 20 mV/cm, 60 kHz electric field. Morphological and biochemical changes were imaged using endogenous two-photon excited fluorescence (TPEF) and quantitatively assessed through eccentricity calculations and extraction of the redox ratio from NADH, FAD and lipofuscin contributions. Real time reverse transcriptase-polymerase chain reactions (RT-PCR) were used to track osteogenic differentiation markers, namely alkaline phosphatase (ALP) and collagen type 1 (col1), and stress response markers, such as heat shock protein 27 (hsp27) and heat shock protein 70 (hsp70). Comparisons of collagen deposition between the stimulated hMSCs and controls were examined through second harmonic generation (SHG) imaging.</p> <p>Results</p> <p>Quantitative differences in cell morphology, as described through an eccentricity ratio, were found on days 2 and days 5 (p < 0.05) in samples exposed to the electric field. A delayed but two fold increase in ALP and col1 transcript was detected by week 2 (p < 0.05) in differentiating hMSCs exposed to an electric field in comparison to the nonstimulated controls. Upregulation in stress marker, hsp27, and type 1 collagen deposition were correlated with this response. Increases in NADH, FAD, and lipofuscin were traced in the stimulation group during the first week of field exposure with differences statistically significant on day 10 (p < 0.05). Changes in hsp27 expression correlate well with changes in lipofuscin detected in the stimulation group, suggesting a connection with oxidative stress. Both differentiation factors and electrical stimulation improved hMSC differentiation potential to bone based on calcium deposition on day 28.</p> <p>Conclusions</p> <p>Electrical stimulation is a useful tool to improve hMSC osteogenic differentiation, while heat shock proteins may reveal underlying mechanisms, and optical non-invasive imaging may be used to monitor the induced morphological and biochemical changes.</p

Temporal decorrelation of collective oscillations in neural networks with local inhibition and long-range excitation

We consider two neuronal networks coupled by long-range excitatory interactions. Oscillations in the gamma frequency band are generated within each network by local inhibition. When long-range excitation is weak, these oscillations phase-lock with a phase-shift dependent on the strength of local inhibition. Increasing the strength of long-range excitation induces a transition to chaos via period-doubling or quasi-periodic scenarios. In the chaotic regime oscillatory activity undergoes fast temporal decorrelation. The generality of these dynamical properties is assessed in firing-rate models as well as in large networks of conductance-based neurons.Comment: 4 pages, 5 figures. accepted for publication in Physical Review Letter

Visuospatial Attention to Single and Multiple Objects Is Independently Impaired in Parkinson's Disease

Parkinson’s disease (PD) is associated with deficits in visuospatial attention. It is as yet unknown whether these attentional deficits begin at a perceptual level or instead reflect disruptions in oculomotor or higher-order processes. In the present study, non-demented individuals with PD and matched normal control adults (NC) participated in two tasks requiring sustained visuospatial attention, both based on a multiple object tracking paradigm. Eye tracking was used to ensure central fixation. In Experiment 1 (26 PD, 21 NC), a pair of identical red dots (one target, one distractor) rotated randomly for three seconds at varied speeds. The task was to maintain the identity of the sole target, which was labeled prior to each trial. PD were less accurate than NC overall (p = .049). When considering only trials where fixation was maintained, however, there was no significant group difference, suggesting that the deficit’s origin is closely related to oculomotor processing. To determine whether PD had additional impairment in multifocal attention, in Experiment 2 (25 PD, 15 NC), two targets were presented along with distractors at a moderate speed, along with a control condition in which dots remained stationary. PD were less accurate than NC for moving (p = 0.02) but not stationary targets. This group difference remained significant when considering only trials where fixation was maintained, suggesting the source of the PD deficit was independent from oculomotor processing. Taken together, the results implicate separate mechanisms for single vs. multiple object tracking deficits in PD