Characteristics of synaptic connections between rodent primary somatosensory and motor cortices

The reciprocal connections between primary motor (M1) and primary somatosensory cortices (S1) are hypothesized to play a crucial role in the ability to update motor plans in response to changes in the sensory periphery. These interactions provide M1 with information about the sensory environment that in turn signals S1 with anticipatory knowledge of ongoing motor plans. In order to examine the synaptic basis of sensorimotor feedforward (S1–M1) and feedback (M1–S1) connections directly, we utilized whole-cell recordings in slices that preserve these reciprocal sensorimotor connections. Our findings indicate that these regions are connected via direct monosynaptic connections in both directions. Larger magnitude responses were observed in the feedforward direction (S1–M1), while the feedback (M1–S1) responses occurred at shorter latencies. The morphology as well as the intrinsic firing properties of the neurons in these pathways indicates that both excitatory and inhibitory neurons are targeted. Differences in synaptic physiology suggest that there exist specializations within the sensorimotor pathway that may allow for the rapid updating of sensory–motor processing within the cortex in response to changes in the sensory periphery.     

Characteristics of synaptic connections between rodent primary somatosensory and motor cortices

The reciprocal connections between primary motor (M1) and primary somatosensory cortices (S1) are hypothesized to play a crucial role in the ability to update motor plans in response to changes in the sensory periphery. These interactions provide M1 with information about the sensory environment that in turn signals S1 with anticipatory knowledge of ongoing motor plans. In order to examine the synaptic basis of sensorimotor feedforward (S1-M1) and feedback (M1-S1) connections directly, we utilized whole-cell recordings in slices that preserve these reciprocal sensorimotor connections. Our findings indicate that these regions are connected via direct monosynaptic connections in both directions. Larger magnitude responses were observed in the feedforward direction (S1-M1), while the feedback (M1-S1) responses occurred at shorter latencies. The morphology as well as the intrinsic firing properties of the neurons in these pathways indicates that both excitatory and inhibitory neurons are targeted. Differences in synaptic physiology suggest that there exist specializations within the sensorimotor pathway that may allow for the rapid updating of sensory-motor processing within the cortex in response to changes in the sensory periphery.     

Component-Specific Self-Regulation of Slow Cortical Potentials and its Effect on Behavior: An Exploratory Study

In the present study, the possibility of component-specific self-regulation of the contingent negative variation (CNV) and the functional significance of the iCNV (initial or early CNV component) and tCNV (terminal or late CNV component) were investigated in twenty-four healthy volunteers. The subjects were able to achieve control over a particular CNV component within four sessions. Regulation of the tCNV was more successful than for the iCNV. Specific control over iCNV was associated with strategies mainly related to the pre-stimulus interval or the warning stimulus (S1), while regulation of the tCNV was assigned to activities during the whole interstimulus interval or around the imperative stimulus (S2). It can be concluded that component-specific regulation of the CNV can be used in studies of the psychophysiological meaning of this potential, representing different stages of information processing. The role of cortical pre-activation in the generation of the iCNV and the phasic performance-directed activation of the tCNV can be hypothesized.     

Task-dependent interaction between parietal and contralateral primary motor cortex during explicit versus implicit motor imagery

Both mental rotation (MR) and motor imagery (MI) involve an internalization of movement within motor and parietal cortex. Transcranial magnetic stimulation (TMS) techniques allow for a task-dependent investigation of the interhemispheric interaction between these areas. We used image-guided dual-coil TMS to investigate interactions between right inferior parietal lobe (rIPL) and left primary motor cortex (M1) in 11 healthy participants. They performed MI (right index-thumb pinching in time with a 1 Hz metronome) or hand MR tasks, while motor evoked potentials (MEPs) were recorded from right first dorsal interosseous. At rest, rIPL conditioning 6 ms prior to M1 stimulation facilitated MEPs in all participants, whereas this facilitation was abolished during MR. While rIPL conditioning 12 ms prior to M1 stimulation had no effect on MEPs at rest, it suppressed corticomotor excitability during MI. These results support the idea that rIPL forms part of a distinct inhibitory network that may prevent unwanted movement during imagery tasks.     

Motor skill acquisition influences brain responsiveness in sprinters

Contingent negative variation (CNV) and reaction time were examined in four groups of eight young adult men: controls, witnesses, students in physical and athletic education, and sprinters. Subjects, except the control group, were asked to detect and respond quickly by pressing a button in the following experimental conditions: 1) simple auditory stimuli, 2) paired auditory stimuli, 3) mixed simple and paired auditory stimuli.- A higher CNV voltage and lower reaction time and reaction time variability were obvious in students in physical and athletic education and sprinters, compared to controls and witnesses. In all the groups CNV amplitude declined in the third condition, reaction time and reaction time variability augmented from condition 1 to condition 3. These results show that relationships couple attentiveness and motor activation processes. The motor activation differed for simple starter and presignalled starter conditions (conditions 1 and 2). An increase of discrimination difficulty diminished the performance.     

CNV-like potentials on the cortical surface associated with conditioning in head-restrained rats

Head-restrained rats were conditioned to perform a CNV task: to press a lever in response to an imperative auditory stimulus (S2) given 1.5 sec after a warning stimulus (S1) for a drop of jelly food. With an electrode on the surface of the forelimb cortex, (1) sharp wave complexes immediately after S1 and S2, and (2) a negative slow potential (SP) between S1 and S2, on which early and late components were discernible, were recorded in association with performance of this task. With the electrode at a depth of 2 mm in the same cortical area, the corresponding field potential showed a long-lasting positive shift in addition to the components of the surface potential. These monopolar recordings were obtained with respect to a common reference at the frontal sinus. The surface-minus-depth potential (the transcortical potential), consequently, showed a surface-negative tonic wave, confirming Pirch's report (1980). During extinction of this conditioning, the SP between S1 and S2 disappeared, while the sharp waves following S1 and S2 remained with little modification, suggesting that the sharp waves are a kind of evoked potential (EP) elicited by the stimuli.Recording from 5 surface electrodes set in an array over the left hemisphere contralateral to the used forelimb during development of the conditioning revealed not only a spatial distribution of the SP but also a transition of the potentials. As the conditioning progressed, the negativity of the early SP component tended to increase, while that of the late component tended to decrease and was confined to the sensorimotor cortex. The similarities of the rat cortical surface potentials to the human and monkey CNV in their wave form and function suggests that the rat brain can produce electrical activity analogous to the human CNV.     

The recovery functions of auditory event-related potentials during split-second discriminations

We examined the recovery cycles of auditory event-related potentials (ERPs) in a high-speed auditory discrimination task and in passive conditions. Each trial contained 3 tones cued by a warning flash. In passive conditions, auditory ERPs consisted mainly of N1 (108 msec) and P2 (213 msec) components superimposed on a small CNV. The N1 and P2 were comparable in amplitude and both had prolonged refractory periods. In discriminative reaction time (DRT) conditions the same tones cued or inhibited press responses and elicited additional endogenous components (principally the Nd and P3). ERPs in DRT conditions were superimposed upon a prominent CNV that began after the warning cue and lasted throughout the signal delivery period.The N1 was larger in active than passive conditions and showed less marked refractory effects, while the P2 was smaller and showed more marked refractoriness. Differences between active and passive conditions could be explained by the presence of an endogenous negative potential (the Nd) with a short refractory period that was superimposed upon the N1 and P2.The P3 was recorded only in active conditions. At short ISIs (0.5 sec), P3 amplitudes were reduced and P3 latencies lengthened in parallel with prolongations in reaction time due to so-called psychological refractory period (PRP) effects. Both P3 recovery and the PRP reflected central mechanisms since they were observed at short ISIs when stimuli cueing different responses succeeded one another.N1 and P3 amplitudes diminished over the course of the experiment in both active and passive conditions. The decrease (amounting to about 30% of initial amplitudes) did not appear due to reductions in vigilance, since it was not accompanied by changes in reaction time or response accuracy, or by changes in other endogenous components (CNV or Nd). Short-term N1 habituation was unaffected by long-term amplitude reductions suggesting that independent mechanisms were responsible for the two phenomena.     

Motor Planning in Chronic Upper-Limb Hemiparesis: Evidence from Movement-Related Potentials

Background

Chronic hemiplegia is a common long-term consequence of stroke, and subsequent motor recovery is often incomplete. Neurophysiological studies have focused on motor execution deficits in relatively high functioning patients. Much less is known about the influence exerted by processes related to motor preparation, particularly in patients with poor motor recovery.

Methodology/Principal Findings

The current study investigates motor preparation using a modified response-priming experiment in a large sample of patients (n = 50) with moderate-to-severe chronic hemiparesis. The behavioural results revealed that hemiparetic patients had an increased response-priming effect compared to controls, but that their response times were markedly slower for both hands. Patients also demonstrated significantly enhanced midline late contingent negative variation (CNV) during paretic hand preparation, despite the absence of overall group differences when compared to controls. Furthermore, increased amplitude of the midline CNV correlated with a greater response-priming effect. We propose that these changes might reflect greater anticipated effort to respond in patients, and consequently that advance cueing of motor responses may be of benefit in these individuals. We further observed significantly reduced CNV amplitudes over the lesioned hemisphere in hemiparetic patients compared to controls during non-paretic hand preparation, preparation of both hands and no hand preparation. Two potential explanations for these CNV reductions are discussed: alterations in anticipatory attention or state changes in motor processing, for example an imbalance in inter-hemispheric inhibition.

Conclusions/Significance

Overall, this study provides evidence that movement preparation could play a crucial role in hemiparetic motor deficits, and that advance motor cueing may be of benefit in future therapeutic interventions. In addition, it demonstrates the importance of monitoring both the non-paretic and paretic hand after stroke and during therapeutic intervention.     

Interhemispheric interactions between the human primary somatosensory cortices

In the somatosensory domain it is still unclear at which processing stage information reaches the opposite hemispheres. Due to dense transcallosal connections, the secondary somatosensory cortex (S2) has been proposed to be the key candidate for interhemispheric information transfer. However, recent animal studies showed that the primary somatosensory cortex (S1) might as well account for interhemispheric information transfer. Using paired median nerve somatosensory evoked potential recordings in humans we tested the hypothesis that interhemispheric inhibitory interactions in the somatosensory system occur already in an early cortical processing stage such as S1. Conditioning right S1 by electrical median nerve (MN) stimulation of the left MN (CS) resulted in a significant reduction of the N20 response in the target (left) S1 relative to a test stimulus (TS) to the right MN alone when the interstimulus interval between CS and TS was between 20 and 25 ms. No such changes were observed for later cortical components such as the N20/P25, N30, P40 and N60 amplitude. Additionally, the subcortically generated P14 response in left S1 was also not affected. These results document the existence of interhemispheric inhibitory interactions between S1 in human subjects in the critical time interval of 20-25 ms after median nerve stimulation.     

Locus of Psychological Control and Peculiarities of Event-Related EEG Potentials

In a group including 74 adults of both sexes, we examined interrelations between the locus of psychological control (diagnosed using the Rotter questionnaire) and parameters of event-related EEG potentials, ERPs, recorded in the course of performance of two behavioral test acts with a motor component. Task A corresponded to maximally fast pushing on the button after a signal with warning; the time of the sensorimotor reaction was measured. Task B included internal counting of a definite time interval limited by two pushings on the button. Under these conditions, we recorded the contingent negative variation (CNV), the P300 potential, and, in task B, the readiness potential (RP). EEG leads C3 and C4, according to the 10-20 system, were used. Internals (estimates by the questionnaire, 6 stens or higher) were characterized by higher amplitudes of the terminal CNV (CNV-T), integral CNV, and P300 in task A, by greater RP and CNV amplitudes in task B, and also by shorter reaction times and their smaller dispersion. It should be supposed that the corresponding peculiarities of the neurodynamic constitution of an individual are determined, to a considerable extent, by the specificity of organization and functioning of a few neurotransmitter (aminergic in particular) and neurohumoral systems.     

Relation between warning stimuli and contingent negative variation in man

Seven right handed male students were submitted to standard and target paired auditory stimuli to determine the relationship between contingent negative variation (CNV) and the slow negative waves following non paired stimuli. The warning stimuli informed subjects whether or not the impending unconditional stimulus implied a motor response. Subjects were instructed to execute the motor task at less than one second after unconditional stimulus. They were informed that the standard warning stimulus would be followed by an additional stimulus which confirmed its detection. Recordings of standard warning stimulus condition showed a subsequent increase in CNV amplitude. This significant increase appeared to be related to an enhancement in the subject's expectation towards the additional stimulus. The lowered CNV voltage in target condition seemed to be linked to the instructions, which involved a motor preparation after the imperative stimuli occurrence. It is suggested that the CNV may represent not only a general anticipatory but also an orienting process related to the signal value of the warning stimulus.     

Adaptation changes in dynamic postural control and contingent negative variation during backward disturbance by transient floor translation in the elderly

ABSTRACT: BACKGROUND: We investigated adaptation changes in dynamic postural control and contingent negative variation (CNV) in 13 young and 12 elderly adults. Subjects repeatedly underwent backward postural disturbance by a forward floor translation (S2) 2 s after an auditory warning signal (S1). Initial and second sets were conducted, each set with 20 trials. Posterior peak position of the center of pressure in the anteroposterior direction (CoPy) after S2 was identified. Electroencephalograms from Cz were averaged for each set, and the CNV negative peak was identified. RESULTS: Compared with the first trial, the posterior peak position of CoPy changed significantly forward from the 12th trial in the young and from the 19th trial in the elderly during the initial set. The mean of the posterior peak position was more forward in second set than in the initial set for both groups and was significantly backward in the elderly compared to the young for both sets. These findings indicate that subjects in both groups adapted better to the postural disturbance in the second set than in the initial set, and the adaptation was later in the elderly. Late CNV in the young started to increase negatively from the middle of the S1-S2 period and peaked just before S2. Peak CNV amplitude was larger in the second set than in the initial set. In contrast, late CNV in the elderly exhibited no negative increase as in the young and peaked in the middle of the S1-S2 period, which was followed by gradual decreasing toward S2. No adaptive changes were found in late CNV for the elderly. CONCLUSIONS: It is conceivable that reduced activation of the frontal lobe may be one of the factors contributing to the decrease in postural adaptability in the elderly. The elderly may use various brain regions for the adaptation of dynamic postural control compared with the young.     

Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research

We review the contributions and limitations of genome-wide array-based identification of copy number variants (CNVs) in the clinical diagnostic evaluation of patients with mental retardation (MR) and other brain-related disorders. In unselected MR referrals a causative genomic gain or loss is detected in 14-18% of cases. Usually, such CNVs arise de novo, are not found in healthy subjects, and have a major impact on the phenotype by altering the dosage of multiple genes. This high diagnostic yield justifies array-based segmental aneuploidy screening as the initial genetic test in these patients. This also pertains to patients with autism (expected yield about 5-10% in nonsyndromic and 10-20% in syndromic patients) and schizophrenia (at least 5% yield). CNV studies in idiopathic generalized epilepsy, attention-deficit hyperactivity disorder, major depressive disorder and Tourette syndrome indicate that patients have, on average, a larger CNV burden as compared to controls. Collectively, the CNV studies suggest that a wide spectrum of disease-susceptibility variants exists, most of which are rare (<0.1%) and of variable and usually small effect. Notwithstanding, a rare CNV can have a major impact on the phenotype. Exome sequencing in MR and autism patients revealed de novo mutations in protein coding genes in 60 and 20% of cases, respectively. Therefore, it is likely that arrays will be supplanted by next-generation sequencing methods as the initial and perhaps ultimate diagnostic tool in patients with brain-related disorders, revealing both CNVs and mutations in a single test.     

Adaptation changes in dynamic postural control and contingent negative variation during repeated transient forward translation in the elderly

Background

Adaptation changes in postural control and contingent negative variation (CNV) for the elderly were investigated during repeated forward floor translation.

Methods

Fifteen healthy elderly persons, living in the suburban area of Kanazawa City, Japan, underwent backward postural disturbance by a forward-floor translation (S2) 2 s after an auditory warning signal (S1). A set with 20 trials was repeated until a negative peak of late CNV was recognized in the 600-ms period before S2, and the last set was defined as the final set. Electroencephalograms, center of foot pressure in the anteroposterior direction (CoPap), and electromyograms of postural muscles were analyzed.

Results

CoPap displacement generated by the floor translation was significantly decreased until the twelfth trial in the first set, and mean CoPap displacement was smaller in the second and final sets than in the first set. The mean displacement was significantly smaller in the final set than the previous set. A late CNV with a negative peak was not recognized in the first and second sets. However, most subjects (13/15) showed a negative peak by the fourth set, when the late CNV started to increase negatively from about 1,000 ms after S1 and peaked at about 300 ms before S2. At about 160 ms before the CNV peak, the CoPap forward shift started. The increase in timing of the gastrocnemius activity related to the CoPap shift was significantly correlated with the CNV peak timing (r = 0.64). After S2, peak amplitudes of the anterior postural muscles were significantly decreased in the final set compared to the first set.

Conclusions

It was demonstrated that even for the elderly, with so many repetitions of postural disturbance, a late CNV with a negative peak was recognized, leading to accurate postural preparation. This suggests the improvement of frontal lobe function (e.g., anticipatory attention and motor preparation) in the elderly.     

Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders

Genomic disorders are a group of human genetic diseases caused by genomic rearrangements resulting in copy-number variation (CNV) affecting a dosage-sensitive gene or genes critical for normal development or maintenance. These disorders represent a wide range of clinically distinct entities but include many diseases affecting nervous system function. Herein, we review selected neurodevelopmental, neurodegenerative, and psychiatric disorders either known or suggested to be caused by genomic rearrangement and CNV. Further, we emphasize the cause-and-effect relationship between gene CNV and complex disease traits. We also discuss the prevalence and heritability of CNV, the correlation between CNV and higher-order genome architecture, and the heritability of personality, behavioral, and psychiatric traits. We speculate that CNV could underlie a significant proportion of normal human variation including differences in cognitive, behavioral, and psychological features.     

Copy number polymorphism in plant genomes

Copy number variants (CNVs) are genomic rearrangements resulting from gains or losses of DNA segments. Typically, the term refers to rearrangements of sequences larger than 1 kb. This type of polymorphism has recently been shown to be a key contributor to intra-species genetic variation, along with single-nucleotide polymorphisms and short insertion-deletion polymorphisms. Over the last decade, a growing number of studies have highlighted the importance of copy number variation (CNV) as a factor affecting human phenotype and individual CNVs have been linked to risks for severe diseases. In plants, the exploration of the extent and role of CNV is still just beginning. Initial genomic analyses indicate that CNVs are prevalent in plants and have greatly affected plant genome evolution. Many CNV events have been observed in outcrossing and autogamous species. CNVs are usually found on all chromosomes, with CNV hotspots interspersed with regions of very low genetic variation. Although CNV is mainly associated with intergenic regions, many CNVs encompass protein-coding genes. The collected data suggest that CNV mainly affects the members of large families of functionally redundant genes. Thus, the effects of individual CNV events on phenotype are usually modest. Nevertheless, there are many cases in which CNVs for specific genes have been linked to important traits such as flowering time, plant height and resistance to biotic and abiotic stress. Recent reports suggest that CNVs may form rapidly in response to stress.     

EEG Investigations of Duration Discrimination: The Intermodal Effect Is Induced by an Attentional Bias

Previous studies indicated that empty time intervals are better discriminated in the auditory than in the visual modality, and when delimited by signals delivered from the same (intramodal intervals) rather than from different sensory modalities (intermodal intervals). The present electrophysiological study was conducted to determine the mechanisms which modulated the performances in inter- and intramodal conditions. Participants were asked to categorise as short or long empty intervals marked by auditory (A) and/or visual (V) signals (intramodal intervals: AA, VV; intermodal intervals: AV, VA). Behavioural data revealed that the performances were higher for the AA intervals than for the three other intervals and lower for inter- compared to intramodal intervals. Electrophysiological results indicated that the CNV amplitude recorded at fronto-central electrodes increased significantly until the end of the presentation of the long intervals in the AA conditions, while no significant change in the time course of this component was observed for the other three modalities of presentation. They also indicated that the N1 and P2 amplitudes recorded after the presentation of the signals which delimited the beginning of the intervals were higher for the inter- (AV/VA) compared to the intramodal intervals (AA/VV). The time course of the CNV revealed that the high performances observed with AA intervals would be related to the effectiveness of the neural mechanisms underlying the processing of the ongoing interval. The greater amplitude of the N1 and P2 components during the intermodal intervals suggests that the weak performances observed in these conditions would be caused by an attentional bias induced by the cognitive load and the necessity to switch between modalities.     

CCR3 and choroidal neovascularization

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly in industrialized countries. The "wet" AMD, characterized by the development of choroidal neovacularization (CNV), could result in rapid and severe loss of central vision. The critical role of vascular endothelial growth factor A (VEGF-A) in CNV development has been established and VEGF-A neutralization has become the standard care for wet AMD. Recently, CCR3 was reported to play an important role in CNV development and that CCR3 targeting was reported to be superior to VEGF-A targeting in CNV suppression. We investigated the role of CCR3 in CNV development using the Matrigel induced CNV and found that in both rats and mice, CNV was well-developed in the control eyes as well as in eyes treated with CCR3 antagonist SB328437 or CCR3 neutralizing antibodies. No statistically significant difference in CNV areas was found between the control and SB328437 or CCR3-ab treated eyes. Immunostaining showed no specific expression of CCR3 in or near CNV. In contrast, both VEGF-A neutralizing antibodies and rapamycin significantly suppressed CNV. These results indicate that CCR3 plays no significant role in CNV development and question the therapeutic approach of CCR3 targeting to suppress CNV. On the other hand, our data support the therapeutic strategies of VEGF-A and mTOR (mammalian target of rapamycin) targeting for CNV.