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Visual evoked potential (VEP) plasticity is a promising assay for noninvasive examination of long-term potentiation (LTP)-like synaptic processes in the cerebral cortex. We conducted longitudinal and cross-sectional investigations of VEP plasticity in controls and individuals with bipolar disorder (BD) type II. VEP plasticity was assessed at baseline, as described previously (Elvsåshagen et al. Biol Psychiatry 2012), and 2.2 years later, at follow-up. The longitudinal sample with VEP data from both time points comprised 29 controls and 16 patients. VEP data were available from 13 additional patients at follow-up (total n = 58). VEPs were evoked by checkerboard reversals in two premodulation blocks before and six blocks after a plasticity-inducing block of prolonged (10 min) visual stimulation. VEP plasticity was computed by subtracting premodulation VEP amplitudes from postmodulation amplitudes. Saliva samples for cortisol analysis were collected immediately after awakening in the morning, 30 min later, and at 12:30 PM, at follow-up. We found reduced VEP plasticity in BD type II, that impaired plasticity was present in the euthymic phases of the illness, and that VEP plasticity correlated negatively with depression severity. There was a positive association between VEP plasticity and saliva cortisol in controls, possibly reflecting an inverted U-shaped relationship between cortisol and synaptic plasticity. VEP plasticity exhibited moderate temporal stability over a period of 2.2 years. The present study provides additional evidence for impaired LTP-like cortical plasticity in BD type II. VEP plasticity is an accessible method, which may help elucidate the pathophysiological and clinical significance of synaptic dysfunction in psychiatric disorders.

Background: Advances in the treatment of acute lymphoblastic leukemia (ALL) have led to great improvements in survival rates and outcomes, but there is concern about cognitive late effects. We aimed to determine whether ALL survivors have smaller cortical surface area and/or thickness, and test whether this is related to disease and treatment variables and self-reported executive functioning in everyday life., Procedure: Magnetic resonance imaging (MRI) scans from 130 adult long-term survivors of childhood ALL (age: 18-46 years; age at diagnosis: 0-16 years; years since diagnosis: 7-40) and 130 healthy controls were assessed to estimate and compare regional cortical surface area and thickness. Information on disease and treatment factors were obtained from patients' records, and executive functioning in survivors was measured using a validated questionnaire (BRIEF-A)., Results: Smaller cortical surface area was observed in several regions in both cerebral hemispheres in ALL survivors. In these regions, mean surface area was 4.1-5.5% smaller in ALL survivors compared to healthy controls. In contrast, only one region showed lower cortical thickness in ALL survivors. There were no significant associations between cortical surface area/thickness in these regions and disease or treatment variables. In ALL survivors, smaller surface area in prefrontal regions, encompassing parts of the superior frontal gyri and the left anterior cingulate cortex, was associated with problems in executive functioning, specifically with emotional control and self-monitoring., Conclusions: ALL survivors had smaller surface area in several cortical regions and smaller surface area in prefrontal regions was associated with reported problems in executive functioning., (© 2015 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Objective: We investigated cerebral cortical thickness and its relation to measurements of difficulties with identifying and describing emotions in patients with borderline personality disorder (BPD)., Method: Eighteen SCID-II-diagnosed female patients with BPD and 21 healthy female controls underwent magnetic resonance imaging and completed the Toronto Alexithymia Scale (TAS). First, regional cortical thickness across the cerebral surface was compared between patients and healthy controls. Then, analyses of the association between cortical thickness and TAS subscales were performed in patients., Results: Compared with controls, patients exhibited clusters of significantly reduced cortical thickness in the left medial and lateral prefrontal cortex, left temporoparietal junction, bilateral temporal poles, and bilateral paracentral lobules. Significant negative associations were observed between cortical thickness and the 'Difficulties Describing Feelings' TAS subscale (DDF) scores in patients. The anatomical distribution of these associations was highly overlapping with the group differences in cortical thickness., Conclusion: The pattern of regions exhibiting cortical thinning in patients resembles a network of cortical structures repeatedly shown to be involved in social cognition. The results of the DDF analyses suggest that the thinning may partly be related to interpersonal dysfunction in patients with BPD. The pattern of thinning may represent a potential biological marker for BPD., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: We examined women with recurrent brief depression (RBD) with and without episodes of hypomania with an n-back working memory paradigm to assess how working memory load affects the neurological network corresponding to working memory for these groups., Method: Participants (n=33) were medication-free and mostly euthymic while performing a 1-back and a 2-back task in the fMRI scanner. Differential activation results between the tasks were assessed globally and within seven predefined regions of interest associated with working memory activation. The patient groups were compared with healthy women and matched for age, handedness, and length of education., Results: Poor task modulation was observed in both RBD groups in the prefrontal cortex (BA9) in the 1-back task and activation during the 2-back task, particularly in a subgroup with a history of brief hypomanic episodes (RBD-H) compared with the subgroup without such episodes (RBD-O). Task modulation in the right parahippocampal gyrus (BA27) distinguished the RBD-O group, and task modulation in the right insula clearly distinguished the RBD-H group., Limitations: Small sample size and recruitment of most patients through media that may induce a selection bias towards better-functioning subjects., Conclusion: The observed lack of deactivation within the right insula has also been reported in patients with bipolar I disorders. Activation differences in BA9 and the parahippocampal region between RBD patients with and without a history of hypomania suggest different functional hypersensitivity of early limbic regions and ability to sustain attention and working memory, respectively, possibly identifying functional differences between the two subgroups., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Recent experimental studies have shown that developing cortex in several animals species, including humans, exhibits spontaneous intermittent activity that is believed to be crucial for the proper wiring of early brain networks. The present study examined the developmental changes in these spontaneous activity transients (SAT) and in other ongoing cortical activities in human preterm babies. Full-band electroencephalography (FbEEG) recordings were obtained from 16 babies at conceptional ages between 32.8 and 40 wk. We examined the SATs and the intervening ongoing cortical activities (inter-SAT; iSAT) with average waveforms, their variance and power, as well as with wavelet-based time-frequency analyses. Our results show, that the low frequency power and the variance of the average waveform of SAT decrease during development. There was a simultaneous increase in the activity at higher frequencies, with most pronounced increase at theta-alpha range (4-9 Hz). In addition to the overall increase, the activity at higher frequencies showed an increased grouping into bursts that are nested in the low frequency (0.5-1 Hz) waves. Analysis of the iSAT epochs showed a developmental increase in power at lower frequencies in quiet sleep. There was an increase in a wide range of higher frequencies (4-16 Hz), whereas the ratio of beta (16-30 Hz) and theta-alpha (4-9 Hz) range activity declined, indicating a preferential increase at theta-alpha range activity. Notably, SAT and iSAT activities remained distinct throughout the development in all measures used in our study. The present results are consistent with the idea that SAT and the other ongoing cortical activities are distinct functional entities. Recognition of these two basic mechanisms in the cortical activity in preterm human babies opens new rational approaches for an evaluation and monitoring of early human brain function.

Spontaneous transients of correlated activity are a characteristic feature of immature brain structures, where they are thought to be crucial for the establishment of precise neuronal connectivity. Studies on experimental animals have shown that this kind of early activity in cortical structures is composed of long-lasting, intermittent network events, which undergo a developmental decline that is closely paralleled by the maturation of GABAergic inhibition. In order to examine whether similar events occur in the immature human cortex, we performed direct current-coupled electroencephalography (EEG) recordings from sleeping preterm babies. We show now that much of the preterm EEG activity is confined to spontaneous, slow activity transients. These transients are characterized by a large voltage deflection that nests prominent oscillatory activity in several frequency bands covering the whole frequency spectrum of the preterm EEG (<0.1-30 Hz). The slow voltage deflections had an amplitude of up to 800 microV. Most of these 'giant' events originated in the temporo-occipital areas, with a maximum rate of about 8/min, and their occurrence as well as amplitude showed a decline by the time of normal birth. In age-matched fetal brain tissue, this decrease in the spontaneous activity transients was associated with a developmental up-regulation of the neuronal chloride extruder K+-Cl- cotransporter 2, a crucial molecule for the generation of inhibitory GABAergic Cl- currents. Our work indicates that slow endogenous activity transients in the immature human neocortex are mostly confined to the prenatal stage and appear to be terminated in parallel with the maturation of functional GABAergic inhibition.

The present study stems from our previous observations that the brains of adult estrogen receptor beta knockout (ERbeta-/-) mice show regional neuronal hypocellularity especially in the cerebral cortex. We now show that ERbeta is necessary for late embryonic development of the brain and is involved in both neuronal migration and apoptosis. At embryonic day (E)18.5, ERbeta-/- mouse brains were smaller than those of the wild-type (WT) littermates, and there were fewer neurons in the cortex. There were no differences in size or cellularity at E14.5. When proliferating cells were labeled with 5'-bromodeoxyuridine (BrdUrd) on E12.5, a time when cortical neurogenesis in mice begins, and examined on E14.5, there was no difference between WT and ERbeta-/- mice in the number of labeled cells in the cortex. However, when BrdUrd was administered between E14.5 and E16.5, a time when postmitotic neurons migrate to layers of the cortex, there were fewer BrdUrd-labeled cells in the superficial cortical layers by E18.5 and postnatal day 14 in mice lacking ERbeta. At E18.5, there were more apoptotic cells in the ventricular zone of mice lacking ERbeta. In addition, the processes of the cortical radial glia, which are essential for guiding the migrating neurons, were fragmented. These findings suggest that by influencing migration and neuronal survival, ERbeta has an important role in brain development.

Evoked responses were mapped in the cerebral cortex following low intensity electrical stimulation in serial penetrations of the medial and intralaminar nuclei of the thalamus of the cat. A projection was found from one of the intralaminar nuclei, the central lateral nucleus (CL) to the midsuprasylvian gyrus, mainly areas 5 and 7. The projection is suggested to be direct, since the evoked responses had a short latency initial positivity. The most characteristic type of response consisted of this early positivity followed by two successive negativities. The earlier, so called first negativity followed high frequency stimulation and was recorded in a smaller area of the cortex than the later, so called second negativity. The first negativity is suggested to depend on monosynaptic depolarization and activation of cortical cells. The second negativity failed at frequencies higher than 10 Hz and was strongly depressed by the administration of barbiturates; it is suggested to depend on polysynaptic depolarization and cellular activity. In electrode penetrations of the cortex both negativities reversed at the border between cortical layers II and III, indicating a superficial termination of thalamic afferents in the cortex. The cortical evoked response to CL stimulation was facilitated by light mechanical and low intensity electrical stimulation of the periphery, as well as by electrical stimulation of the tooth pulp. The possible significance and function of this projection is discussed in relation to arousal, attention and pain.

In lightly chloralose-anaesthetized cats selective stimulation of tooth pulp afferents elicited responses in coronal, anterior suprasylvian and adjacent cortical gyri. In the lateral part of coronal gyrus the potentials evoked from the contralateral canine tooth pulps were initially positive. Such responses from the upper and lower teeth had different cortical distribution suggesting a topographical organization. In the regions adjacent to those with initially positive responses stimulation of the same tooth pulp evoked initially negative potentials. Stimulation of ipsilateral tooth pulp afferents elicited almost exclusively initially negative potentials with a similar distribution as the responses of contralateral teeth but with longer latency. Laminar analysis showed that the region with initial positivity in the response to stimulation of the tooth pulp coincided with an intracortical negative focal potential of maximum amplitude mainly in lamina IV. In areas with initially negative responses the maximum of the focal potential following tooth pulp stimulation was obtained in superficial cortical layers. It is postulated that the projection system underlying the initially positive cortical responses has a topographically arranged cortical projection terminating mainly in lamina IV. The projection system eliciting the initially negative potentials, has a widespread cortical distribution and produces excitation predominantly in the superficial laminae.

The cortical projection of tooth pulp afferents has been investigated by extracellular recordings in lightly chloralose anaesthetized cats. The results indicate two different projection systems from the tooth pulp afferents terminating on the cortical cells. One system appears to be specific with topographical distribution and activates cells mainly in lamina IV in a restricted region of the coronal gyrus. The cells in this area receive excitation also from restricted cutaneous fields. At stimulation of the tooth pulps with single electrical pulses cells are activated with high discharge probability and with a stable latency. The other system projects mainly to cells in the superficial cortical laminae in a much larger area. These cells receive input from large bilateral cutaneous fields but show less discharge probability and require often temporal summation to discharge at tooth pulp stimulation.

The projection of tooth pulp afferents to cortical cells was studied in intracellular recordings. In a small region of the coronal gyrus, cells in lamina IV were responding at stimulation of contralateral tooth pulp afferents with short latency, steeply rising EPSPs, and one or two action potentials followed by an IPSP. These cells received convergence from skin afferents. In a large cortical area in the coronal, anterior suprasylvian and anterior ectosylvian gyri, tooth pulp stimulation elicited long latency, long lasting EPSPs not succeeded by hyperpolarization mainly in superficial cortical cells. These EPSPs could elicit trains of spikes. A complex type of responses consisted of a short latency EPSP with one or two spikes followed by hyperpolarization which in part was counteracted by a second, long latency EPSP of long duration. Stimulation of low threshold contralateral skin afferents usually gave short latency EPSPs with spikes followed by long lasting hyperpolarization. A common feature of many cells was a high convergence from tooth pulp afferents and bilateral low threshold skin afferents. The response characteristics at tooth pulp stimulation compared to low threshold input are discussed in relation to cortical mechanisms of pain.

There is evidence that the cerebral cortex is involved in the perception of pain but no specific area appears to be the 'pain centre'. Limited knowledge exists on the cortical processing of the noxious input. The nociceptors are most likely to activate at least two different systems with different characteristics. One has a bilateral cortical projection, no apparent topographical pattern, low synaptic security and excites cells in large areas. This system may give rise to the widespread increase in blood flow and the widely distributed surface potentials recorded in man following a painful stimulus. Noxious stimuli also excite a system with contralateral topographical projection, high synaptic security and termination in lamina IV. This system produces EPSP-IPSP sequences in cells in a restricted cortical area. Pronounced inhibition of cells in lamina IV and more superficial layers is induced by activity in low threshold afferents. Thus, similarly as at the segmental spinal level, the nociceptive input to cortical cells is processed and integrated with the activity in other afferent systems.

1. The relation between thalamic and cortical spontaneous spindles was investigated in cats anaesthetized with barbiturates.2. Simultaneous recordings with multiple electrodes in the thalamus and cortex revealed a high correlation between thalamic and cortical spindle activity, both with regard to the occurrence of the spindles as well as to their individual waves, provided a critical location of the electrodes was secured. The results indicate a point-to-point relation between a group of thalamic cells and a small cortical area to which these cells project. In the spontaneous rhythm, the cortical columns are probably individually controlled by a thalamic rhythmic entity. This point-to-point relation was found in all the major sensory projection systems and in one thalamic ;association' nucleus and its corresponding ;association' cortex.3. Cortical barbiturate spindles appeared either as local spindles in a restricted cortical area or as compound spindles in several areas. Spindles recorded from electrodes separated by 2 mm or more were clearly different with regard to intraspindle wave frequency, duration, and the time of start and stop of the spindle. These differences increased with increasing distance between the electrodes, and were most pronounced when the corticograms of the two hemispheres were compared.4. Spontaneous spindle activity interfered with orthodromic transmission through n. ventralis posterolateralis (VPL) and medial geniculate nucleus (MG), judged by depression of the thalamic and cortical responses to peripheral nerve volleys or clicks. Such inhibition required the afferent volley to be delivered at a particular time of the spontaneous oscillations. Further, orthodromic volleys reset the rhythmic spindle waves in the appropriate thalamic and cortical areas.5. These findings lead to a new concept of the thalamic pace-maker function. During barbiturate anaesthesia, small assemblages of thalamic neurones seem to have the ability to generate independent rhythmic discharges, and thereby control the rhythm of the particular cortical column to which this thalamic group projects.6. During barbiturate anaesthesia, many facultative pace-makers seem to be present in the thalamus. The total number may be as large as 25,000-35,000. Usually, many of these rhythmic thalamic units beat in synchrony or near synchrony.

1. Stimulation of Group I muscle afferents in contralateral forelimb nerves evoked a response in nucleus ventralis posterolateralis (VPL) in the thalamus of the cat. This response was located in the rostral two-thirds of VPL in a narrow zone near the dorsomedial border of the nucleus.2. Group I afferents in nerves from more than one of the muscles in the contralateral forelimb often excited the same thalamic relay cell. In addition these cells were often discharged by skin afferents from the contralateral forelimb. They were not affected by electrical stimulation of the dorsal column-lemniscal or the spino-cervico-lemniscal paths from the contralateral hind limb.3. In experiments with peripheral conduction paths of similar length, the latency of the thalamic focal potential evoked by stimulation of Group I muscle afferents in the nerve to m. extensor carpi radialis was 3.8 S.E. +/- 0.1 msec, and that of the focal potential evoked by skin afferents (n. radialis superficialis) in the centromedial part of VPL was 4.3 +/- 0.1 msec.4. The majority of the thalamic neurones discharged by Group I muscle afferents responded with a latency shorter than 1 msec to electrical stimulation of the cerebral cortex in the region of the post-cruciate dimple. A considerable number of the thalamic Group I relay cells were also discharged with a similar short latency from another cortical focus located on either side of the anterior suprasylvian sulcus near the S II hind limb areas. These responses were considered to be antidromic in nature, and the findings were interpreted as indicating two separate cortical projection areas for the Group I path. The second projection area was assumed to be located in the cortical fold formed by the anterior suprasylvian sulcus.5. Cortical stimulation also excited the thalamic Group I relay cells trans-synaptically. Trans-synaptic excitation with short (1-2 msec) and longer (2-7 msec) latency was observed. The cortical focus near the S II area was particularly potent in evoking trans-synaptic excitation in the thalamic region where the Group I relays were located.

1. The origin of thalamic and cortical spontaneous spindles was studied in cats anaesthetized with sodium pentobarbital.2. Complete removal of all cortical grey matter left the thalamic rhythmic spindle activity unchanged.3. Removal of the entire thalamus or pronounced oedema in the thalamus abolished completely the spindle activity in the corresponding hemisphere.4. In a neuronally isolated cortical area, a fast, low voltage background activity appeared, interrupted by occasional irregular rapid potential changes (sharp waves) of high voltage. Regular spindle rhythms were seldom observed unless excited by a depolarizing drug. Spontaneous spindles did not invade the isolated cortex via a bridge of intact cortical tissue.5. With increasingly larger destruction of the thalamus in a rostro-caudal direction, the activity in the post-cruciate cortex did not change until the anterior third of the thalamus was encroached upon. A transverse section in front of the thalamus nearly eliminated the cortical spindles.6. Complete removal of the mid line and intralaminar nuclei left the spontaneous rhythmic activity of the lateral thalamic nuclei and of the frontal cortex principally unchanged.7. Removal of the laterally located thalamic nuclei, including the n. ventralis posterolateralis (VPL), abolished virtually all spontaneous spindle activity of the frontal cortex, including the post-cruciate area.8. Local cortical cooling reduced the amplitude but not the frequency of the cortical spindles.9. Cooling of the whole brain reduced both the amplitude and the frequency of the spindles. At low temperatures, all spindle activity in the cortex disappeared, and occasional sharp waves occurred, as with de-afferentation.10. It is concluded that the rhythm of the cortical spontaneous barbiturate spindles is generated exclusively by thalamic neurones. The electromotive force of the corticographic waves, however, has a cortical origin.