Transient and state modulation of beta power in human subthalamic nucleus during speech production and finger movement.

Signs of Parkinson's disease (PD) are augmented by speech and repetitive motor tasks. The neurophysiological basis for this phenomenon is unknown, but may involve augmentation of ß (13-30 Hz) oscillations within the subthalamic nucleus (STN). We hypothesized that speech and motor tasks increase ß power in STN and propose a mechanism for clinical observations of worsening motor state during such behaviors. Subjects undergoing deep brain stimulation (DBS) surgery performed tasks while STN local field potential (LFP) data were collected. Power in the ß frequency range was analyzed across the entire recording to observe slow shifts related to block design and during time epochs synchronized to behavior to evaluate immediate fluctuations related to task execution. Bilaterally symmetric ß event related desynchronization was observed in analysis time-locked to subject motor and speech tasks. We also observed slow shifts of ß power associated with blocks of tasks. Repetitive combined speech and motor, and isolated motor blocks were associated with the highest bilateral ß power state. Overt speech alone and imagined speech were associated with a low bilateral ß power state. Thus, changing behavioral tasks is associated with bilateral switching of ß power states. This offers a potential neurophysiologic correlate of worsened PD motor signs experienced during clinical examination with provocative tasks: switching into a high ß power state may be responsible for worsening motor states in PD patients when performing unilateral repetitive motor tasks and combined speech and motor tasks. Beta state changes could be chronically measured and potentially used to control closed loop neuromodulatory devices in the future.

Expression of the inhibitor of apoptosis protein family in multiple sclerosis reveals a potential immunomodulatory role during autoimmune mediated demyelination.

A failure of autoreactive T cells to undergo apoptosis may contribute to the pathogenesis of multiple sclerosis (MS). The role of the inhibitor of apoptosis (IAP) family of anti-apoptotic proteins such as X-linked IAP (XIAP), human inhibitor of apoptosis-1 (HIAP-1), human inhibitor of apoptosis-2 (HIAP-2), neuronal apoptosis inhibitory protein (NAIP) and Survivin in relapsing-remitting, secondary-progressive, primary-progressive or benign forms of MS is unclear. We report here that expression of the IAP family of genes in peripheral blood samples and brain tissues from MS cases support a role for differential regulation of these potent anti-apoptotic proteins in the pathology of MS. XIAP mRNA and protein levels were elevated in peripheral blood mononuclear cells from patients with active disease relative to normal subjects. In patients with active MS, HIAP-1 and HIAP-2 mRNA levels were elevated in resting T cells while NAIP mRNA was increased in whole blood. In post-mortem MS brain tissue, XIAP and HIAP-1 in myelin lesions were co-localized with microglia and T cells, respectively. Only in primary-progressive patients was Survivin expression elevated suggestive of a distinct pathological basis for this subtype of MS. Taken together, these results suggest that patterns of inhibitor of apoptosis expression in immune cells may have value in distinguishing between MS subtypes and offer insight into the mechanisms responsible for their distinct clinical courses.

Peripheral phosphodiesterase 4 inhibition produced by 4-[2-(3,4-Bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141) prevents experimental autoimmune encephalomyelitis.

Administration of phosphodiesterase 4 (PDE4) inhibitors suppresses the pathogenesis associated with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In the present study, we compared the effects of rolipram and 4-[2-(3,4-bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141), a novel nonbrain penetrant PDE4 inhibitor, on the onset and severity of clinical signs in a chronic, nonrelapsing/remitting model of EAE. Both rolipram (10 mg/kg p.o.) and L-826,141 (3 mg/kg p.o.) reduced the severity of EAE relative to controls, whereas L-826,141 (3 mg/kg p.o.) also delayed disease onset. To assess whether L-826,141 prevented EAE progression after the first signs of clinical onset, rolipram (10 mg/kg p.o.) or L-826,141 (3 or 30 mg/kg p.o.) were administered 24 h after the first signs of EAE were observed. Only L-826,141 at a dose of 30 mg/kg p.o. significantly decreased the clinical severity of EAE compared with vehicle controls. Immunohistochemical detection of the neuronal activity marker Fos confirmed that L-826,141 did not reach concentrations in the central nervous system sufficient to activate central neurons. Lipopolysaccharide-induced tumor necrosis factor-alpha in whole blood and plasma concentrations of L-826,141 revealed that only the 30-mg/kg dose resulted in levels sufficient to produce a near complete inhibition of PDE4 activity in immune cells. Taken together, these results demonstrate that peripheral PDE4 inhibition, produced by L-826,141, prevents the progression of EAE after the first onset of clinical signs, and suggest that similar compounds may have clinical efficacy in the treatment of MS.

Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington's disease transgenic mice prior to the onset of motor symptoms.

Inheritance of a single copy of the gene encoding huntingtin (HD) with an expanded polyglutamine-encoding CAG repeat leads to neuronal dysfunction, neurodegeneration and the development of the symptoms of Huntington's disease (HD). We have found that the steady-state mRNA levels of two members of the phosphodiesterase (PDE) multi-gene family decrease over time in the striatum of R6 transgenic HD mice relative to age-matched wild-type littermates. Phosphodiesterase 10A (PDE10A) mRNA and protein levels decline in the striatum of R6/1 and R6/2 HD mice prior to motor symptom development. The rate of reduction in PDE10A protein correlates with the rate of decline of the message and the decrease in PDE10A mRNA and protein is more rapid in R6/2 compared with R6/1 mice. Both PDE10A protein and mRNA, therefore, decline to minimum levels prior to the onset of overt physical symptoms in both strains of transgenic mice. Moreover, protein levels of PDE10A are decreased in the caudate-putamen of grade 3 HD patients compared with age-matched neuropathologically normal controls. Striatal PDE1B mRNA levels also decline in R6/1 and R6/2 HD mice; however, the decrease in striatal PDE10A levels (>60%) was greater than that observed for PDE1B and immediately preceded the onset of motor symptoms. In contrast, PDE4A mRNA levels are relatively low in the striatum and do not differ between age-matched wild-type and transgenic HD mice. This suggests that the regulation of PDE10A and PDE1B, but not PDE4A, mRNA levels is dependent on the relative expression of or number of CAG repeats within the human HD transgene. The loss of phosphodiesterase activity may lead to dysregulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in the striatum, a region of the brain that contributes to the control of movement and cognition.

Changes in brain cholecystokinin and anxiety-like behavior following exposure of mice to predator odor.

Exposure of CD-1 mice to a familiar environment lined with clean shavings (control odor) as well as a familiar environment lined with soiled rat shavings (predator odor) induced anxiety in the light/dark box. Mice exposed to the familiar environment or predator odor displayed decreased latency to enter the dark chamber of the light/dark box and spent less time in the light portion of the apparatus relative to home-caged mice. Mice exposed to the familiar environment lined with clean shavings or predator odor displayed elevated cholecystokinin mRNA levels from the ventral tegmental area, medial and basolateral nuclei of the amygdala relative to home-caged mice. Exposure of CD-1 mice to 2, 5 or 10 min of predator odor increased acoustic startle relative to mice merely exposed to the familiar environment lined with clean shavings at protracted intervals. Mice exposed to the familiar environment lined with clean shavings did not exhibit enhanced startle relative to home-caged mice. Exaggerated startle reactivity was in evidence immediately, 24, and 48 h following a 5-min exposure of mice to predator odor. In contrast, a 10-min exposure of mice to predator odor produced an oscillating pattern of enhanced startle evident during the immediate and 48-h post-stressor intervals only. However, when the startle stimulus was withheld 1 h following odor presentation, mice exhibited enhanced startle patterns reminiscent of the 5-min exposure. The 2-min exposure of mice to predator odor produced a delayed onset of enhanced startle observed at the 168-h test interval only. Potential anxiogenic influences of mesocorticolimbic cholecystokinin availability as well as the time course and underlying neuronal substrates of long-term behavioral disturbances as a result of psychogenic stressor manipulations are discussed.

Idiopathic normal pressure hydrocephalus: a systematic review of diagnosis and outcome.

OBJECTIVE: Patient selection for cerebrospinal fluid diversion is difficult, because idiopathic normal pressure hydrocephalus (INPH) mimics other neurodegenerative disorders and no findings reliably predict outcome. The literature was reviewed to identify diagnostic criteria that predict shunt response and to formulate prognostic expectations. METHODS: MEDLINE was searched, and 44 articles meeting predetermined criteria were included. RESULTS: Clinical series were frequently retrospective with small patient numbers and unstandardized outcome evaluation. Clinical findings suggestive of shunt responsiveness were the complete triad (gait disturbance, urinary incontinence, and dementia) with early gait disturbance. Degree of hydrocephalus was not correlated with clinical improvement. Reduction of the subcortical low-blood flow area was correlated with improvement in three small studies. Clinical response to prolonged cerebrospinal fluid drainage predicted shunt outcome in all cases in two small series. Overall, 59% (range, 24-100%) of patients improved after shunting, and 29% (range, 10-100%) of patients experienced prolonged improvement. Complications occurred in 38% (range, 5-100%) of patients, additional surgery was required in 22% (range, 0-47%) of patients, and there was a 6% (range, 0-35%) combined rate of permanent neurological deficit and death. CONCLUSION: Shunting INPH is associated with an approximately 29% rate of significant improvement and a 6% significant complication rate. Enlargement of the subcortical low-flow area and clinical improvement secondary to prolonged lumbar drainage may provide additive predictive value above clinical and computed tomographic criteria. A multicenter clinical trial that focuses on the value of ancillary tests, defines the clinical course of a patient with a ventriculoperitoneal shunt, and evaluates the cost effectiveness of shunting INPH is needed to better describe outcome from shunting in INPH.

Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line--derived neurotrophic factor in patients with Parkinson's disease. Report of two cases and technical considerations.

The authors have studied the ability of glial cell line-derived neurotrophic factor (GDNF) to promote survival of human fetal dopaminergic tissue after a storage period of 6 days and subsequent implantation into the human putamen. The results indicate that GDNF promotes survival of stored dopaminergic cells. Cells stored without GDNF had a 30.1% decrease in survival time compared with those exposed to GDNF. Two patients with Parkinson's disease received bilateral putaminal implants of fetal dopaminergic cells exposed to GDNF for 6 days and showed enhancement of graft survival as assessed by positron emission tomography scanning. A mean increase of 107% in putaminal fluorodopa uptake from baseline values was observed 12 months postgrafting.

Proactive influence of a surgical stressor on locomotor activity, exploration and anxiety-related behaviour following acute footshock in the mouse.

The putative proactive influence of graded surgical stressors including intraventricular cannulation, sham surgery and no surgery on footshock-associated variations of locomotor activity, rearing and anxiogenic behaviour in the light-dark paradigm was evaluated among CD-1 mice. Neither sham surgery nor cannulation of the lateral ventricle altered baseline measures of locomotor activity or rearing relative to the performance of nonoperated control animals. Cannulation exacerbated the depressant influence of acute footshock on locomotor activity, while sham surgery mitigated the disruptive effect of the stressor on locomotor activity during the initial 15-min period of the test session. Footshock suppressed the vertical activity scores of mice regardless of surgical history. Only intraventricular cannulation reduced the baseline time in light scores of mice in the light-dark paradigm with repeated testing relative to animals in the sham surgery and no-surgery conditions. Baseline transition scores were not differentially affected by surgical history. Typically, transition scores were reduced on day 2 relative to day 1, but additional performance decrements were precluded on day 3. Footshock interacted with the surgical stressor of intraventricular cannulation in exaggerating reduced time in light relative to the performance of mice in the remaining surgical conditions. Transition frequency was not differentially influenced by the nature of the surgical stressor and subsequent exposure to footshock. The implications of these data for stressor-induced pathology are discussed.

Vulnerability to stressor-induced disturbances in self-stimulation from the dorsal and ventral A10 area: differential effects of intraventricular D-Ala2-Met5-enkephalinamide, D-Ala2, N-Me-Phe4, Gly-Ol5-enkephalin, and D-Pen2, D-Pen5-enkephalin administration.

D-Ala2-Met5-enkephalinamide (DALA) (1.0 microg/microl) was administered intraventricularly to mice responding for electrical stimulation from the dorsal or ventral aspects of the VTA immediately prior to footshock (Experiment 1). Predictably, footshock reduced self-stimulation from the dorsal but not the ventral VTA immediately, 24, and 168 h following the stressor. Intraventricular DALA administration effected a partial attenuation of stressor-induced self-stimulation reductions from the dorsal VTA immediately and 24 h poststressor. Deficits appeared among DALA-Shocked mice responding for brain stimulation from the ventral VTA during comparable test intervals. The long-term depressant influence of footshock on self-stimulation from the dorsal VTA was abolished among DALA-treated mice and DALA-associated reductions in self-stimulation from the ventral A10 region among stressed mice were not evident 1 week later. Administration of D-Ala2, N-Me-Phe4, Gly-Ol5-enkephalin (DAGO) (0.01 microg/microl) or D-Pen2, D-Pen5-enkephalin (DPDPE) (1.0 microg/microl) intraventricularly prior to footshock effected an immediate and a delayed antagonism, respectively, of the stressor on self-stimulation from the dorsal VTA, which persisted for 1 week. Prophylactic administration of 0.001 microg/microl DAGO or 0.01 microg/microl DPDPE prior to the stressor failed to influence self-stimulation from the ventral VTA (Experiment 2). Administration of 0.01 microg/microl DAGO or 1.0 microg/microl DPDPE among mice responding for brain stimulation from the dorsal VTA following footshock produced a weak therapeutic effect immediately poststressor, but effected protracted amelioration of footshock-induced reductions of self-stimulation from the dorsal VTA (Experiment 3). Taken together, mu, delta, and mu-delta activation influenced self-stimulation differentially from the dorsal and ventral VTA according to the temporal order of opioid peptide challenge relative to stressor imposition. These data are discussed with respect to stressors, motivational alterations, and the putative modulating influence of endogenous enkephalin activity in subareas of the VTA.

Self-stimulation from the mesencephalon following intraventricular interleukin-2 administration.

Intracranial self-stimulation was evaluated among CD-1 mice responding for brain stimulation from the dorsal and ventral aspects of the ventral tegmental area (VTA). Intraventricular interleukin-2 (IL-2) administration (5 ng) in a 1-microl volume elevated the stimulation frequency required to effect half-maximal responding for brain stimulation from the dorsal A10 region 15 min, 24 h, 48 h, and 1 week following drug administration relative to vehicle-treated animals. Intraventricular IL-2 administration did not influence responding for brain stimulation from the ventral A10 area, and performance of these animals was indistinguishable from the performance of vehicle-challenged animals implanted with a stimulating electrode in the ventral A10 area. These data suggest that central IL-2 administration reduces the value of previously rewarding brain stimulation from subregions of the VTA. The implications of these data for behavioural pathology are discussed.