Autonomic cardiovascular responses in parkinsonism: effect of levodopa with dopa-decarboxylase inhibition

ABSTRACT – Autonomically mediated cardiovascular responses to certain manoeuvres were studied in 20 parkinson patients, 24 h off levodopa-decarboxylase inhibitor medication and again one h after medication. Results were compared with 15 healthy control subjects. The heart rate at rest was higher in parkinson, the respiratory sinus arrhythmia was lower, while the Valsalva ratio, the heart rate and blood pressure responses during an orthostatic test and the heart rate response to a dive reflex test were normal. These findings indicate a normal function of peripheral autonomic nerves and a possible central parasympathetic dysfunction.
There were significantly attenuated responses of heart rate, blood pressure and contralateral forearm blood flow to an isometric handgrip. Since the peripheral autonomic nerves seemed to be normal, these results could be related to a reduced central command and/or diminished stimulation of postulated peripheral ergoreceptors in parkinsonism.
There was no major effect on the cardiovascular responses by the acutely administered medication.     

Paralimbic and medial prefrontal cortical involvement in neuroendocrine responses to traumatic stimuli

OBJECTIVE: Hypothalamic-pituitary-adrenal axis activity and cortisol release are consequences of central stress system activation, but they may also influence cognitive and emotional processes within the brain. Despite the importance of central stress response systems, little is known about the specific brain circuits through which psychosocial stimuli activate the hypothalamic-pituitary-adrenal axis and through which cortisol feedback modulates central processing. The authors used [(15)O]H(2)O positron emission tomography (PET) on subjects with posttraumatic stress disorder (PTSD) to study these circuits. METHOD: Participants were combat-PTSD patients, combat-exposed healthy comparison subjects, and noncombat-exposed healthy comparison subjects. Participants were scanned using [(15)O]H(2)O PET while they experienced a series of emotional-induction conditions, which included aversive pictures and autobiographic narratives. Blood samples were obtained 2 minutes before and 5 minutes after each activation scan in order to measure the subjects' plasma adrenocorticotropic hormone and cortisol levels. RESULTS: In voxel-wise analyses, the authors found that adrenocorticotropic hormone responses were covaried with regional cerebral blood flow (rCBF) in the dorsal medial prefrontal cortex, rostral anterior cingulate cortex, and right insula, with some differences between PTSD patients and comparison subjects. Prestimulus cortisol levels covaried with rCBF responses in the rostral anterior cingulate cortex. In combat-PTSD patients only, prestimulus cortisol levels covaried with rCBF in the subgenual anterior cingulate cortex. CONCLUSIONS: These findings provide evidence of cortical involvement in hypothalamic-pituitary-adrenal responses to psychological stimuli, specifically implicating the insula, dorsal medial prefrontal cortex, and rostral anterior cingulate cortex. These findings also show, for the first time, that cortisol may modulate activity in specific brain areas such as the rostral and subgenual anterior cingulate cortices. Differential patterns of covariation between combat veterans with and without PTSD potentially implicate the dorsal medial prefrontal cortex and subgenual anterior cingulate cortex as areas of dysregulation in PTSD.     

Selective impairment of excitatory pressor responses after prolonged simulated microgravity in humans

The haemodynamic and autonomic effects of prolonged exposure to simulated microgravity were assessed non-invasively in seven healthy volunteers completing a 42-day -6 degrees head down tilt. Before, during and after head down tilt, subjects were exposed to moderate excitatory stimuli (mental arithmetic and static handgrip) to gauge possible progressive impairment of pressor responses. Before and after head down tilt, subjects were also exposed to orthostatic stress, to assess influences of simulated microgravity on orthostatic defence. Simple haemodynamics (heart rate and systolic arterial blood pressure), linear (i.e., oscillatory) components of beat-by-beat variability, non-linear properties (i.e., corrected conditional entropy (CCE)) of RR interval variability, and baroreflex slope furnished a non-invasive evaluation of autonomic regulatory mechanisms. Pressor responses to mental arithmetic and to handgrip were markedly impaired after 42 days head down tilt, whereas responses in markers of autonomic regulation were not modified. Standing, performed 8 days after head down tilt to limit the risk of syncope, still induced a variable degree of hypotension, with signs of progressively greater sympathetic activation than before head down tilt. Simulated microgravity-induced reduction of pressor responses, in spite of largely maintained autonomic activation, favours the hypothesis of a peripheral impairment of cardiovascular homeostasis. rights reserved.     

Event-related beta EEG-changes during passive and attempted foot movements in paraplegic patients

A number of electroencephalographic (EEG) studies report on motor event-related desynchronization and synchronization (ERD/ERS) in the beta band, i.e. a decrease and increase of spectral amplitudes of central beta rhythms in the range from 13 to 35 Hz. Following an ERD that occurs shortly before and during the movement, bursts of beta oscillations (beta ERS) appear within a 1-s interval after movement offset. Such a post-movement beta ERS has been reported after voluntary hand movements, passive movements, movement imagination, and also after movements induced by functional electrical stimulation. The present study compares ERD/ERS patterns in paraplegic patients (suffering from a complete spinal cord injury) and healthy subjects during attempted (active) and passive foot movements. The aim of this work is to address the question, whether patients do have the same focal beta ERD/ERS pattern during attempted foot movement as healthy subjects do. The results showed midcentral-focused beta ERD/ERS patterns during passive, active, and imagined foot movements in healthy subjects. This is in contrast to a diffuse and broad distributed ERD/ERS pattern during attempted foot movements in patients. Only one patient showed a similar ERD/ERS pattern. Furthermore, no significant ERD/ERS patterns during passive foot movement in the group of the paraplegics could be found.     

"Central command" and sympathetic activation

The concepts of "central command" and of peripheral feedback mechanisms are analysed in order to individuate the main regulatory components of sympathetic efferent activity. In recent years a new afferent channel has been described: it consists of cardiovascular sympathetic afferent fibres which play a tonic function in the regulation of the sympathetic outflow. This afferent channel mediates reflexes which are mainly excitatory in nature with positive feedback characteristics. In this way, each particular haemodynamic neurally-regulated state can be hypothesized as under the control of "central command" and of opposite peripheral influences represented by the continuous interaction of negative and positive feedback mechanisms.     

Central control components of a 'simple' stretch reflex

The monosynaptic stretch reflex is a fundamental feature of sensory-motor organization in most animal groups. In isolation, it serves largely as a negative feedback devoted to postural controls; however, when it is involved in diverse movements, it can be modified by central command circuits. In order to understand the implications of such modifications, a model system has been chosen that has been studied at many different levels: the crayfish walking system. Recent studies have revealed several levels of control and modulation (for example, at the levels of the sensory afferent and the output synapse from the sensory afferent, and via changes in the membrane properties of the postsynaptic neuron) that operate complex and highly adaptive sensory-motor processing. During a given motor task, such mechanisms reshape the sensory message completely, such that the stretch reflex becomes a part of the central motor command.     

Effect of task conditions on brain responses to threatening faces in social phobics: an event-related functional magnetic resonance imaging study.

BACKGROUND: The aim of this study was to identify brain activation to socially threatening stimuli in social phobic subjects during different experimental conditions. METHODS: With event-related functional magnetic resonance imaging, brain activation to photographs and schematic pictures depicting angry or neutral facial expressions was measured in social phobic subjects and healthy control subjects, while subjects assessed either emotional expression (angry vs. neutral; explicit task) or picture type (photographic vs. schematic; implicit task). RESULTS: Compared with control subjects, phobics showed greater responses to angry than to neutral photographic faces in the insula regardless of task, whereas amygdala, parahippocampal gyrus, and extrastriate visual cortex were more strongly activated only during the implicit task. Phobics, in contrast to control subjects, showed similar activation patterns during both tasks. For schematic angry versus neutral faces, activation of insula and extrastriate visual cortex was found in phobics, but not in control subjects, during both tasks. CONCLUSIONS: Differences between social phobics and control subjects in brain responses to socially threatening faces are most pronounced when facial expression is task-irrelevant. Phobics intensively process angry (photographic as well as schematic) facial expressions, regardless of whether this is required. The insula plays a unique role in the processing of threat signals by social phobics.     

Autonomic function in amyotrophic lateral sclerosis: a study of cardiovascular responses

Autonomically mediated cardiovascular responses were evaluated in 15 ALS patients and compared with 15 healthy subjects. The respiratory sinus arrhythmia, the heart rate response to a Valsalva manoeuvre, to isometric handgrip and to a dive reflex test was normal, indicating a normal function of vagal nerves. The heart rate and blood pressure responses during an orthostatic test were normal, indicating a normal function of sympathetic nerves. The increase in blood pressure and blood flow in the contralateral forearm which occurs on handgrip in healthy subjects was reduced in the ALS patients. The cause of this is unclear, but could be related to decreased function of "ergoreceptors" or altered vascular reactivity in atrophic muscle.     

Nonlinear cortical modulation of muscle fatigue: a functional MRI study

Muscle fatigue has been studied for over a century, but almost no data are available to indicate how the brain perceives fatigue and modulates its signals to the fatiguing muscle. In this study, brain activation was measured by functional magnetic resonance imaging (fMRI) during a sustained (2-min) maximal-effort handgrip contraction while handgrip force and finger muscle electromyographic (EMG) data were recorded simultaneously by a magnetic resonance environment-adapted force-EMG measurement system. The results showed decoupled progresses in brain and muscle activities when muscle was fatigued and correlated behaviors among the cortical areas being analyzed. While handgrip force and EMG signals declined in parallel during the course of muscle fatigue, fMRI-measured brain activities first substantially increased and then decreased. This similar signal modulation occurred not only in the primary sensorimotor areas but also in the secondary and association cortices (supplementary motor, prefrontal, and cingulate areas). The nonlinear changes of brain signal may reflect an early adjustment to strengthen the descending command for force-loss compensation and subsequent inhibition by sensory feedback as fatigue became more severe. The close association in the activation pattern in many cortical regions may reflect integrated processing of information in the brain.     

Classical conditioned response of rectosigmoid motility and regional cerebral activity in humans

The relationship between the central processes of classical conditioning and conditioned responses of the gastrointestinal function is incompletely understood in humans. We tested the hypothesis that the rectosigmoid motility becomes conditioned with anticipatory painful somatosensory stimulus and that characteristic brain areas become activated during anticipation. In nine right-handed healthy male subjects, a loud buzzer (CS, conditional stimulus) was paired with painful transcutaneus electrical nerve stimulation to the right hand (unconditional stimulus). Rectosigmoid muscle tone measured by the barostat as the intrabag volume, phasic contractions of the bowel measured as the number of phasic volume events (PVEs), and regional cerebral blood flow assessed by positron emission tomography (PET), were measured before and after conditioning. Following conditional trials, the bag volume after CS alone did not show significant changes between before and after the stimulus, but the number of PVEs after 2-minute interval of the CS alone was significantly greater than that before the stimulus (P < 0.05). The PET data showed the conditioning elicited significant cerebral activation of the prefrontal, anterior cingulate, parietal and insula cortices (P < or = 0.001, uncorrected). Rectosigmoid motility can be conditioned with increase in phasic contractions in humans.     

Effect of levodopa on pain threshold in Parkinson's disease: a clinical and positron emission tomography study.

Patients suffering from Parkinson's disease (PD) frequently experienced painful sensations that could be in part due to central modification of nociception. We compared pain threshold before and after administration of levodopa in PD patients and in controls, and investigated cerebral activity with positron emission tomography (PET) during experimental nociceptive stimulation. Pain threshold was determined using thermal stimulation during two randomized conditions: off and on. We performed H(2) (15)O PET analysis of regional cerebral blood flow on subjects while they received alternate randomized noxious and innocuous stimuli during off and on conditions. In off condition, pain threshold in nine PD patients was significantly lower than in nine controls. Administration of levodopa significantly raised pain threshold in PD patients but not in controls. During off condition, there was a significant increase in pain-induced activation in right insula and prefrontal and left anterior cingulate cortices in PD compared to control group. Levodopa significantly reduced pain-induced activation in these areas in PD. This study shows that pain threshold is lower in PD patients but returns to normal ranges after levodopa administration. Moreover, PD patients have higher pain-induced activation in nociceptive pathways, which can be reduced by levodopa.     

Hypothalamic mechanisms coordinating cardiorespiratory function during exercise and defensive behaviour

Defensive behaviour evoked by mild or moderate psychological stress as well as increased activity and arousal are part of everyday life in humans and other animals. Both defensive behaviour and exercise are associated with marked and often quite stereotyped changes in autonomic and respiratory function. These patterned responses are generated by feed-forward or "central command" mechanisms, and are also modulated by feedback from peripheral receptors. In this review we first describe the pattern of autonomic and respiratory changes associated with defensive behaviour and exercise, and then discuss the central mechanisms that generate these patterned responses in the light of recent studies, with a particular focus on the role of the dorsomedial hypothalamus (DMH). We consider the hypothesis that the cardiorespiratory changes associated with defensive behaviour and exercise may, at least in part, be driven by common central mechanisms. Finally, we discuss the possible role of the DMH in generating circadian rhythms in arterial blood pressure and heart rate, and also in generating longer-term increases in sympathetic activity in some types of hypertension.     

Individual integration of positron emission tomography and high-resolution magnetic resonance imaging.

We have developed, validated, and employed a technique of retrospective spatial alignment and integrated display of positron emission tomographic (PET) and high-resolution magnetic resonance (MR) brain images. The method was designed to improve the anatomical evaluation of functional images obtained from single subjects. In the first computational step, alignment of PET and MR data sets is achieved by iteratively matching in three orthogonal views the outermost scalp contours derived from front-to-back projections of each data set. This procedure avoids true three-dimensional modeling, runs without user interaction, and tolerates missing parts of the head circumference in the image volume, as usually the case with PET. Thereafter, high-resolution MR sections corresponding to the PET slices are reconstructed from the spatially transformed MR data. In a phantom study of this method, PET/MR alignment of the phantom's surface was accurate with average residual misfits of 2.17 to 2.32 mm as determined in three orthogonal planes. In-plane alignment of the phantom's insertion holes was accurate with an average residual misfit of 2.30 mm. In vivo application in six subjects allowed the individual anatomical localization of regional CBF (rCBF) responses obtained during unilateral manual exploration. In each subject, the maxima of the rCBF activations in the hand area were precisely allocated to gray matter in the anterior or posterior wall of the central sulcus. The configuration of the rCBF responses closely followed the gyral structures. The technique provided a better topographical understanding of rCBF changes in subtraction images of PET activation studies. It opens the perspective for studies of structural-functional relationships in individual subjects.     

Cerebello-frontal cortical projections in humans studied with the magnetic coil.

Focal stimulation over human cerebellum with a figure 8 magnetic coil (MC) results in an evoked wave recorded from bipolar scalp electrodes on the interaural line and more anteriorly. In 3 subjects, the wave responses along the interaural line had latencies of 8.8-13.8 msec, lasted 17.4-29.0 msec and had a maximum amplitude of 14.4-26.8 microV. The responses were recorded more anteriorly from leads midway between the interaural line and frontal leads; responses recorded from frontal leads were up to 3.5 msec later. The evoked wave was preceded by a diphasic EMG response with a latency of 1.2-2.0 msec. Analysis of the averaged responses recorded by adjoining bipolar leads indicated that the response was predominantly surface positive and crossed. Control experiments eliminated eye movement and somatosensory input as explanations of the evoked response, thereby identifying it as a cortical response. The surface positive wave in humans was compared with the responses recorded in cat and monkey to cerebellar stimulation. The responses in humans could reflect dysfacilitation through MC activation of Purkinje cells, or feed-forward facilitation through transsynaptic or antidromic activation of dentate neurons. The latency of the surface positive wave exceeds that of cerebellar inhibition of MC elicited hand muscle responses, but the discrepancy is at least partly accounted for by the extra delay required to set up the indirect cortico-spinal component required for motoneuron discharge. Estimates made of the cerebello-frontal cortical and peripheral feedback loop times suggest that the central has less than one quarter the delay of the peripheral loop, which would be especially advantageous during fast skilled movements of the fingers.     

Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism

Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory γ-amino butyric acid α2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI). In a sample of 173 families (449 subjects), 129 of whom had at least one member diagnosed with alcohol dependence or abuse, carriers for the G allele in two single-nucleotide polymorphisms (SNPs) and haplotypes were more likely to have alcohol dependence symptoms (rs279858, P=0.01; rs279826, P=0.05; haplotype, P=0.02) and higher NEO Personality Inventory-Revised (NEO-PI-R) Impulsiveness scores (rs279858, P=0.016; rs279826, P=0.012; haplotype, P=0.032) with a stronger effect in women (rs279858, P=0.011; rs279826, P=0.002; haplotype, P=0.006), all P-values are corrected for family history and age. A subset of offspring from these families (n=44, 20 females), genotyped for GABRA2, participated in an fMRI study using a monetary incentive delay task. Increased insula activation during reward (r(2)=0.4; P=0.026) and loss (r(2)=0.38; P=0.039) anticipation was correlated with NEO-PI-R Impulsiveness and further associated with the GG genotype for both SNPs (P's<0.04). Our results suggest that GABRA2 genetic variation is associated with Impulsiveness through variation of insula activity responses, here evidenced during anticipatory responses.     

Cardiac dysrhythmias during cardiovascular autonomic reflex tests

To assess the possible dysrhythmogenic effect of cardiovascular autonomic function tests, ECG tracings of 925 consecutive subjects, taken during a battery of cardiovascular autonomic reflex tests were analyzed. The battery included the Valsalva manoeuvre, deep breathing test, orthostatic and isometric handgrip. The frequency of ventricular extrasystoles increased during or after the tests, compared with the resting phase, in 11% of healthy subjects, in 11% of diabetic subjects and in 23% of subjects with a previous myocardial infarction (p = 0.001vs healthy subjects). In patients with previous myocardial infarction, the most dysrhythmogenic individual tests were orthostatic and isometric handgrip. In nine subjects, other cardiac rhythm disturbances were detected (including nonsustained ventricular tachycardia, conduction block, and atrial fibrillation). In all cases, the dysrhythmias were asymptomatic and resolved without medical intervention. In conclusion, we consider the cardiovascular reflex test battery safe for the patient. However, due to occasional potentially significant dysrhythmias we recommend continuous monitoring of the electrocardiogram and immediate access to resuscitation facilities during cardiovascular autonomic testing.     

Passive music listening spontaneously engages limbic and paralimbic systems

In this PET study, non-musicians passively listened to unfamiliar instrumental music revealed afterward to elicit strongly pleasant feelings. Activations were observed in the subcallosal cingulate gyrus, prefrontal anterior cingulate, retrosplenial cortex, hippocampus, anterior insula, and nucleus accumbens. This is the first observation of spontaneous responses in such limbic and paralimbic areas during passive listening to unfamiliar although liked music. Activations were also seen in primary auditory, secondary auditory, and temporal polar areas known to respond to music. Our findings complement neuroimaging studies of aesthetic responses to music that have used stimuli selected by subjects or designed by experimenters. The observed pattern of activity is discussed in terms of a model synthesizing emotional and cognitive responses to music.     

The role of the salience network in processing lexical and nonlexical stimuli in cochlear implant users

Previous positron emission tomography (PET) studies have shown that various cortical areas are activated to process speech signal in cochlear implant (CI) users. Nonetheless, differences in task dimension among studies and low statistical power preclude from understanding sound processing mechanism in CI users. Hence, we performed activation likelihood estimation meta‐analysis of PET studies in CI users and normal hearing (NH) controls to compare the two groups. Eight studies (58 CI subjects/92 peak coordinates; 45 NH subjects/40 peak coordinates) were included and analyzed, retrieving areas significantly activated by lexical and nonlexical stimuli. For lexical and nonlexical stimuli, both groups showed activations in the components of the dual‐stream model such as bilateral superior temporal gyrus/sulcus, middle temporal gyrus, left posterior inferior frontal gyrus, and left insula. However, CI users displayed additional unique activation patterns by lexical and nonlexical stimuli. That is, for the lexical stimuli, significant activations were observed in areas comprising salience network (SN), also known as the intrinsic alertness network, such as the left dorsal anterior cingulate cortex (dACC), left insula, and right supplementary motor area in the CI user group. Also, for the nonlexical stimuli, CI users activated areas comprising SN such as the right insula and left dACC. Previous episodic observations on lexical stimuli processing using the dual auditory stream in CI users were reconfirmed in this study. However, this study also suggests that dual‐stream auditory processing in CI users may need supports from the SN. In other words, CI users need to pay extra attention to cope with degraded auditory signal provided by the implant. Hum Brain Mapp 36:1982–1994, 2015. © 2015 Wiley Periodicals, Inc.     

Mapping metabolic brain activation during human volitional swallowing: a positron emission tomography study using [18F]fluorodeoxyglucose.

We have previously shown that labelled water positron emission tomography (H2(15)O PET) can be used to identify regional cerebral blood flow (rCBF) changes in the human brain during volitional swallowing. (18F) fluorodeoxyglucose (FDG PET), by comparison, uses a glucose analogue to quantitatively measure regional cerebral glucose metabolism (rCMRglc) rather than rCBF. The main advantage of FDG PET is improved spatial resolution, and because of its pharmacodynamic properties, activation can be performed external to the scanner, allowing subjects to assume more physiologic positions. We therefore conducted a study of the brain's metabolic response while swallowing in the erect seated position, using FDG PET. Eight healthy male volunteers were studied with a randomised 2 scan paradigm of rest or water swallowing at 20-second intervals for 30 minutes. Data were analysed with SPM99 using multisubject conditions and covariates design. During swallowing, analysis identified increased rCMRglc (P<0.01) in the following areas: left sensorimotor cortex, cerebellum, thalamus, precuneus, anterior insula, left and right lateral postcentral gyrus, and left and right occipital cortex. Decreased rCMRglc were also seen in the right premotor cortex, right and left sensory and motor association cortices, left posterior insula and left cerebellum. Thus, FDG PET can be applied to measure the brain metabolic activity associated with volitional swallowing and has the advantage of normal task engagement. This has implications for future activation studies in patients, especially those suffering swallowing problems after brain injury.     

Effects of exercise intensity, posture, pressure on the back and ambient temperature on palmar sweating responses due to handgrip exercises in humans

We have, by using newly developed ratemeters, attempted to examine the effects of exercise intensity, posture, pressure on the skin of the back, and ambient hyperthermic conditions (approximately 30 degrees C) on the 5-s handgrip exercise-mediated responses of active palmar sweating in humans. Thirty-five right-handed male (n=5) and female (n=30) volunteer students (20.2+/-1.3 years old) participated in the present study. Oral explanation of only the isometric handgrip exercise (IHG) caused a rapid and oscillatory response (pre-operational) of active palmar sweating in almost all subjects (10 of 14 subjects). Performing the IHG for 5-s caused a significant increase in active sweating rate (operation-mediated response) in both ipsi- and contra-lateral palmar surfaces of the thumbs of all subjects. The operation-mediated responses of active palmar sweating to the IHG were reproducible, resulting in no habituation. The increase of operation-mediated responses to the IHG was dependent upon exercise intensity (100-25% maximal voluntary contractions). The IHG-mediated ipsi- and contra-lateral responses of active palmar sweating were significantly decreased by changing the body posture from a seated to a supine position or by pressing the skin of the back. Ambient hyperthermic conditions (approximately 30 degrees C) for 60 min also resulted in a significant decrease in the back-pressure-dependent reduction of the operation-mediated responses of active palmar sweating to the IHG. In conclusion, in order to optimize the precision and reproducibility of clinical tests involving palmar sweating responses, it is important that subjects maintain a constant handgrip force and posture and that ambient temperature be kept under normothermic conditions.