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SUMMARY The diagnosis and management of disorders of consciousness in children continue to present a clinical, research, and ethical challenge. Though the practice guidelines for diagnosis and management of disorders of consciousness in adults are supported by decades of empirical and pragmatic evidence, similar guidelines for infants and children are lacking. The maturing conscious experience and the limited behavioral repertoire to report consciousness in this age group restrict extrapolation from the adult literature. Equally challenging is the process of heightened structural and functional neuroplasticity in the developing brain, which adds a layer of complexity to the investigation of the neural correlates of consciousness in infants and children. This review discusses the clinical assessment of pediatric disorders of consciousness and delineates the diagnostic and prognostic utility of neurophysiological and neuroimaging correlates of consciousness. The potential relevance of these correlates for the developing brain based on existing theoretical models of consciousness in adults is outlined.

Deep brain stimulation applied at high frequency (HFS) to the subthalamic nucleus (STN) is used to ameliorate the symptoms of Parkinson's disease. The mechanism by which this is achieved remains controversial. In particular, it is uncertain whether HFS has a suppressive or excitatory action locally within the STN. Brief exposure of rats to ether anesthesia evokes pathological burst firing and associated expression of the immediate early gene c-Fos in STN neurons. We used this ether model of STN activation to test the effect of a range of HFS parameters on c-Fos expression evoked by the anesthetic. The elevated baseline of c-Fos expression afforded the possibility of detecting further excitatory, or suppressive effects of STN HFS. Four HFS protocols were examined; 130, 200 and 260 Hz with 60 µs, and 130 Hz with 90 µs pulse width (HFS intensity:150-300 µA). All HFS protocols were applied for 20 min while the animals were exposed to ether. Ether-evoked expression of c-Fos immunoreactivity was suppressed by HFS at 200 and 260 Hz with a pulse width of 60 µs, and by 130 Hz when the pulse width was increased to 90 µs. HFS at 130 Hz with the 60 µs pulse width had no significant effect and HFS alone caused negligible c-Fos expression in the STN. These findings suggest that HFS of the STN causes significant suppression of evoked neuronal activity. It remains to be determined whether this locally suppressive property of HFS is associated with the efficacy of STN deep brain stimulation to relieve the symptoms of Parkinson's disease.

Although the brain’s ability to change constantly in response to external and internal inputs is now well recognized the mechanisms behind it in normal aging and neurodegeneration are less well understood. To gain a better understanding, transcranial magnetic stimulation (TMS) has been used extensively to characterize non-invasively the cortical neurophysiology of the aging and degenerating brain. Furthermore, there has been a surge of studies examining whether repetitive TMS (rTMS) can be used to improve functional deficits in various conditions including normal aging, Alzheimer’s and Parkinson’s disease. The results of these studies in normal aging and neurodegeneration have emerged reasonably coherent in delineating the main pathology in spite of considerable technical limitations, omnipresent methodological variability, and extraordinary patient heterogeneity. Nevertheless, comparing and integrating what is known about TMS measurements of cortical excitability and plasticity in disorders that predominantly affect cortical brain structures with disorders that predominantly affect subcortical brain structures may provide better understanding of normal and abnormal brain aging fostering new. The present review provides a TMS perspective of changes in cortical neurophysiology and neurochemistry in normal aging and neurodegeneration by integrating what is revealed in individual TMS measurements of cortical excitability and plasticity in physiological aging, Alzheimer’s, Parkinson’s, and Huntington’s, disease. The paper also reflects on current developments in utilizing TMS as a physiologic biomarker to discriminate physiologic aging from neurodegeneration and its potential as a method of therapeutic intervention.

Objective Little is known whether and how chronic exposure to dopaminergic treatment alters physiological mechanisms in Parkinson’s disease (PD). Methods Two clinically similar groups of PD patients, one consisting of drug-naive patients and another of patients already on chronic dopaminergic medication (when off medication), were compared to each other and to a control group. Plasticity and excitability of the hand primary motor cortex of the more affected side were evaluated using transcranial magnetic stimulation (TMS) techniques. Results There was little difference between two patient groups, and both groups showed similar differences in comparison to controls: decreased facilitatory sensory-motor plasticity (as measured by paired associative stimulation [PAS] protocol), impaired short-interval intracortical inhibition (SICI), and diminished slope of input–output curves at higher TMS intensities. The exception was that 30 min after PAS, intracortical facilitation (ICF) was significantly reduced in drug-naive patients, whereas it changed much less in other two groups. Conclusions Chronic exposure to dopaminergic drugs does not affect substantially the features of motor cortex excitability and plasticity in PD. There is little interaction between plasticity and excitability features of motor cortex in PD. Significance Reduced response to facilitatory PAS protocol, reduced SICI, and reduced slope of the input–output curve at higher TMS pulse intensities, seem to be physiological markers for the presence of the pathological disease process in PD. Long term treatment does not seem to change the underlying physiology of the disease.

The complex interplay between hypernatremic osmotic disturbances and cerebral lesions is yet to be clarified. In this review, we discuss, on the basis of the reported data of hypernatremic CNS challenge in the adult population, the clinical and radiologic features of the condition. Our search captured 20 case studies and 1 case series with 30 patients in total who acquired acute hypernatremia due to different etiologies and developed CNS lesions. We explored the associations between premorbid conditions, clinical presentation, hypernatremic state, correction rate, and radiologic appearance, including the localization of brain lesions and the outcomes. The results revealed that altered mental status was the most commonly reported symptom and osmotic demyelination syndrome in the form of extrapontine myelinolysis was the prevailing radiologic pattern. Finally, we contrasted, when appropriate, clinical and experimental data related to hypernatremic and hyponatremic osmotic insults to aid the understanding of the pathophysiology of CNS osmotic brain injury.

Brain MRI and ¹⁸F-FDG PET/CT scans were performed in a patient who had survived a suicide attempt by fluoxetine overdose. The patient presented with the following clinical signs and symptoms, and neuroimaging findings: severe signs of serotonin toxicity, including comatose state, akinetic rigid syndrome and dysautonomia; bilateral globus pallidus changes consistent with extensive pallidal necrosis and subsequent reversible diffuse ischemic changes in white matter, with posterior predominance, involving the splenium of the corpus callosum on brain MRI; and marked hypometabolism in the frontal, parietal and temporal cortical regions as well as in both caudate nuclei on ¹⁸F-FDG PET/CT performed 37 days later. These findings suggest that acute severe serotonin toxicity can induce structural and long-standing functional changes in multiple cortical and subcortical brain regions that are associated with cognitive and extrapyramidal syndromes.

Background The dorsolateral prefrontal cortex (DLPFC) plays an important role in the regulation of food intake. Several previous studies demonstrated that a single session of transcranial direct current stimulation (tDCS) of the DLPFC reduces food craving and caloric intake. Objectives We hypothesized that repeated tDCS of the right DLPFC cortex may exert long-term changes in food craving in young, healthy adults and that these changes may differ between normal and overweight subjects. Methods Thirty healthy individuals who reported frequent food cravings without a prior history of eating disorders were initially recruited. Subjects were randomized into an ACTIVE group who received 5 days of real tDCS (20 minutes, anode right-cathode left montage, 2 mA with current density kept at 0.06 mA/cm2, 1 min ramp-up/ramp-down), and a SHAM group, who received one day of real tDCS, on the first day (same parameters), followed by 4 days of sham tDCS. Food craving intensity was examined by Food Craving Questionnaires State and Trait and Food Craving Inventory before, during, (5-days) and one month (30-days) after tDCS. Results Single session of tDCS significantly reduced the intensity of current food craving (FCQ-S). Five days of active tDCS significantly reduced habitual experiences of food craving (FCQ-T), when compared to baseline pre-stimulation levels. Furthermore, both current (FCQ-S) and habitual craving (FCQ-T) were significantly reduced 30 days after active tDCS, while sham tDCS, i.e. a single tDCS session did not have significant effects. Also, active tDCS significantly decreased craving for fast food and sweets, and to a lesser degree for fat, while it did not have significant effects on craving for carbohydrates (FCI). There were no significant differences between individual FCQ-T subscales (craving dimensions) after 5 or 30 days of either sham or active tDCS. Changes in craving were not significantly associated with the initial weight, or with weight changes 30 days after the stimulation in the subjects. Conclusions The results confirm earlier findings that single session of tDCS has immediate effects in reducing food craving. They also show that repeated tDCS over the right DLPFC may increase the duration of its effects, which may be present 30 days after the stimulation. These results support further investigation of the use of tDCS in obesity.

Recent evidence suggests that the dynamic-scaling behavior of the time-series of signals extracted from separate peaks of tremor spectra may reveal existence of multiple independent sources of tremor. Here, we have studied dynamic characteristics of the time-series of hand tremor movements in essential tremor (ET) patients using the detrended fluctuation analysis method. Hand accelerometry was recorded with (500 g) and without weight loading under postural conditions in 25 ET patients and 20 normal subjects. The time-series comprising peak-to-peak (PtP) intervals were extracted from regions around the first three main frequency components of power spectra (PwS) of the recorded tremors. The data were compared between the load and no-load condition on dominant (related to tremor severity) and non-dominant tremor side and with the normal (physiological) oscillations in healthy subjects. Our analysis shows that, in ET, the dynamic characteristics of the main frequency component of recorded tremors exhibit scaling behavior. Furthermore, they show that the two main components of ET tremor frequency spectra, otherwise indistinguishable without load, become significantly different after inertial loading and that they differ between the tremor sides (related to tremor severity). These results show that scaling, a time-domain analysis, helps revealing tremor features previously not revealed by frequency-domain analysis and suggest that distinct oscillatory central circuits may generate the tremor in ET patients.

s / Brain Stimulation 8 (2015) 395e411 398 at 5Hz intervals). After this patient remitted following TBS-20Hz, this parameter was then successfully applied to other patients with treatment refractory MDD who had failed TBS-50Hz. We began to use TBS-20Hz as our initial treatment parameter after multiple patients failed TBS-50Hz but remitted after TBS-20Hz. Results: 9 of 10 MDD patients treated with TBS-20Hz remitted, with an average BDI-II score drop of 20 points (s.d.1⁄416.8), or 64.3%. Our only non-remitter had suffered a CVA several years prior, possibly altering the position of the LDLPFC target location. Discussion: The strong response seen after TBS-20Hz suggests this and perhaps other alternate pulse parameters could improve the efficacy and durability of TMS treatment for depression. Therefore, a larger controlled trial is warranted to confirm and expand upon these results.

Primary writing tremor (PWT) is a rare disease of unknown pathophysiology. We studied changes in silent period (SP) duration, after transcranial magnetic stimulation (TMS), set at 20% above the motor threshold in 6 PWT patients and 7 healthy control subjects. SP duration was tested during a task-specific act, i.e., writing that induced tremor in all patients in the affected hand (Wr); nonspecific voluntary contraction of intensity, matching that developed during writing (VCWr); and during near maximal voluntary contraction (VCNmax). There were no differences in SP duration during Wr and VCWr contraction on the right affected side or between sides in both PWT patients and control subjects, nor between the groups. However, during VCNmax, SP significantly shortened on both sides in PWT patients, whereas there were no changes in control subjects. Although it appears that inhibitory mechanism are not directly involved in the generation of the tremulous activity, the shortening of SP indicates that central inhibitory mechanisms are affected in PWT patients. Therefore, whereas the underlying pathophysiological mechanisms in PWT and writer's cramp may share common features, the results indicate that PWT is not a variant of focal task-specific dystonia but rather a separate nosological entity.

The distribution of Fos-immunoreactive (Fos-ir) and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-reactive neurons in the rat lumbar spinal cord was examined following muscle fatigue caused by intermittent high-rate (100 s(-1)) electrical stimulation of the triceps surae muscle or the ventral root L5 (VRL5) for 30 min. Following both types of stimulation, the fatigue-related c-fos gene expression was more extensive in the L2-L5 segments on the stimulated side, and the majority of Fos-ir neurons were concentrated in the dorsal horn. After direct muscle stimulation, the highest number of Fos-ir neurons were detected in two regions: layer 5, and superficial layers (1 and 2(o)), although many labeled cells were also found in layers 3, 4, 6, and 7. In response to VRL5 stimulation, the maximal density of Fos-ir neurons was detected in the middle and lateral parts of layers 1 and 2(o), the zone of termination of high-threshold muscle afferents(.) Statistically significant prevalence of Fos-ir cell number was also found in layers 5 and 7 on the stimulated side. A few Fos-ir neurons were detected in the ventral horn (layer 8 and area 10) on both sides. The lamellar distribution of NADPH-d-reactive neurons was similar over all experimental groups of animals. In the L3-L6 segments, such reactive cells were arranged in two distinct regions: dorsal horn (layers 2(i), 3, and 5) and area 10; in the L1 and L2 segments, an additional cluster of NADPH-d positive cells was found in the intermediolateral cell column (IML). Double-labeled cells were not detected. We suggest that c-fos expression in response to muscle fatigue reveals activity of functionally different types of spinal neurons which could operate together with NOS-containing cells in pre-motoneuronal networks to modulate the motoneuron output.

The effects of prior vibration of the antagonist triceps muscle on the performance of rapid discrete elbow flexion movements were studied in healthy volunteers. The subjects performed 520 movements over five experimental sessions. The application of prior vibration resulted in a shift of the initial position, an undershoot of the final position in untrained subjects, and also in trained subjects if not applied during practice. On the contrary, no undershoot occurred in trained subjects when prior vibration was applied during practice. Improvement in movement performance, as judged by a decrease in variability of the final position, was less successful when vibration was applied during practice. It is supposed that the undershoots were due to prior vibration-induced alterations in proprioceptive messages and a consequent erroneous sense of the arm position. These effects seem to be overcome by practice, but also seem to interfere with learning-based movement improvement.

Changes in discharge rate of fusimotor neurones to pretibial flexor muscles were recorded during and after long-lasting fatiguing isometric and/or isotonic contractions of triceps surae in decerebrate cats. The contractions were elicited by electrical stimulation of the nerves to triceps. Fusimotor spikes were recorded from nerve filaments dissected free from the peroneal nerve. Responses of the fusimotor neurones were diverse. In isometric regime, 22 out of 40 units recorded exhibited an initial increase at the onset of muscle contraction, different in amplitude and duration among the units. In seven of these units an additional brisk burst of spike discharges, of different duration, occurred at the end of the contraction. In 15 fusimotor neurones (14 units with the initial response and an additional unit without it) a slow increase in discharge rate developed, starting during the contraction and outlasting it. In another eleven units the initial response was a decrease in discharge rate, lasting in six of them throughout the contraction. Another six units exhibited a sustained increase in discharge rate throughout the contraction, as well as, at a lower level, but still above the spontaneous one, thereafter. Similar patterns of changes in discharge rate, recorded in 31 of the units, were encountered during isotonic triceps contractions. It should be mentioned that many (about 20) additional silent neurones, responding to manipulating the skin and paw and/or stroking the fur, but not to triceps contractions were encountered. The majority of changes in discharge rate of fusimotor neurones to pretibial flexors differed markedly from those found previously in fusimotor neurones to triceps and hamstring muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective Motor learning is the core cognitive function in neurorehabilitation and in various other skill-training activities (e.g. sport, music). Therefore, there is an increasing interest in the use of transcranial magnetic stimulation (TMS) methods for its enhancement. However, although usually assumed, a potential placebo effect of TMS methods on motor learning has never been systematically investigated. Methods Improvement of performance on the Purdue Pegboard Task over three test-blocks (T0, T1, and T2), separated by >20 min, was used to evaluate motor learning. In Experiment-1, two groups of 10 participants each were compared: one group immediately before T1 received a sham intermittent theta burst stimulation procedure (P-iTBS group), while another did not have any intervention at all (control – CON group). In Experiment-2, a third group of participants (six subjects) who received sham high-frequency repetitive TMS procedure before T1 (P-rTMS group) was compared with P-iTBS group. Results All three groups showed significant learning over time, but without any difference between them, either in Experiment-1 between P-iTBS and CON, or in Experiment-2 between P-rTMS and P-iTBS. Conclusion The results suggest lack of any placebo effect of TMS on motor learning. Significance The results may help in designing further TMS–motor learning studies and in interpreting their results.

Extrapontine myelinolysis (EPM) and cortical laminar necrosis (CLN) have rarely been reported in association with severe hypernatremia. We describe a patient with EPM associated with CLN following severe hypernatremia due to hypertonic peritoneal lavage after a ruptured hydatid cyst of the liver. Clinical and neuroimaging findings in acute stage and serial brain MRI at two and five month follow-up are discussed in detail.

In anaesthetised rats, Fos-immunoreactive and NADPH-diaphorase-positive neurons in the medulla and, for comparison, in the spinal cord were studied after fatiguing stimulation of the hindlimb muscles. Following both direct muscle stimulation and L5 ventral root stimulation, fatigue-related c-fos gene expression was most prominent in the dorsal horn of the ipsilateral L2-L5 segments and within the ipsilateral nucleus tractus solitarius, the caudoventrolateral and rostroventrolateral reticular nuclei, and the intermediate reticular nucleus at levels of -14.3 and -13.8 mm, and contralaterally at -13.2 mm caudal to the bregma. The order of intensity of c-fos expression was as follows: nucleus tractus solitarius>caudoventrolateral and rostroventrolateral reticular nuclei>intermediate reticular nucleus>lateral paragigantocellular nucleus. NADPH-diaphorase reactivity was changed in the following sequence: NTS>intermediate reticular nucleus lateral paragigantocellular nucleus>rostroventrolateral reticular nucleus. Fos-immunoreactive neurons were codistributed with NADPH-diaphorase-reactive cells within the dorsomedial and ventrolateral medulla, and double-staining neurons were found in the nucleus tractus solitarius, intermediate reticular nucleus and lateral paragigantocellular nucleus. The patterns of distribution of c-fos expression and NADPH-diaphorase reactivity show that afferent signals arising from fatiguing muscles may activate spinal and medullary neurons which are involved in nociceptive and cardiovascular reflex pathways. The functional role of nitric oxide (NO) in the generation of cardiovascular and somatosensory responses in the medulla during fatigue of skeletal muscles is discussed.

Changes in responses to transcranial magnetic stimulation (TMS) during submaximal isometric voluntary contraction (60% of maximal voluntary contraction (MVC) of the adductor pollicis muscle and the subsequent recovery period have been studied in healthy volunteers. TMS at twice the motor threshold was applied during the sustained contraction, as well as at rest and during short-lasting (2 s) 60% MVCs before and immediately after the sustained contraction, and at 5 min intervals during the recovery period. Both motor evoked potential (MEP) magnitude (peak and area) and silent period (SP) duration in electromyographic activity (EMG) of the adductor pollicis muscle showed a gradual decrease up to the endurance point and an increase thereafter. MEPs elicited at rest immediately after the fatiguing contraction were larger, whereas those elicited later on during the recovery period did not differ significantly from the controls. It is suggested that the changes in responses to TMS, divergent from those in ongoing voluntary EMG during the sustained 60% MVC, indicate complex processes at levels preceding the motor cortex output cells in an attempt to maintain a submaximal contraction of the fatigued muscle. The increase in MEP magnitude after the sustained 60% MVC may indicate residual changes in cortical activity after fatiguing contraction.