Altered structural and effective connectivity in anorexia and bulimia nervosa in circuits that regulate energy and reward homeostasis.

Anorexia and bulimia nervosa are severe eating disorders that share many behaviors. Structural and functional brain circuits could provide biological links that those disorders have in common. We recruited 77 young adult women, 26 healthy controls, 26 women with anorexia and 25 women with bulimia nervosa. Probabilistic tractography was used to map white matter connectivity strength across taste and food intake regulating brain circuits. An independent multisample greedy equivalence search algorithm tested effective connectivity between those regions during sucrose tasting. Anorexia and bulimia nervosa had greater structural connectivity in pathways between insula, orbitofrontal cortex and ventral striatum, but lower connectivity from orbitofrontal cortex and amygdala to the hypothalamus (P<0.05, corrected for comorbidity, medication and multiple comparisons). Functionally, in controls the hypothalamus drove ventral striatal activity, but in anorexia and bulimia nervosa effective connectivity was directed from anterior cingulate via ventral striatum to the hypothalamus. Across all groups, sweetness perception was predicted by connectivity strength in pathways connecting to the middle orbitofrontal cortex. This study provides evidence that white matter structural as well as effective connectivity within the energy-homeostasis and food reward-regulating circuitry is fundamentally different in anorexia and bulimia nervosa compared with that in controls. In eating disorders, anterior cingulate cognitive-emotional top down control could affect food reward and eating drive, override hypothalamic inputs to the ventral striatum and enable prolonged food restriction.

Orbitofrontal cortex volume and brain reward response in obesity.

BACKGROUND/OBJECTIVES: What drives overconsumption of food is poorly understood. Alterations in brain structure and function could contribute to increased food seeking. Recently, brain orbitofrontal cortex (OFC) volume has been implicated in dysregulated eating but little is known how brain structure relates to function. SUBJECTS/METHODS: We examined obese (n=18, age=28.7±8.3 years) and healthy control women (n=24, age=27.4±6.3 years) using a multimodal brain imaging approach. We applied magnetic resonance and diffusion tensor imaging to study brain gray and white matter volume as well as white matter (WM) integrity, and tested whether orbitofrontal cortex volume predicts brain reward circuitry activation in a taste reinforcement-learning paradigm that has been associated with dopamine function. RESULTS: Obese individuals displayed lower gray and associated white matter volumes (P<0.05 family-wise error (FWE)- small volume corrected) compared with controls in the orbitofrontal cortex, striatum and insula. White matter integrity was reduced in obese individuals in fiber tracts including the external capsule, corona radiata, sagittal stratum, and the uncinate, inferior fronto-occipital, and inferior longitudinal fasciculi. Gray matter volume of the gyrus rectus at the medial edge of the orbitofrontal cortex predicted functional taste reward-learning response in frontal cortex, insula, basal ganglia, amygdala, hypothalamus and anterior cingulate cortex in control but not obese individuals. CONCLUSIONS: This study indicates a strong association between medial orbitofrontal cortex volume and taste reinforcement-learning activation in the brain in control but not in obese women. Lower brain volumes in the orbitofrontal cortex and other brain regions associated with taste reward function as well as lower integrity of connecting pathways in obesity (OB) may support a more widespread disruption of reward pathways. The medial orbitofrontal cortex is an important structure in the termination of food intake and disturbances in this and related structures could contribute to overconsumption of food in obesity.

[Similarities in periodical structures in the position of nucleotides in regions of initiation of replication of bacterial genomes]. / Skhodstvo periodicheskikh struktur v raspolozhenii nukleotidov na uchastkakh nachala replikatsii bakterial'nykh genomov.

The regions of initiation of replication of some bacterial genomes were studied by the method of Fourier matrix analysis. A generalized spectral portrait of the primary structures of E. coli-like regions of initiation of replication in bacteria was obtained, which reflects the features of their structural and functional organization. It contains well-pronounced peaks that correspond to the periods T = 2, 11, 17, 27, 86-105 of nucleotides. The peaks corresponding to T = 9, 13, 14, 18, 19, 33-35, 45-47, 74-85, 106-110 are less pronounced. The uniqueness of the Fourier spectrum corresponding to the region of initiation of replication of E. coli oriC was considered by the example of the complete genome of E. coli. Some regions of the E. coli genome were identified that differ from oriC in the primary structure but have Fourier spectra resembling the spectrum of oriC. A number of these regions are alternative points of initiation of replication in sdrA(rnh) mutants of E. coli, the others are localized in yet unidentified regions of the E. coli genome but are capable, in our opinion, to participate in the initiation of replication. Thus, from the similarity of spectral portraits of different regions of the genome, it was possible to reveal several regions that have similar functions, i.e., are involved in initiation of replication.

Reduced gastrin releasing peptide in cerebrospinal fluid after recovery from bulimia nervosa.

People with anorexia (AN) and bulimia nervosa (BN) have altered patterns of eating. It is possible that alterations of the neuropeptide gastrin releasing peptide (GRP), a bombesin (BBS) -like peptide with potent central anorexigenic activity, could contribute to disturbed eating behavior. To avoid the confounding effects of pathologic eating behavior, we measured cerebrospinal fluid (CSF) GRP concentrations in women who were long-term recovered (>1 year, normal weight, and regular menstrual cycles, no binging or purging) from AN (REC AN, N=12) or BN (REC BN, N=21) compared to healthy control women (NC, N=15). CSF GRP was significantly lower (chi(2)=9.41(3), p<0.01) in REC BN (9.6+/-3.1 pg/ml) compared to NC (13.4+/-5.5 pg/ml) and REC AN (11.6+/-2.9 pg/ml). Persistent GRP abnormalities after recovery from BN raise the possibility that this alteration might be trait-related and contribute to episodic hyperphagia in BN.

Altered response to meta-chlorophenylpiperazine in anorexia nervosa: support for a persistent alteration of serotonin activity after short-term weight restoration.

OBJECTIVE: Patients with anorexia nervosa (AN) have disturbances of appetite and behaviors, such as dysphoria, inhibition, and obsessions, that could be related to altered serotonin activity. To investigate such relationships, we administered meta-chlorophenylpiperazine (m-CPP), a relatively serotonin-specific drug. METHODS: To avoid the confounding effects of malnutrition or weight loss, we studied 12 patients with restricting-type AN between 5 and 17 days after a return to a normal weight and while on a stable dietary intake. We compared them to 12 healthy control women (CW). m-CPP was administered double blind and placebo controlled. RESULTS: Although weight restored, AN women had lower body weight and increased ratings for depression and obsessionality compared with CW. After m-CPP, AN women had an elevation in mood and a reduction in body image distortion when compared with placebo. After m-CPP, groups had similar cortisol, adrenocorticotropin (ACTH), and growth hormone responses whereas AN women had an uncertain reduction in prolactin response. DISCUSSION: These data support other studies that suggest that altered serotonin activity persists after weight restoration in AN patients. The finding that m-CPP temporarily improved mood and reduced body image distortions supports the hypothesis that altered serotonin activity may contribute to the pathophysiology of AN.

Altered serotonin 2A receptor activity in women who have recovered from bulimia nervosa.

OBJECTIVE: The authors' goal was to confirm that brain serotonin (5-HT) alterations are present in patients who have recovered from bulimia nervosa. Positron emission tomography imaging with [(18)F]altanserin was used to characterize binding of the 5-HT(2A) receptor, which might contribute to altered feeding, mood, or impulse control. METHOD: Nine women who had recovered from bulimia nervosa (they had no episodes of binge eating or purging, were at normal weight, and had regular menstrual cycles for more than 1 year) were compared with 12 female volunteers who had never had bulimia. RESULTS: The healthy volunteers, but not the women who had recovered from bulimia nervosa, had an age-related decline in 5-HT(2A) binding. Women who had recovered from bulimia nervosa had a reduction of medial orbital frontal cortex 5-HT(2A) binding. CONCLUSIONS: The lack of age-related changes in 5-HT activity is further evidence of 5-HT alterations in subjects who have recovered from bulimia nervosa. In addition, vulnerabilities for eating disorders, impulse dyscontrol, and mood disturbances may involve 5-HT and frontal lobe activity.

Could reduced cerebrospinal fluid (csf) galanin contribute to restricted eating in anorexia nervosa?

Galanin (GAL) and gamma amino butyric acid (GABA) are orexigenic neuropeptides that could contribute to the pathogenesis of anorexia nervosa (AN). To avoid the confounding effects of the ill state, we studied women who were recovered (> 1 year, normal weight, and regular menstrual cycles, no binging or purging) from AN (REC AN) and matched healthy control women (NC). CSF GAL was reduced in REC AN (64.4 +/- 8.6 pg/ml) compared to NC (72.0 +/- 11.6 pg/ml; p <.05), GABA was similar between groups. In the brain, GAL stimulates appetite and fat consumption. These data raise the question of whether alterations in brain GAL activity plays a role in clinical symptoms in AN, such as food restriction and fat avoidance.

Sertraline in underweight binge eating/purging-type eating disorders: five case reports.

DISCUSSION: Control trials show that antidepressants are efficacious in eating disorders. Although selective serotonin reuptake inhibitors (SSRIs) are used in clinical practice, there are relatively few controlled or open trials demonstrating that SSRIs are effective. We report five cases of underweight women with binge eating/purging-type eating disorders who gained weight and had reduced core eating disorder behaviors in response to sertraline.

Regional cerebral blood flow after recovery from bulimia nervosa.

When ill, women with bulimia nervosa (BN) show alterations of regional cerebral blood flow (rCBF). In this study we investigated rCBF in nine women in long-term recovery from BN (RBN, n=9), i.e. more than 1 year without bingeing/purging behavior, normal weight, stable food intake, and regular menses, and compared them with age-matched healthy control women (CW, n=13). Positron emission tomography (PET) was used for the assessment of rCBF. There were no significant differences in rCBF between groups. However, rCBF was significantly inversely related to length of recovery in RBN for the left and right prefrontal cortex (BA 10), right medial orbital frontal cortex (BA 11), left subgenual cingulate (BA 25), right anterior cingulate (BA 32), left sensory motor cortex (BA 1,2,3,4), left and right lateral temporal (BA 21), and left occipital cortex (BA 17), as well as left thalamus. This finding suggests that previously reported alterations in rCBF during the ill state of BN may be a state-related phenomenon that remits with recovery. It is also possible that reductions in rCBF occur in a later stage of recovery from BN.

CSF oxytocin and vasopressin levels after recovery from bulimia nervosa and anorexia nervosa, bulimic subtype.

BACKGROUND: When ill, people with eating disorders have disturbances of the neuropeptides vasopressin and oxytocin. METHODS: To avoid the confounding effects of the ill state, we studied women who were recovered (more than 1 year, normal weight, and regular menstrual cycles, no bingeing or purging) from bulimia nervosa (rBN) or binge eating/purging-type anorexia nervosa (rAN-BN), and matched healthy control women. RESULTS: Vasopressin was elevated in rAN-BN and showed a trend towards elevation in rBN. In rBN, elevated cerebrospinal fluid vasopressin may be related to having a lifetime history of major depression. In comparison, cerebrospinal fluid oxytocin was normal in recovered subjects, but elevated levels in some rBN might be related to birth control pill use. CONCLUSIONS: These data confirm and extend the possibility that elevated cerebrospinal fluid vasopressin may be related to the pathophysiology of eating disorders, and/or a lifetime history of major depression.

[Analysis of peculiarities in nucleotides disposition in the origin of chromosome replication-oriC from Escherichia coli]. / Analiz osobennostei raspredeleniia nukleotidov na uchastke nachala replikatsii khromosomy-oriC iz Escherichia coli.

Along with symmetrical features (palindromes, direct and inverted repeats), periodicities in the disposition of nucleotides in the origin of chromosome replication oriC from E. coli were studied by means of Fourier analysis. Peaks corresponding to the periods T = 2, 17, 95-100 nucleotides are the highest in the Fourier spectrum of oriC. Peaks corresponding to the periods T = 3, 11, 19, 13, 24, 27, 28, 41, 79-81 nucleotides are also prominent, but not so high. Thus, the main periodicities of the oriC spectrum of are not multiple of the B-DNA sugar-phosphate backbone period, which destabilize DNA at oriC and contributes to the spontaneous unwinding of DNA. The differences between the Fourier spectrum of oriC and those of regions adjacent to oriC are demonstrated.

Anorexia and bulimia nervosa.

Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by abnormal patterns of weight regulation and eating behavior and by disturbances in attitudes and perceptions toward weight and body shape. Etiologic research has indicated substantial genetic influence on these disorders, suggesting significant biological contributions to their development. Obsessional, perfectionistic, and anxious personality styles may be premorbid traits that contribute to this pathogenesis. Studies of neuroendocrine, neuropeptide, and neurotransmitter functioning in patients with AN and BN indicate that disturbances of these systems may contribute to the maintenance as well as the etiology of these sometimes fatal disorders. The efficacy of psychological treatments and pharmacotherapy has been more clearly established for BN than for AN.

Altered dopamine activity after recovery from restricting-type anorexia nervosa.

When ill, women with eating disorders have disturbances of mood and behavior and alterations of catecholamine activity. It is not known whether these alterations are cause or consequence of pathological eating behaviors. To avoid confounding effects of pathologic eating behavior, we studied women who were recovered (> 1 year, normal weight, regular menstrual cycles, no restricting eating pattern, no bingeing or purging) from anorexia nervosa (AN) and bulimia nervosa (BN) compared to healthy control women. Recovered AN women had significantly lower height-adjusted weight than did recovered BN women. CSF HVA (pmol/ml +/- SD), a major metabolite of dopamine, was significantly lower (p < .02) in six restricting-type AN women (131 +/- 49) compared to 19 BN women (216 +/- 73) and at a trend (p < .08) less than 13 bulimic-type AN women (209 +/- 53, p < .06) and 18 control women (202 +/- 57, p < .08). These four groups had similar values for CSF MHPG, a norepinephrine metabolite. Dopamine neuronal function has been associated with motor activity, reward, and novelty seeking. These behaviors are altered in restricting-type AN compared to other eating disorder subtypes. A trait-related disturbance of dopamine metabolism may contribute to a vulnerability to develop this sub-type of eating disorder.

[Periodicity in contacts of RNA-polymerase with promotors]. / Periodichnosti v kontaktakh RNK-polimerazy s promotorami.

Periodicities in the position of E.coli RNA polymerase promoter contacts on several promoters (lacUV5, T7 A3, tetR, lambda cin, lambda c17, RNA1, and trp S.t.) were found by means of Fourier analysis. The comparison of the Fourier spectrum of core RNA polymerase contacts on the lacUV5 promoter and that of holoenzyme revealed a more prominent 7-periodicity in the Fourier spectrum of holoenzyme contacts. 6-, 7-, and 8-periodicities were found in the primary structure of the majority of E.coli promoters. It is shown that RNA polymerase recognizes specific periodic patterns in the promoter structure.

G and T nucleotide contents show specie-invariant negative correlation for all three codon positions.

The nucleotide contents of the three codon positions show a number of statistical pairwise correlations, some of which are universal for all analysed genomes. Among the most prominent of these correlations are negative correlations between G and T contents found in genes of all species analysed. The pair A/C, which is complementary to G/T shows similar negative correlation in genes of most species. In the genes of several species including all mammalian genes studied, positive correlations between A and T contents, and G and C contents are found. Since these regularities are observed in all three codon positions they are connected with amino-acid content of proteins. Such correlations may origin from features of the mutation process or/and translation reading frame check. The well-known bias of the preference for G in the first codon position and its deficiency in the second is accompanied by opposite bias in T content. In the third codon position there is no general nucleotide preference, but its content is often biased with regard to GC content of the gene. G and T contents in this case are always shifted in the opposite directions Several ideas are drawn to explain this preference.

[Fourier analysis of nucleotide sequences. Periodicity in E. coli promoter sequences]. / Fur'e-analiz nukleotidnykh posledovatel'nostei. Periodichnosti v promoternykh posledovatel'nostiakh E. coli.

Fourier spectra of E. coli promoter DNA sequences have been obtained. The periodical structure of individual promoter sequences is characterized. E. coli promoter sequences are classified according to their Fourier spectra using three feature sets: 1--the number of peaks in Fourier spectra; 2--values of power spectra for promoter primary structures and their similarity with physical periodicities in the backbone of polynucleotide; 3--the presence of blocks made of equal nucleotides. The comparison of Fourier spectra of promoter sequences and corresponding genes is provided. The conclusion that different ways of stabilization of promoter secondary structure in the case of different primary structure periodicities is drawn. The intermittence of AT- and GC-blocks, and variety of Fourier spectra mean DNA hydrate shell in DNA promoters is non-contiguous and non-stable at junction points. Characteristic features of prokaryotic promoters Fourier spectra differ from human promoters.

[Statistics of periodic regularities in sequences of human introns]. / Statistika periodicheskikh zakonomernostei v posledovatel'nostiakh intronov cheloveka.

A formula for the calculation of average power of a Fourier harmonic of a nucleotide sequence with given composition by means of the matrix Fourier analysis method is suggested. A search for the periodic regularities with the periods from two to ten nucleotides was carried out on a sample set of human exons and introns. It is shown that all the periodicities researched, including the three nucleotides period, are random in introns, whereas in exons the 3 periodic regularity is much stronger. The periods that are not multiples of 3, however, are also random in exons. The two nucleotides periodicity, which is, according to the literature, over-represented in introns, appears to be also random in the case under study. The results are important for the development of the algorithms for the coding regions search in DNA, and for the understanding of the global statistic regularities in human genome.