Intrinsic Neural Activity Research Articles

L-DOPA changes spontaneous low-frequency BOLD signal oscillations in Parkinson's disease: a resting state fMRI study

Analysis of the amplitude of low frequency BOLD signal fluctuations (ALFF) in the resting state has recently been used to study the dynamics of intrinsic neural activity. Several studies have also suggested its potential as a biomarker for neuropsychiatric disease. In the current study, we quantified ALFF to determine changes in intrinsic neural oscillations in patients with Parkinson's disease (PD) on and off L-DOPA. Twenty-four PD patients and 24 healthy age-matched controls participated in the study. PD patients underwent two resting state fMRI sessions, either ON a controlled dose of L-DOPA or following a placebo pill (OFF). Control participants underwent one test session. We found that there was increased amplitude of low frequency BOLD signal oscillations for PD patients OFF L-DOPA in the primary and secondary motor areas, and in the middle and medial prefrontal cortices. L-DOPA significantly reduced the amplitude of low frequency oscillations within these regions. The degree of ALFF in the premotor cortex predicted patients' motor performance as measured by the Grooved Pegboard task, such that greater ALFF was associated with poorer performance. These results are in line with the pathophysiology of PD, which shows changes in neural oscillations. Thus, frequency domain analyses of resting state BOLD fMRI signals may provide a useful means to study the pathophysiology of PD and the physiology of the brain's dopaminergic pathways.

Sustained versus transient brain responses in schizophrenia: the role of intrinsic neural activity

Schizophrenia patients (SZ) show early visual processing deficits in many, but not all, tasks. These deficits may be associated with dysregulation of intrinsic oscillatory activity that compromises signal-to-noise in the SZ brain. This question was studied using visual steady-state stimulation and post-steady-state presentation of transient visual stimuli. SZ had higher intrinsic oscillatory activity at the steady-state stimulation frequency (12.5Hz) and at the 6.25Hz subharmonic, showed a significant decrease in visual steady-state magnitude over 2s of stimulation, and were unable to promptly terminate the steady-state response following stimulation offset. If adjustment for levels of intrinsic brain activity were made, however, it would have appeared that SZ had activity of similar magnitude as healthy subjects following steady-state stimulus termination, indicating that such adjustments could substantially alter theoretical interpretations. Visual evoked potential abnormalities (N1/P2 amplitudes) present among SZ at the initiation of steady-state stimulation were less apparent in the 750ms immediately following steady-state stimulation offset. Higher intrinsic oscillatory brain activity may be a fundamental characteristic of SZ that merits further evaluation for understanding this disorder's neuropathological correlates and associated symptomatology.

Dispositional mindfulness and depressive symptomatology: Correlations with limbic and self-referential neural activity during rest.

To better understand the relationship between mindfulness and depression, we studied normal young adults (n = 27) who completed measures of dispositional mindfulness and depressive symptomatology, which were then correlated with (a) rest: resting neural activity during passive viewing of a fixation cross, relative to a simple goal-directed task (shape-matching); and (b) reactivity: neural reactivity during viewing of negative emotional faces, relative to the same shape-matching task. Dispositional mindfulness was negatively correlated with resting activity in self-referential processing areas, whereas depressive symptomatology was positively correlated with resting activity in similar areas. In addition, dispositional mindfulness was negatively correlated with resting activity in the amygdala, bilaterally, whereas depressive symptomatology was positively correlated with activity in the right amygdala. Similarly, when viewing emotional faces, amygdala reactivity was positively correlated with depressive symptomatology and negatively correlated with dispositional mindfulness, an effect that was largely attributable to differences in resting activity. These findings indicate that mindfulness is associated with intrinsic neural activity and that changes in resting amygdala activity could be a potential mechanism by which mindfulness-based depression treatments elicit therapeutic improvement.

Central effects of BoNT

Botulinum neurotoxins A and E (BoNT/A and BoNT/E) are bacterial enzymes that exert a long-lasting inhibition of transmitter release via the cleavage of the synaptic protein SNAP-25. We have studied the trafficking and functional effects of BoNT/A and BoNT/E after in vivo injection into the rodent hippocampus and visual cortex. We found that BoNT/A and BoNT/E inhibit glutamate release and silence the activity of pyramidal neurons. BoNT/A, but not BoNT/E, exhibits retrograde axonal transport following uptake at the nerve terminal. This retrograde spread has important implications for the clinical applications of BoNT/A. We have exploited the silencing effects of BoNT/E in two lines of research. First, we have demonstrated the anti-epileptic effects of in vivo administration of BoNT/E. Indeed, BoNT/E prevents spontaneous recurrent seizures in a mouse model of temporal lobe epilepsy. Second, we have used BoNT/E to address the role of intrinsic neural activity in maturation of the visual cortex during the developmental critical period. Unilateral, intracortical injections of BoNT/E were made in rat pups at the time of eye opening and resulted in the silencing of the treated, but not contralateral, hemisphere for a period of 2 weeks. We found that visual acuity was permanently reduced in the blocked hemisphere, and the critical period for ocular dominance plasticity persisted into adulthood.

Transient Synaptic Silencing of Developing Striate Cortex Has Persistent Effects on Visual Function and Plasticity

Neural circuits in the cerebral cortex are shaped by experience during "critical periods" early in life. For example, visual cortex is immature at the time of eye opening and gradually develops its functional properties during a sensitive period. Very few reports have addressed the role of intrinsic neural activity in cortical maturation. Here we have exploited the bacterial enzyme botulinum neurotoxin E (BoNT/E) to produce a unilateral, reversible blockade of neural activity in rat visual cortex during the sensitive period. BoNT/E is a highly selective protease that interferes with transmitter release via cleavage of the synaptic protein SNAP-25 (synaptosomal-associated protein of 25 kDa). Unilateral, intracortical injections of BoNT/E were made at the time of eye opening and resulted in the silencing of the treated, but not contralateral, hemisphere for a period of 2 weeks. We found that visual acuity was permanently reduced in the blocked hemisphere, and the critical period for ocular dominance plasticity persisted into adulthood. Unexpectedly, these effects extended equally to the contralateral, uninjected side, demonstrating a fundamental role for interhemispheric connections in cortical maturation.

Functional Heterogeneity of Retinal Dopaminergic Neurons Underlying Their Multiple Roles in Vision

Dopaminergic neurons play key roles in the CNS, mediating basic mechanisms of vision, movement, motivation, and mood. The most accessible dopaminergic neurons of the vertebrate CNS are the dopaminergic amacrine cells of the retina. Here, we have characterized the intrinsic neural activity, synaptic input, and light responses of retinal dopaminergic neurons in situ, using targeted electrophysiological recordings of fluorescent neurons in TH::RFP (tyrosine hydroxylase gene promoter::red fluorescent protein) transgenic mice. Dopaminergic amacrine cells exhibit two classes of intrinsic bursting in the dark, shaped by inhibitory synaptic inputs, and two classes of light responses, ON-transient and ON-sustained, as well as light-independent activity, tuned to mediate specific dopaminergic functions in vision. The functional heterogeneity revealed in dopaminergic amacrine cells provides a cellular basis for the multiple roles of dopaminergic amacrine neurons in vision and is likely a general property of dopaminergic neurons throughout the CNS.

Is cell death necessary for hippocampal mossy fiber sprouting?

To examine the relationship between cell death and sprouting of the mossy fibers, repeated seizures of the hippocampal-parahippocampal circuit were elicited in anesthetized rats. The presence of mossy fiber growth was assessed with the Timm's stain for zinc. At 4 weeks, after 18 repeated seizures, there was a significant increase in the degree of zinc containing granules in the inner molecular layer of the dentate gyrus. The amount of sprouting was less than that seen four weeks after a single injection of kainic acid. A silver impregnation stain and an assay for damaged DNA were used to detect damaged or dying neurons and immunohistochemistry for a 72 kDa heat shock protein was used to detect any neurons that had suffered potentially injurious stress. The same number of repeated seizures that caused sprouting of the mossy fibers did not cause detectable cell death or severe stress in any cells within the hippocampus, subicular region or adjacent entorhinal cortex. These experiments demonstrate that repeated seizures of the hippocampal-parahippocampal circuits can cause sprouting of mossy fibers in the absence of evidence of cell death. This supports the hypothesis that alterations in intrinsic neural excitability and impulse activity from the dentate gyrus can result in growth of axonal processes in the adult rat brain.

Enteric neural regulation of slow waves in circular muscle of the canine proximal colon.

The spontaneous electrical activities of circular muscle cells of the canine proximal colon were studied with intracellular micro-electrodes. All circular muscle cells exhibited slow waves at frequencies ranging between 2.8 and 7.0 cycles/min. The slow waves consisted of an upstroke phase followed by a plateau phase of variable duration (2-40 s). Many cells displayed a slow diastolic depolarization, or 'pre-potential' between slow waves. Slow waves spontaneously varied in duration and frequency in most preparations, creating distinctive slow wave patterns. Atropine, 2 X 10(-6) M, decreased the durations of slow waves in many preparations and often changed the pattern to a series of relatively uniform slow waves. A further reduction in mean slow wave duration was produced by additional treatment with tetrodotoxin, 10(-6) M. These results suggested that slow wave duration and pattern were affected by spontaneous discharge from both cholinergic and non-cholinergic excitatory nerves. Transmural nerve stimulation caused a short latency increase in slow wave duration (up to 38 s) that was abolished by atropine. In the presence of atropine, transmural stimulation evoked inhibitory junction potentials that reduced the amplitude and duration of the subsequent slow wave. The slow wave of reduced amplitude was followed by a slow wave of increased duration. The increase in duration of the slow wave did not appear to be related to the size of the preceding hyperpolarization, suggesting it was mediated by the release from non-cholinergic excitatory nerves. All responses to transmural stimulation were blocked by tetrodotoxin. Microejection of acetylcholine on to the muscle adjacent to the micro-electrode also produced an atropine-sensitive increase in slow wave duration. Tissues that had been stored in the cold overnight to reduce intrinsic neural activity exhibited regular slow waves of short duration. It is proposed that the basic myogenic pattern of spontaneous slow wave activity consists of regularly occurring slow waves of short duration (2-5 s). Intrinsic cholinergic and non-cholinergic excitatory nerves appear to modulate slow wave activity in vitro, producing distinctive slow wave patterns of variable instantaneous frequency and duration.

Slow wave heterogeneity within the circular muscle of the canine gastric antrum.

A cross-sectional preparation was designed in which multiple micro-electrodes can be precisely positioned to impale smooth muscle cells anywhere from the serosa to the submucosa. Intracellular electrical recordings were obtained from gastric antral circular muscle cells from the myenteric plexus to the submucosa. The resting membrane potential changed linearly as a function of distance from the myenteric plexus to the submucosa. Slow wave upstroke dV/dt, upstroke potential amplitude, and plateau potential amplitude changed linearly as a function of distance from the myenteric plexus to the submucosa. When slow waves were recorded simultaneously from a circular cell near the myenteric plexus and from a cell near the submucosa, the event always occurred first in the cell near the myenteric plexus. Electrical differences did not appear to be caused by electrotonic decay of slow waves as they propagated through the circular muscle. Electrical differences could not be explained on the basis of differences in intrinsic neural activity or prostaglandin synthesis. Membrane polarization could not explain the differences in slow waves between myenteric and submucosal circular muscle cells. The conclusion of this paper is that fundamental differences exist between the excitability mechanisms and/or passive membrane properties of cells near the myenteric plexus and the submucosa. These differences might be manifest in different motor performance of these two muscle cell populations.