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Examples include growth factors occur in MTLE as well as in relevant animal models and are and cytokines cheap brahmi 60caps mastercard treatment hypercalcemia, which have been shown to be neuroactive seen both in the hippocampus, so far the most thoroughly in various test systems. Thus, various members of the neuro- investigated brain region, and in extrahippocampal areas trophin family, including nerve growth factor, brain-derived such as the entorhinal cortex (56). These although their effects vary widely in both qualitative and receptors, which mediate most fast excitatory neurotrans- quantitative terms (80). All reports of these neuroactive ef- mission, are also composed of an array of subunits, which fects are so far based on exogenously applied neurotrophins; assemble to form distinct receptor subtypes (73). Receptor that is, the results could be compromised by the finding 1850 Neuropsychopharmacology: The Fifth Generation of Progress that the concentrations used for experimentation exceeded ologic properties and the histochemical staining pattern of physiologic levels. Still, it is certainly of interest that the astrocytes in area CA1of the hippocampus differ from those brain concentration of some neurotrophins, such as BDNF, in area CA3 (88). Similar differences are likely to exist in increases dramatically after seizures, whereas others, such as other brain areas as well, adding another layer of complexity neurotrophin 3, decrease. The high-affinity trk receptors to the study of neuron-glia interactions as they pertain to and low-affinity p75 receptors for neurotrophins also appear mechanisms of epileptogenesis and chronic epilepsy. Because normal expres- Expression sion and seizure-induced changes of these putative neuro- Prolonged seizure activity, especially episodes of status epi- modulators occur throughout the limbic system, critical lepticus, often has dramatic effects on gene expression, in- seizure-related effects may not only take place in the hippo- ducing a bewildering array of new genes in the brain. The campus, where most studies have been performed to date. A popular hypothesis to explain these changes is of the immune system. However, some of these compounds, that seizures induce, or influence the expression of, genes for example, interleukin 1(IL-1), IL-6, and tumor necrosis that are normally expressed during development. Sequelae factor- , are expressed in the brain, influence neuronal ac- of seizures may therefore mimic or, to use a more teleologic tivity, and therefore have potential links to seizure mecha- term, recapitulate development. In particular, the mRNA for IL-1 and IL-6, as well zure-induced up-regulation of growth factors and proteins as IL receptors, is increased by seizures (82). Moreover, IL- that are involved in synaptogenesis (89). Other investigators 1 is elevated in tissue from patients with epilepsy (83). This implies the up-regulation Neuron-Glia Interactions of systems that inhibit neuronal activity. Indeed, seizures lead to changed expression of glutamate decarboxylase, the The importance of glia to neuronal function has been appre- enzyme responsible for GABA synthesis, and GABA recep- ciated since the early period of neuroscience research. Besides other roles in brain physiology, glial may be part of the development of the epileptic state. Thus, cells may play a significant role in the modulation of seizure a first seizure may induce gene expression of substances that phenomena. Thus, both astrocytes and microglial cells, the will contribute to further hyperexcitability. One example is two major glial cell types in the brain, are rapidly activated the neurotrophin BDNF, which is normally expressed in by seizure activity in the limbic system (84). It is currently dentate gyrus granule cells and, to a lesser extent, other areas unclear, however, whether this cellular reaction has procon- of the hippocampus and other brain regions (91). Astrocytes have the ability single seizure, BDNF message, protein, and the high-affin- to buffer extracellular potassium and can avidly accumulate ity trkB receptor all increase in granule cells (92,93). Moreover, astro- cause BDNF enhances neuronal activity in the hippocam- cytes increase the production and release of the endogenous pus, the increase in expression could have functional neuroinhibitory and anticonvulsant compound kynurenate, consequences; that is, it could lead to a reduction in seizure possibly as an early defensive response to seizures (85). BDNF also has effects on neuronal structure and These and many conceptually related data indicate a protec- could thus contribute to structural changes occurring after tive function of astrocytes in epileptogenesis and, perhaps, seizures that, in turn, increase susceptibility to seizures (81, in chronic epilepsy. Because BDNF, and other neurotrophins and neuro- croglia also synthesize endogenous proconvulsive agents modulators, are expressed in extrahippocampal regions, this such as quinolinate (86) and cytokines (87), which may hyperexcitability may also occur in these areas. Synaptic Reorganization Of possible relevance to their role in epilepsy, glial cells in limbic brain areas are heterogeneous with regard to both As mentioned above, seizures induce many genes in the structure and function. These genes express a variety of different proteins, Chapter 127: Temporal Lobe Epilepsy 1851 which often closely resemble or duplicate those that are product. This selectivity is particularly important in the preferentially expressed during brain development.
Chapter 53: Neural Circuitry and the Pathophysiology of Schizophrenia 735 tive density generic brahmi 60caps line treatment naive. Dopamine (DA)-containing axons from the not appear to be reduced (35,95), although less rigorous ventral mesencephalon have a bilaminar distribution in the methods were employed in these studies. PFC (84), forming a dense band in layers 1 through the In summary, although a reduction in neuron number most superficial portion of layer 3 and a second band of cannot be completely excluded, the subtle reduction in lower density in layers deep 5 and 6. In more densely inner- dPFC gray matter in schizophrenia may be attributable to vated regions, such as dorsomedial PFC (area 9), labeled a combination of smaller neurons and a decrease in dPFC axons are also present in high density in the middle cortical neuropil, the axon terminals, distal dendrites and dendritic layers, forming a third distinctive band in deep layer 3. The spines that represent the principal components of cortical noradrenergic (NA) projection from the locus coeruleus ex- synapses. Indeed, as described in more detail below, these hibits a different, and in some ways complementary, laminar two factors may be interrelated. The den- sity of NA axons is substantially greater in the deep cortical Candidate Sources for Synaptic layers, especially layer 5, than in the more superficial cortical Reductions laminae. In particular, few NA axons are present in layer 1, which receives a dense DA innervation. In contrast, the The apparent reduction in synaptic connectivity in the relatively uniform laminar distribution of cholinergic (87) dPFC of subjects with schizophrenia may be attributable and serotonergic (88) axons contrasts with the substantial to one or more of the following sources of synapses: axon heterogeneity exhibited by both DA and NA axons. Although none of these sources can be excluded at present, INTEGRITY OF PREFRONTAL CORTICAL some are more likely to be major contributors than others. CIRCUITRY IN SCHIZOPHRENIA For example, one subcortical source, the DA projections from the mesencephalon, may be reduced in number in In this section, we consider how this knowledge about the schizophrenia as evidenced by the report of diminished den- normal organization of dPFC circuitry can be used to inter- sities of axons immunoreactive for tyrosine hydroxylase, the pret studies of the integrity of different types of neural ele- rate limiting enzyme in catecholamine synthesis, and the ments in subjects with schizophrenia. As noted, several lines DA membrane transporter in the dPFC (96). However, of evidence support the hypothesis that schizophrenia is these reductions appeared to be restricted to the deep corti- associated with a decrease in the synaptic connectivity of cal layers. Furthermore, an in vivo neuroimaging study the dPFC. However, these abnormalities do not appear to found a reduced density of DA D1 receptors in the dPFC be a consequence of a decreased complement of dPFC neu- of subjects with schizophrenia (97); however, DA axons are rons, because several postmortem studies (34,37,89) have estimated to contribute less than 1% of cortical synapses reported either a normal or increased cell packing density (84). Consequently, even the complete loss of DA projec- in the dPFC. In addition, the one study that used unbiased tions to the dPFC could not, in isolation, account for the approaches to determine the total number of PFC neurons observed reductions in gray matter volume or synaptophysin did not observe a reduction in subjects with schizophrenia protein levels. The relatively small contributions that (90); however, the approaches used in these studies probably NA-, serotonin-, and acetylcholine-containing axons make lacked adequate sensitivity to detect reduced numbers of to the total number of synapses in the dPFC also argues small subpopulations of PFC neurons. Some studies that against disturbances in these systems as the principal cause focused on certain neuronal subpopulations have reported of reduced synaptic connectivity in this brain region. However, the latter abnormality was not observed in reduced somal volume in subjects with schizophrenia (89, another study (35), and it should be noted that a reduction 93) may suggest that the synapses furnished by the intrinsic in neuronal density when using immunocytochemical axon collaterals of these neurons are reduced in number, markers might reflect an alteration in the target protein because somal volume tends to be correlated with the size rather than in the number of cells. Evidence for a distur- Smaller neuronal cell bodies could also contribute to the bance in intrinsic connectivity is supported by recent studies observed reduction in PFC gray matter in schizophrenia. Among 250 functional gene groups, the most marked decreased in subjects with schizophrenia (89,93). In addi- changes in expression were present in the group of genes that tion, this reduction in somal volume may be associated with encode for proteins involved in the regulation of presynaptic a decrease in total length of the basilar dendrites of these neurotransmitter release. In contrast, the size of GABA neurons does indicate a general impairment in the efficacy of synaptic 736 Neuropsychopharmacology: The Fifth Generation of Progress transmission within the dPFC in schizophrenia, whether PFC, and, given the dependence of working memory tasks they represent a 'primary' abnormality intrinsic to the on the integrity of thalamo–prefrontal connections (29), to dPFC or a 'secondary' response to altered afferent drive the disturbances in working memory observed in schizo- to this brain region remains to be determined. However, in contrast to other species, the primate because the specific genes in this group that were most al- MDN contains both cortically projecting neurons and local tered appeared to differ across subjects, it seems unlikely circuit neurons. Thus, it is critical to determine which sub- that these findings can be explained solely by reduction in population(s) of MDN neurons are affected in schizophre- the number of intrinsic dPFC synapses. Interestingly, the density of neurons in the anterior this view, the expression of synaptophysin mRNA does not thalamic nuclei that contain parvalbumin (113), a calcium- appear to be reduced in the dPFC of subjects with schizo- binding protein present in thalamic projection neurons phrenia (50,100), suggesting that the reduction in this syn- (114), is reduced in schizophrenia; however, whether this aptic protein marker in the dPFC may have an extrinsic reduction represents an actual loss of neurons, as opposed source. Consistent with this interpretation, synaptophysin to an activity-dependent decrease in parvalbumin expres- mRNA levels are reduced in cortical areas that do furnish sion, is not known. However, whether these Within the dPFC, five other lines of evidence are also transcriptional changes are present in PFC-projecting neu- consistent with a reduction in inputs from the MDN (Fig. First, a preliminary report notes that subjects with synaptophysin protein in the terminal fields of these neu- schizophrenia, but not those with major depression, have a rons, have not been assessed. For example, some structural MRI studies have revealed a In contrast, parvalbumin-labeled varicosities were not de- reduction in thalamic volume in subjects with schizophrenia creased in layers 2 to superficial 3, suggesting that the reduc- (103–106). In addition, thalamic volume was correlated tion in layers deep 3 and 4 might not be attributable to with prefrontal white matter volume in schizophrenic sub- changes in the axon terminals of the parvalbumin-contain- jects (107), suggesting that a reduction in thalamic volume ing subset of cortical GABA neurons present in cortical was associated with fewer axonal projections to the PFC.
Brain in attention deficit disorder with and without hyperactivity: a Res 1995;676:343–351 proven brahmi 60caps symptoms quitting tobacco. The nucleus accumbens motor-limbic interface of 163–188. Neurosci Biobehav Rev 2000;24: history and comorbidity on the neuropsychological performance 133–136. Toward defining cleus accumbens slices and monoamine levels in a rat model for a neuropsychology of attention deficit-hyperactivity disorder: attention-deficit hyperactivity disorder. Neurochem Res 1995; performance of children and adolescents from a large clinically 20:427–433. Neuropsychological chrome oxidase mapping study, cross-regional and neurobehav- function in adults with attention-deficit hyperactivity disorder. Psychological adjustment psychosocial risk factors in DSM-III attention deficit disorder. J Atten J Am Acad Child Adolesc Psychiatry 1990;29:526–533. Attention dysfunc- of attention deficit hyperactivity disorder: evidence for single tion and psychopathology in college men. Attention deficit disor- Tohen M, Tsuang MT, Zahner GEP, eds. Further evidence and verbal learning deficits in adults diagnosed with attention for family-genetic risk factors in attention deficit hyperactivity deficit disorder. Neuropsychiatry Neuropsychol Behav Neurol disorder: patterns of comorbidity in probands and relatives psy- 1995;8:282–292. Evidence of familial (ADHD): diagnostic classification estimates for measures of association between attention deficit disorder and major affec- frontal lobe/executive functioning. Neuropsychological assessment of atten- disorder and major depression share familial risk factors? Attention deficit strain I/LnJ: a putative model of ADHD? Neurosci Biobehav disorder and conduct disorder: longitudinal evidence for a famil- Rev 2000;24:45–50. J Am Acad Child Adolesc Psychiatry 1994; cial disorders among relatives of ADHD children: parsing famil- 33:858–868. Attention-deficit vation in ADHD: preschool and elementary school boys and hyperactivity disorder with bipolar disorder: a familial subtype? J Am Acad Child Adolesc Psychiatry 1999;38:1363–1371. J Am Acad Child Adolesc Psychiatry 1997;36:1378–1387;discus- 64. Familial association rine-18]fluorodopa positron emission tomographic study. J between attention deficit disorder and anxiety disorders. Evidence dysfunction in attention deficit/hyperactivity disorder revealed for the independent familial transmission of attention deficit by fMRI and the counting stroop. Biol Psychiatry 1999;45: hyperactivity disorder and learning disabilities: results from a 1542–1552. Refining the ADHD metabolism in adults with hyperactivity of childhood onset. Toward guidelines porter density is elevated in patients with attention deficit hyper- for pedigree selection in genetic studies of attention deficit hy- activity disorder. Neuropsychiatry Neuropsychol Behav Neurol 1997;10: tence and remission of ADHD: results from a four-year prospec- 151–154. Herskovits EH, Megalooikonomou V, Davatzikos C, et al. High risk for attention head injury predictive of subsequent development of attention- deficit hyperactivity disorder among children of parents with deficit/hyperactivity disorder? Analysis with brain-image data- childhood onset of the disorder: a pilot study. Diagnostic continuity anomalies in children with attention-deficit hyperactivity disor- between child and adolescent ADHD: findings from a longitu- der. Demonstration of The aetiological role of genes, family relationships and perinatal vertical transmission of attention deficit disorder.
Evidence for vasodilation in cirrhosis that precedes? UNaV FIGURE 2-31 Vasodilators Vasoconstrictors Alterations in cardiovascular hem odynam ics in hepatic cirrhosis trusted brahmi 60 caps schedule 9 medications. H epatic dysfunction and Nitric oxide portal hypertension increase the production and im pair the m etabolism of several vasoac- Glucagon CGRP tive substances. The overall balance of vasoconstriction and vasodilation shifts in favor of ANP SNS dilation. Vasodilation m ay also shift blood away from the central circulation toward the VIP RAAS periphery and away from the kidneys. Som e of the vasoactive substances postulated to Substance P Vasopressin ET-1 participate in the hem odynam ic disturbances of cirrhosis include those shown here. Prostaglandin E2 AN P— atrial natrivretic peptide; ET-1— endothelin-1; CGRP— calcitonin gene related Encephalins TNF peptide; RAAS— renin/angiotensin/aldosterone system ; TN F— tum or necrosis factor; Andrenomedullin VIP— vasoactive intestinal peptide. Com pared with control subjects (A), patients with cirrhosis (B) have decreased central and increased non- 1. The higher cardiac output (CO ) results from peripheral vasodila- 1. Perfusion of the kidney is reduced significantly in patients with cirrhosis. Com pared with control rats, rats having cir- Cirrhosis & L-name rhosis induced by carbon tetrachloride and phenobarbital exhibited increased plasm a renin activity (PRA) and plasm a arginine vaso- 10 10 pressin (AVP) concentrations. At steady state, the urinary N a excre- tion (UN aV) was sim ilar in both groups. After treatm ent with L- N AM E for 7 days, plasm a renin activity decreased to norm al lev- els, AVP concentrations decreased toward norm al levels, and urinary N a excretion increased by threefold. These changes were 5 5 associated with a norm alization of m ean arterial pressure and car- diac output. A prim ary decrease in system ic + 20 Fluid intake 20 vascular resistance (indicated by dark blue Net volume arrow), induced by m ediators shown in intake 10 10 Figure 2-31, leads to a decrease in arterial Nonrenal fluid loss – pressure. The reduction in system ic vascular + 0 0 resistance, however, is not uniform and 0 10 20 30 favors m ovem ent of blood from the central ECF volume, L (“effective”) circulation into the peripheral + – Rate of change + circulation, as shown in Figure 2-32. Arterial Kidney volume Extracellular of extracellular H ypoalbum inem ia shifts the interstitial to pressure output fluid volume fluid volume blood volum e ratio upward (com pare the + interstitial volum e with norm al [dashed Total peripheral line], and low [solid line], protein levels in Central Peripheral + resistance blood volume blood volume the inset graph). Because cardiac output increases and venous return m ust equal car- + + diac output, dram atic expansion of the + M ean circulatory extracellular fluid (ECF) volum e occurs. Cardiac output Venous return filling pressure M echanisms of Extracellular Fluid Volume Expansion in Nephrotic Syndrome FIGURE 2-35 14 Changes in plasm a protein concentration affect the net oncotic pressure difference across 12 capillaries ( c - i) in hum ans. N ote that m oderate reductions in plasm a protein concen- tration have little effect on differences in transcapillary oncotic pressure. O nly when plas- 10 m a protein concentration decreases below 5 g/dL do changes becom e significant. N ote that urinary N a excretion (squares) increases Plasm a renin activity (PRA) and atrial natriuretic peptide (AN P) before serum album in concentration increases. The data suggest concentration in the nephrotic syndrom e. Shown are PRA and that the natriuresis reflects a change in intrinsic renal N a retention. AN P concentration ( standard error) in norm al persons ingesting The data also em phasize that factors other than hypoalbum inem ia diets high (300 m Eq/d) and low (20 m Eq/d) in sodium (N a) and in m ust contribute to the N a retention that occurs in nephrosis. PRA suppression suggests that prim ary renal N aCl retention plays an im portant role in the pathogenesis of volum e expansion in AGN. Although plasm a renin activity in patients with nephrotic syndrom e is not suppressed to the sam e degree, the absence of PRA elevation in these patients suggests that prim ary renal N a retention plays a significant role in the pathogen- esis of N a retention in N S as well. The glom erular filtration rates (GFR) in norm al and nephrotic rats are shown by the hatched bars. N ote the m odest reduction in GFR in the nephrotic group, a finding that is com m on 60 60 in hum an nephrosis. Fractional reabsorption rates along the proxi- m al tubule, the loop of H enle, and the superficial distal tubule are indicated.
