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Predictability of behavior is an important characteristic in many fields including biology, medicine, marketing, and education. When a sequence of actions performed by an individual can be modeled as a stationary time-homogeneous Markov chain the predictability of the individual’s behavior can be quantified by the entropy rate of the process. This article compares three estimators of the entropy rate of finite Markov processes. The first two methods directly estimate the entropy rate through estimates of the transition matrix and stationary distribution of the process. The third method is related to the sliding-window Lempel–Ziv compression algorithm. The methods are compared via a simulation study and in the context of a study of interactions between mothers and their children.

Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.

Stress is a major trigger of seizures in people with epilepsy. Exposure to stress results in the release of several stress mediators throughout the brain, including the hippocampus, a region sensitive to stress and prone to seizures. Stress mediators interact with their respective receptors to produce distinct effects on the excitability of hippocampal neurons and networks. Crucially, these stress mediators and their actions exhibit unique spatiotemporal profiles, generating a complex combinatorial output with time- and space-dependent effects on hippocampal network excitability and seizure generation.

Managing dynamic information in large multi-site, multi-species, and multi-discipline consortia is a challenging task for data management applications. Often in academic research studies the goals for informatics teams are to build applications that provide extract-transform-load (ETL) functionality to archive and catalog source data that has been collected by the research teams. In consortia that cross species and methodological or scientific domains, building interfaces which supply data in a usable fashion and make intuitive sense to scientists from dramatically different backgrounds increases the complexity for developers. Further, reusing source data from outside one’s scientific domain is fraught with ambiguities in understanding the data types, analysis methodologies, and how to combine the data with those from other research teams. We report on the design, implementation, and performance of a semantic data management application to support the NIMH funded Conte Center at the University of California, Irvine. The Center is testing a theory of the consequences of “fragmented” (unpredictable, high entropy) early-life experiences on adolescent cognitive and emotional outcomes in both humans and rodents. It employs cross-species neuroimaging, epigenomic, molecular, and neuroanatomical approaches in humans and rodents to assess the potential consequences of fragmented unpredictable experience on brain structure and circuitry. To address this multi-technology, multi-species approach, the system uses semantic web techniques based on the Neuroimaging Data Model (NIDM) to facilitate data ETL functionality. We find this approach enables a low-cost, easy to maintain, and semantically meaningful information management system, enabling the diverse research teams to access and use the data.

Memory is strongly influenced by stress but underlying mechanisms are unknown. Here, we used electrophysiology, neuroanatomy, and network simulations to probe the role of the endogenous, stress-related neuropeptide corticotropin-releasing hormone (CRH) in modulating hippocampal function. We focused on neuronal excitability and the incidence of sharp waves (SPWs), a form of intrinsic network activity associated with memory consolidation. Specifically, we blocked endogenous CRH using 2 chemically distinct antagonists of the principal hippocampal CRH receptor, CRHR1. The antagonists caused a modest reduction of spontaneous excitatory transmission onto CA3 pyramidal cells, mediated, in part by effects on IAHP. This was accompanied by a decrease in the incidence but not amplitude of SPWs, indicating that the synaptic actions of CRH are sufficient to alter the output of a complex hippocampal network. A biophysical model of CA3 described how local actions of CRH produce macroscopic consequences including the observed changes in SPWs. Collectively, the results provide a first demonstration of the manner in which subtle synaptic effects of an endogenously released neuropeptide influence hippocampal network level operations and, in the case of CRH, may contribute to the effects of acute stress on memory.

Vulnerability to emotional disorders including depression derives from interactions between genes and environment, especially during sensitive developmental periods. Across evolution, maternal care is a key source of environmental sensory signals to the developing brain, and a vast body of work has linked quantitative and qualitative aspects of maternal care to emotional outcome in children and animals. However, the fundamental properties of maternal signals, that promote advantageous vs pathological outcomes in the offspring, are unknown and have been a topic of intense study. We studied emotional outcomes of adolescent rats reared under routine or impoverished environments, and used mathematical approaches to analyze the nurturing behaviors of the dams. Unexpectedly, whereas the quantity and typical qualities of maternal care behaviors were indistinguishable in the two environments, their patterns and rhythms differed drastically and influenced emotional outcomes. Specifically, unpredictable, fragmented maternal care patterns translated into high-entropy rates of sensory signals to the offspring in the impoverished cages. During adolescence, these offspring had significant reductions in sucrose preference and in peer-play, two independent measures of the ability to experience pleasure. This adolescent anhedonia, often a harbinger of later depression, was not accompanied by measures of anxiety or helplessness. Dopaminergic pleasure circuits underlying anhedonia are engaged by predictable sequences of events, and predictable sensory signals during neonatal periods may be critical for their maturation. Conversely, unpredictability maternal-derived signals may disrupt these developmental processes, provoking anhedonia. In sum, high-entropy and fragmented patterns of maternal-derived sensory input to the developing brain predicts, and might promote, the development of anhedonia in rodents, with potential clinical implications.

The cognitive effects of stress are profound, yet it is unknown if the consequences of concurrent multiple stresses on learning and memory differ from those of a single stress of equal intensity and duration. We compared the effects on hippocampus-dependent memory of concurrent, hours-long light, loud noise, jostling and restraint (multimodal stress) with those of restraint or of loud noise alone. We then examined if differences in memory impairment following these two stress types might derive from their differential impact on hippocampal synapses, distinguishing dorsal and ventral hippocampus. Mice exposed to hours-long restraint or loud noise were modestly or minimally impaired in novel object recognition, whereas similar-duration multimodal stress provoked severe deficits. Differences in memory were not explained by differences in plasma corticosterone levels or numbers of Fos-labeled neurons in stress-sensitive hypothalamic neurons. However, although synapses in hippocampal CA3 were impacted by both restraint and multimodal stress, multimodal stress alone reduced synapse numbers severely in dorsal CA1, a region crucial for hippocampus-dependent memory. Ventral CA1 synapses were not significantly affected by either stress modality. Probing the basis of the preferential loss of dorsal synapses after multimodal stress, we found differential patterns of neuronal activation by the two stress types. Cross-correlation matrices, reflecting functional connectivity among activated regions, demonstrated that multimodal stress reduced hippocampal correlations with septum and thalamus and increased correlations with amygdala and BST. Thus, despite similar effects on plasma corticosterone and on hypothalamic stress-sensitive cells, multimodal and restraint stress differ in their activation of brain networks and in their impact on hippocampal synapses. Both of these processes might contribute to amplified memory impairments following short, multimodal stress.

Stress is ubiquitous in modern life and exerts profound effects on cognitive and emotional functions. Thus, whereas acute stress enhances memory, longer episodes exert negative effects through as yet unresolved mechanisms. We report a novel, hippocampus-intrinsic mechanism for the selective memory defects that are provoked by stress. CRH (corticotropin-releasing hormone), a peptide released from hippocampal neurons during stress, depressed synaptic transmission, blocked activity-induced polymerization of spine actin and impaired synaptic plasticity in adult hippocampal slices. Live, multiphoton imaging demonstrated a selective vulnerability of thin dendritic spines to this stress hormone, resulting in depletion of small, potentiation-ready excitatory synapses. The underlying molecular mechanisms required activation and signaling of the actin-regulating small GTPase, RhoA. These results implicate the selective loss of dendritic spine sub-populations as a novel structural and functional foundation for the clinically important effects of stress on cognitive and emotional processes.

Febrile seizures (FS) are common and are associated with increased probability of temporal lobe epilepsy (TLE). However, whether FS can provoke TLE in the nonpredisposed brain is unknown. Using an immature rat model, we established that long FS cause TLE, and that duration of FS governed the severity of epilepsy. Epileptogenesis was accompanied, perhaps causally, by ion channel dysfunction and inflammatory changes. Because FS are a prevalent antecedent of TLE, studying the epileptogenesis that follows them provides powerful insight and potential therapies for epilepsy. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AC, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at). © 2010 International League Against Epilepsy.

BackgroundEarly-life emotional stress may be associated with affective and cognitive disorders later in life, yet satisfactory animal models for studying the underlying mechanisms are limited. Because maternal presence and behavior critically influence molecular and behavioral stress responses in offspring, we sought to create a model of dysfunctional, fragmented maternal nurturing behavior that would, in turn, provoke chronic early-life stress in the offspring.MethodsSprague-Dawley rat dams' nursing and nurturing behaviors were altered by limiting their ability to create satisfactory nests during postpartum days 2-9. Maternal behavior was observed throughout the diurnal cycle, and the frequency and duration of nurturing behaviors were scored. In addition, potential stress and anxiety of the dams were assessed using behavioral, molecular and hormonal measures.ResultsBoth the quantity and the quality of dams' care of their pups were profoundly influenced by restriction of nesting materials in their cages: licking/grooming activities decreased and the frequency of leaving the pups increased, resulting in fragmented interactions between the dams and pups. The abnormal activity patterns of the dams were accompanied by increased anxiety-like behavior in the open field, but not in the elevated plus maze tests. Additionally, dams' plasma corticosterone levels and adrenal weights were augmented, suggesting chronic stress of these dams. By the end of the limited-nesting, stress-inducing period, hypothalamic corticotropin releasing hormone (CRH) mRNA expression was reduced in the limited-nesting dams, while arginine-vasopressin (AVP) mRNA levels were not significantly affected.ConclusionLimiting dams' ability to construct a nest for their pups leads to an abnormal repertoire of nurturing behaviors, possibly as a result of chronic stress and mild anxiety of the dams. Because the fragmented and aberrant maternal behavior provoked chronic stress in the pups, the limited-nesting paradigm provides a useful tool for studying the mechanisms and consequences of such early-life stress experience in the offspring.

The effects of stress, including their putative contribution to pathological psychiatric conditions, are crucially governed by the age at which the stress takes place. However, the cellular and molecular foundations for the impact of stress on neuronal function, and their change with age, are unknown. For example, it is not known whether 'psychological' stress signals are perceived by similar neuronal populations at different ages, and whether they activate similar or age-specific signaling pathways that might then mediate the spectrum of stress-evoked neuronal changes. We employed restraint and restraint/noise stress to address these issues in juvenile (postnatal day 18, [P18]) and adult rats, and used phosphorylation of the transcription factor CREB (pCREB) and induction of c-fos as markers of hippocampal neuronal responses. Stress-activated neuronal populations were identified both anatomically and biochemically, and selective blockers of the stress-activated hippocampal peptide, corticotropin-releasing hormone (CRH) were used to probe the role of this molecule in stress-induced hippocampal cell activation. Stress evoked strikingly different neuronal response patterns in immature vs adult hippocampus. Expression of pCREB appeared within minutes in hippocampal CA3 pyramidal cells of P18 rats, followed by delayed induction of Fos protein in the same cell population. In contrast, basal pCREB levels were high in adult hippocampus and were not altered at 10-120 min by stress. Whereas Fos induction was elicited by stress in the adult, it was essentially confined to area CA1, with little induction in CA3. At both age groups, central pretreatment with either a nonselective blocker of CRH receptors (alpha-helical CRH [9-41]) or the CRF1-selective antagonist, NBI 30775, abolished stress-evoked neuronal activation. In conclusion, hippocampal neuronal responses to psychological stress are generally more rapid and robust in juvenile rats, compared to fully mature adults, and at both ages, CRH plays a key role in this process. Enhanced hippocampal response to stress during development, and particularly the activation of the transcription factor CREB, may contribute to the enduring effects of stress during this period on hippocampal function.

The hyperpolarization-activated cation current (I(h)), mediated by HCN channels, contributes to intrinsic neuronal properties, synaptic integration and network rhythmicity. Recent studies have implicated HCN channels in neuropathological conditions including epilepsy. While native HCN channels have been studied at the macroscopic level, the biophysical characteristics of individual neuronal HCN channels have not been described. We characterize, for the first time, single HCN currents of excised inside-out patches from somata of acutely dissociated rat hippocampal CA1 pyramidal cells. Hyperpolarization steps elicited non-inactivating channel openings with an apparent conductance of 9.7 pS, consistent with recent reports of native and recombinant HCN channels. The voltage-dependent P(o) had a V(1/2) of -81 +/- 1.8 mV and slope -13.3 +/- 1.9 mV. Blockers of macroscopic I(h), ZD7288 (50 microM) and CsCl (1 mM), reduced the channel conductance to 8 pS and 8.4 pS, respectively. ZD7288 was slightly more effective in reducing the P(o) at depolarized potentials, whereas CsCl was more efficacious at hyperpolarized potentials. The unitary neuronal HCN channels had voltage-dependent latencies to first channel opening and two open states. As expected, ZD7288 and CsCl increased latencies and decreased the properties of both open states. The major endogenous positive modulator of macroscopic I(h) is cAMP. Application of 8Br-cAMP (10 microM) did not affect conductance (9.4 pS), but did increase P(o) and short and long open times. Thus, sensitivity to I(h) modulators supports the single h-channel identity of these unitary currents. Detailed biophysical analysis of unitary I(h) conductances is likely to help distinguish between homomeric and heteromeric expression of these channels - findings that may be relevant toward the pathophysiology of diseases such as epilepsy.

ObjectiveTo determine the current best practice for treatment of infantile spasms in children.MethodsDatabase searches of MEDLINE from 1966 and EMBASE from 1980 and searches of reference lists of retrieved articles were performed. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. One hundred fifty-nine articles were selected for detailed review. Recommendations were based on a four-tiered classification scheme.ResultsAdrenocorticotropic hormone (ACTH) is probably effective for the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment. There is insufficient evidence to determine whether oral corticosteroids are effective. Vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmologic screening is required in patients on vigabatrin; however, the data are insufficient to make recommendations regarding the frequency or type of screening. There is insufficient evidence to recommend any other treatment of infantile spasms. There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis.ConclusionsACTH is probably an effective agent in the short-term treatment of infantile spasms. Vigabatrin is possibly effective.

Neuropeptides modulate neuronal function in hippocampus, but the organization of hippocampal sites of peptide release and actions is not fully understood. The stress-associated neuropeptide corticotropin releasing hormone (CRH) is expressed in inhibitory interneurons of rodent hippocampus, yet physiological and pharmacological data indicate that it excites pyramidal cells. Here we aimed to delineate the structural elements underlying the actions of CRH, and determine whether stress influenced hippocampal principal cells also via actions of this endogenous peptide. In hippocampal pyramidal cell layers, CRH was located exclusively in a subset of GABAergic somata, axons and boutons, whereas the principal receptor mediating the peptide's actions, CRH receptor 1 (CRF1), resided mainly on dendritic spines of pyramidal cells. Acute 'psychological' stress led to activation of principal neurons that expressed CRH receptors, as measured by rapid phosphorylation of the transcription factor cyclic AMP responsive element binding protein. This neuronal activation was abolished by selectively blocking the CRF1 receptor, suggesting that stress-evoked endogenous CRH release was involved in the activation of hippocampal principal cells.

The efficacy of ACTH, particularly in high doses, for rapid and complete elimination of infantile spasms (IS) has been demonstrated in prospective controlled studies. However, the mechanisms for this efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system have been attributed to activation of glucocorticoid receptors. The manner in which activation of these receptors improves IS and the basis for the enhanced therapeutic effects of ACTH--compared with steroids--for this disorder are the focus of this chapter. First, a possible "common excitatory pathway," which is consistent with the many etiologies of IS and explains the confinement of this disorder to infancy, is proposed. This notion is based on the fact that all of the entities provoking IS activate the native "stress system" of the brain. This involves increased synthesis and release of the stress-activated neuropeptide, corticotropin-releasing hormone (CRH), in limbic, seizure-prone brain regions. CRH causes severe seizures in developing experimental animals, as well as limbic neuronal injury. Steroids, given as therapy or secreted from the adrenal gland upon treatment with ACTH, decrease the production and release of CRH in certain brain regions. Second, the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors is considered, focusing on the effects of ACTH on the expression of CRH. Experimental data showing that ACTH potently reduces CRH expression in amygdala neurons is presented. This downregulation was not abolished by experimental elimination of steroids or by blocking their receptors and was reproduced by a centrally administered ACTH fragment that does not promote steroid release. Importantly, selective blocking of melanocortin receptors prevented ACTH-induced downregulation of CRH expression, providing direct evidence for the involvement of these receptors in the mechanisms by which ACTH exerts this effect. Thus, ACTH may reduce neuronal excitability in IS by two mechanisms of action: (1) by inducing steroid release and (2) by a direct, steroid-independent action on melanocortin receptors. These combined effects may explain the robust established clinical effects of ACTH in the therapy of IS.

Over the last few decades, concepts regarding the presence of hormonal and molecular responses to stress during the first postnatal weeks in the rat and the role of the neuropeptide corticotropin releasing hormone (CRH) in these processes, have been evolving. CRH has been shown to contribute critically to molecular and neuroendocrine responses to stress during development. In turn the expression of this neuropeptide in both hypothalamus and amygdala is differentially modulated by single and recurrent stress, and is determined also by the type of stress (eg, psychological or physiological). A likely transcriptional regulatory factor for modulating CRH gene expression, the cAMP responsive element binding protein CREB, is phosphorylated (activated) in the developing hypothalamus within seconds of stress onset, preceding the transcription of the CRH gene and initiating the activation of stress-induced cellular and neuroendocrine cascades. Finally, early life stress may permanently modify the hypothalamic pituitary adrenal axis and the response to further stressful stimuli, and recent data suggest that CRH may play an integral role in the mechanisms of these long-term changes.

The mechanisms of the molecular and neuroendocrine responses to stress in the immature rat have been a focus of intense investigation. A principal regulator of the these responses in both mature and developing rat is the neuropeptide corticotropin releasing hormone (CRH), and levels of hypothalamic CRH mRNA are enhanced by stress. In vitro, transcription of the CRH gene is governed by binding of the phosphorylated form of cAMP responsive element binding protein (pCREB) to the promoter. Here we tested the hypothesis that rapid, stress-induced CRH transcription occurred during the first two postnatal weeks, and is associated with pCREB expression. The time-course of induction of unedited, heteronuclear CRH RNA (CRH hnRNA) was examined in hypothalamic paraventricular nucleus (PVN) of immature rats subjected to both modest and strong acute stressors using in situ hybridization; pCREB abundance was determined in individual neurons in specific PVN sub-nuclei using immunocytochemistry and unbiased quantitative analysis. CRH hnRNA signal was negligible in PVN of immature rats sacrificed under stress-free conditions, but was readily detectable within 2 min, and peaked at 15 min, in PVN of stressed animals. Enhanced pCREB immunoreactivity was evident within 2 min of stress onset, and was enhanced specifically in stress-responsive, CRH-expressing medial parvocellular neurons. These data support the notion that, already during early postnatal life, stress induces rapid CREB phosphorylation, interaction of pCREB-containing transcription complexes with the CRE element of the CRH gene promoter, and initiation of CRH hnRNA production in stress-responsive neurons of rat PVN.

A large body of experience has been compiled in different countries, documenting the efficacy of adenocorticotropic hormone (ACTH) for infantile spasms. This is important, because it may serve as a key for understanding this disorder, as well as for designing better medicines. However, significant discrepancies exist among studies originating in different countries regarding the relative efficacy of small or large ACTH doses. These differences may be caused by a number of factors, including potential genetic or environmental-related differences in the biology of the disorder or associated genetic components that determine responsiveness to ACTH. In addition, striking differences in the preparations used around the world may be responsible. These include bio-availability and extent of blood brain barrier penetration, efficacy in activating the efficacy-mediating 'ACTH receptors', the presence in certain preparations of competing analogs, and others. These issues should not detract from the overall agreement that ACTH might be the most useful medication currently available to treat WS.

West syndrome (WS) is associated with diverse etiological factors. This fact has suggested that there must be a 'final common pathway' for these etiologies, which operates on the immature brain to result in WS only at the maturational state present during infancy. Any theory for the pathogenesis of WS has to account for the unique features of this disorder. For example, how can a single entity have so many etiologies? Why does WS arise only in infancy, even when a known insult had occurred prenatally, and why does it disappear? Why is WS associated with lasting cognitive dysfunction? And, importantly, why do these seizures--unlike most others--respond to treatment by a hormone, ACTH? The established hormonal role of ACTH in human physiology is to function in the neuroendocrine cascade of the responses to all stressful stimuli, including insults to the brain. As part of this function, ACTH is known to suppress the production of corticotropin releasing hormone (CRH), a peptide that is produced in response to diverse insults and stressors.The many etiologies of WS all lead to activation of the stress response, including increased production and secretion of the stress-neurohormone CRH. CRH has been shown, in infant animal models, to cause severe seizures and death of neurons in areas involved with learning and memory. These effects of CRH are restricted to the infancy period because the receptors for CRH, which mediate its action on neurons, are most abundant during this developmental period. ACTH administration is known to inhibit production and release of CRH via a negative feedback mechanism. Therefore, the efficacy of ACTH for WS may depend on its ability to decrease the levels of the seizure-promoting stress-neurohormone CRH.This CRH-excess theory for the pathophysiology of WS is consistent not only with the profile of ACTH effects, but also with the many different 'causes' of WS, with the abnormal ACTH levels in the cerebrospinal fluid of affected infants and with the spontaneous disappearance of the seizures. Furthermore, if CRH is responsible for the seizures, and CRH-mediated neuronal injury contributes to the worsened cognitive outcome of individuals with WS, then drugs which block the actions of CRH on its receptors may provide a better therapy for this disorder.

Hyperpolarization-activated cation currents (I(h)) are found in several brain regions including thalamus and hippocampus. Important functions of these currents in promoting synchronized network activity and in determining neuronal membrane properties have been progressively recognized, but the molecular underpinnings of these currents are only emerging. I(h) currents are generated by hyperpolarization-activated, cyclic nucleotide-gated cation channels (HCNs). These channel proteins are encoded by at least four HCN genes, that govern the kinetic and functional properties of the resulting channels. Because of the potential impact of I(h)-mediated coordinated neuronal activity on the maturation of the functional hippocampal network, this study focused on determining the expression of the four members of the HCN gene family throughout postnatal hippocampal development at both the regional and single cell level.The results of these experiments demonstrated that HCNs 1, 2 and 4 are differentially expressed in interneuronal and principal cell populations of the rat hippocampal formation. Expression profiles of each HCN isoform evolve during postnatal development, and patterns observed during early postnatal ages differ significantly from those in mature hippocampus. The onset of HCN expression in interneurons of the hippocampus proper precedes that in the dentate gyrus, suggesting that HCN-mediated pacing activity may be generated in hippocampal interneurons prior to those in the hilus. Taken together, these findings indicate an age-dependent spatiotemporal evolution of specific HCN expression in distinct hippocampal cell populations, and suggest that these channels serve differing and evolving functions in the maturation of coordinated hippocampal activity.