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Biomedical subjects

C Benkelfat

Publications and source records attributed to C Benkelfat.

At least 19 recordsLinked to original sources
PubMed2006

Acute prefrontal cortex TMS in healthy volunteers: effects on brain 11C-alphaMtrp trapping.

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (LDLPFC) is a technique with purported efficacy as a treatment for major depression. Here, we assessed in vivo, in healthy volunteers, the effect of acute rTMS of the LDLPFC, relative to the stimulation of the left occipital cortex (LOC), on brain regional serotonin synthesis capacity, using the [(11)C]-alpha-methyl-tryptophan ((11)C-alphaMtrp)/PET method. Ten subjects were studied twice, once following rTMS of the LDLPFC and once following rTMS of the LOC in a randomized counterbalanced order. Three blocks of 15 trains of 10 Hz rTMS were delivered 10 min apart. Behavioural and autonomic measures were recorded before and after each rTMS session. Comparisons of TMS-related changes in regional normalized brain uptake and trapping of (11)C-alphaMtrp (K*) values were carried out using SPM99. Statistically significant regional differences were identified on the basis of an extent threshold of 50 voxels, with a peak threshold of p=0.005 uncorrected. Behavioural and autonomic measures were unaffected by rTMS. Relative to LOC stimulation, LDLPFC rTMS was associated with marked changes in normalized K* in limbic areas, with significantly lower values in the left parahippocampal gyrus (BA 28) and the right insula (BA 13), and higher values in the right cingulate gyrus (BA 31) and cuneus (BA 18). These findings indicate that acute rTMS of the LDLPFC in healthy volunteers modulates aspects of tryptophan/5-HT metabolism in limbic areas. Such adaptive changes may contribute to the mechanism of action of prefrontal rTMS in major depression.

Adult↗
PubMed2006

Cortical trapping of alpha-[(11)C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males.

One neural system that may exhibit gender differences is serotonin (5-HT), a neurotransmitter implicated in the regulation of mood, cognitive processes, and impulse-control. However, most of the available evidence of gender-related differences in this system has been indirect and at times contradictory. The objective of the present study was to follow up on preliminary evidence that there are gender differences in brain regional 5-HT synthesis, as measured by trapping of alpha-[(11)C]methyl-l-tryptophan (alpha-[(11)C]MTrp). Sixty-minute dynamic scans were performed in healthy volunteers, 28 women and 31 men. Functional images of the brain trapping constant, used as a proxy for 5-HT synthesis, which correlate in the rat brain with tryptophan's conversion into 5-HT, were transferred to the standardized 3D space. The voxel based comparison was performed by Statistical Parametric Mapping with proportional normalization. There was lower normalized alpha-[(11)C]MTrp trapping in females than males throughout much of the cerebral cortex, including the left middle frontal gyrus, the bilateral inferior frontal gyrus, the bilateral precentral gyrus, the left supramarginal gyrus, the bilateral inferior parietal lobule, the left superior temporal gyrus, the bilateral posterior cingulate gyrus, and the bilateral precuneus. There were no regions in which the normalized trapping was significantly higher in females than in males. Gender differences in sub-cortical sites were not found. Women, compared to men, may have lower rates of this tracer trapping, used as a proxy for 5-HT synthesis, throughout much of the cerebral cortex which is likely related to differences in 5-HT synthesis because relative differences in the normalized trapping should be the same as those in 5-HT synthesis. These differences may be related, at least in part, to previously suggested gender differences in affect, cognitive processes, and susceptibility to 5-HT-related neuropsychiatric and neurological disorders.

Adult↗
PubMed2005

Increasing blood oxygen increases an index of 5-HT synthesis in human brain as measured using alpha-[(11)C]methyl-L-tryptophan and positron emission tomography.

The main objective of this investigation was to test the hypothesis that brain serotonin (5-HT) synthesis, as measured by trapping of alpha-[(11)C]methyl-L-tryptophan (alpha-MTrp) using positron emission tomography (PET), can be modulated by changes in blood oxygen. The study involved six healthy participants (three male and three female), who breathed a 15% or 60% oxygen mixture starting 15 min before the injection of tracer and continuing during the entire acquisition period. Participants were injected with up to 12m Ci of alpha-MTrp. Two sets of PET images were acquired while the participants were breathing each of the oxygen mixtures and, after reconstruction, all images were converted into brain functional images illustrating the brain trapping constant K(*) (microL/g/min). The K(*) values were obtained for 12 regions of interest outlined on the magnetic resonance images. The K(*) values obtained at high and low blood oxygen content were compared by paired statistics using Tukey's post hoc correction. As there were no difference in plasma tryptophan concentrations, these K(*) values are directly related to regional 5-HT synthesis. The results showed highly significant increases (50% on average) in brain serotonin synthesis (K(*) values) at high (mean value of 223+/-41 mmHg) relative to low (mean value 77.1+/-7.7 mmHg) blood oxygen levels. This suggests that tryptophan hydroxylase is not saturated with oxygen in the living human brain and that increases in blood oxygen can elevate brain serotonin synthesis.

Adolescent↗
PubMed2005

Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men.

OBJECTIVE: Major depression is a major risk factor for suicide. However, not all individuals with major depression commit suicide. Impulsive and aggressive behaviors have been proposed as risk factors for suicide, but it remains unclear whether their effect on the risk of suicide is at least partly explained by axis I disorders commonly associated with suicide, such as major depression. With a case-control design, a comparison of the level of impulsive and aggressive behaviors and the prevalence of associated psychopathology was carried out with control for the presence of primary psychopathology. METHOD: One hundred and four male suicide completers who died during an episode of major depression and 74 living depressed male comparison subjects were investigated with proxy-based interviews by using structured diagnostic instruments and personality trait assessments. RESULTS: The authors found that current (6-month prevalence) alcohol abuse/dependence, current drug abuse/dependence, and cluster B personality disorders increased the risk of suicide in individuals with major depression. Also, higher levels of impulsivity and aggression were associated with suicide. An analysis by age showed that these risk factors were more specific to younger suicide victims (ages 18-40). A multivariate analysis indicated that current alcohol abuse/dependence and cluster B personality disorder were two independent predictors of suicide. CONCLUSIONS: Impulsive-aggressive personality disorders and alcohol abuse/dependence were two independent predictors of suicide in major depression, and impulsive and aggressive behaviors seem to underlie these risk factors. A developmental hypothesis of suicidal behavior, with impulsive and aggressive behaviors as the starting point, is discussed.

Adult↗
PubMed2003

Suicide and serotonin: study of variation at seven serotonin receptor genes in suicide completers.

Suicide is an important public health problem, accounting for a significant proportion of total mortality among young people, particularly males. There is growing and consistent evidence suggesting that genetic factors play an important role in the predisposition to suicide. Based on several lines of evidence supporting a reduced serotonergic neurotransmission in subjects who committed suicide, we investigated variation at genes that code for serotonin receptor 1B (5-HTR1B), 1Dalpha (5-HTR1Dalpha), 1E (5-HTR1E), 1F (5-HTR1F), 2C (5-HTR2C), 5A (5-HTR5A), and 6 (5-HTR6) in a total sample of 106 suicide completers and 120 normal controls. No differences were observed in allelic or genotypic distributions between groups for any of the loci investigated. Moreover, further analysis according to suicide method or psychopathology also failed to reveal differences between groups. Our results do not support a substantial role of these serotonergic receptors in suicide completion.

Alleles↗
PubMed2003

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders.

The different 5-HT (serotonin) receptors including the serotonin transporter (5-HTT) are candidate genes for affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). They have been investigated in a number of allelic association studies where the individual results have been inconsistent, and therefore, definite conclusions are difficult to make. Systematic reviews using meta-analytical techniques are a reliable method for objectively and reproducibly assessing individual studies and generating combined result. This study aimed at reviewing published studies investigating the association between affective disorders (MDD and BD) and variation at genes coding for serotonin receptors and the serotonin transporter. We performed National Library of Medicine database searches to identify potential studies. More than 430 articles were reviewed and 86 studies met the inclusion criteria for participation in our review. Of these, 41 studies investigated 45 different 5-HT receptor variants and 45 studies investigated at least one of two commonly studied 5-HTT polymorphisms in MDD. Many studies investigated the association between MDD and BD with the 5-HT2A 102 T/C, the 5-HTT promoter 44 bp insertion/deletion and the intron 2 VNTR polymorphisms, and thus, these could be pooled using meta-analytic techniques. The overall odds ratio (OR) for the combined individual results was significant for BD and the two 5-HTT polymorphisms: Mantel-Haenszel weighted OR=1.14, CI: 1.03-1.26, P=0.015 for the promoter locus (N=3467) and Mantel-Haenszel Weighted odds ratio OR=1.18, CI: 1.05-1.32, P=0.004 for the VNTR locus (N=3620). However, sensitivity analysis indicated that, in each case, the overall positive association could be mostly attributed to the large effect of one individual study. Therefore, these results suggest that, although promising, further studies are required to assess appropriately the evidence suggesting an association between BD and 5-HTT.

Carrier Proteins↗
PubMed2003

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior.

The different serotonin (5-HT) receptors, including the serotonin transporter (5-HTT), are excellent candidate genes for suicide and suicidal behavior, and thus, they have been investigated in a large number of allelic association studies. The individual results of these studies have been inconsistent and definite conclusions are difficult to establish. A reliable method for assessing individual studies and generating combined results is provided by systematic reviews using meta-analytical techniques. In this study, we carried out a systematic review of studies investigating 5-HT receptors and the 5-HTT in suicidal behavior. Studies were identified by means of MEDLINE database searches and by scanning reference lists. More than 190 articles were reviewed and 26 met the inclusion criteria. In all, 14 studies investigated six different 5-HT receptor loci and 12 studies investigated the 5-HTT promoter 44 bp insertion/deletion polymorphism. Two specific meta-analyses were carried out, pooling studies investigating the 5-HT2A 102 T/C and the 5-HTT promoter loci that included, respectively, a total of 1599 and 2539 subjects. The combined evidence was significant for association with the 5-HTT locus (Mantel-Haenszel weighted odds ratio (M-H(w) OR)=1.17 CI : 1.04-1.32, P=0.009), but not for the 5-HT2A 102 T/C variant (M-H(w) OR)=1.09 CI : 0.93-1.27, P=0.319). The 5-HTT result was robust and remained significant following sensitivity analysis, suggesting that 5-HTT may play a role in the predisposition to suicide.

Alleles↗
PubMed2002

Effect on mood of subthalamic DBS for Parkinson's disease: a consecutive series of 24 patients.

A series of 24 consecutive PD patients were prospectively studied prior to and within 6 months postoperatively for mood, motor, and cognitive status to investigate the effects on mood of subthalamic deep brain stimulation (DBS) in PD. In six patients (25%), mood state worsened significantly, and three were transiently suicidal despite clear motor improvement. Caregivers and patients should be educated about the potential impact of this neurosurgical procedure on mood.

Adult↗
PubMed2001

Amygdala-hippocampal volume and verbal memory in first-degree relatives of schizophrenic patients.

Verbal memory deficits have been related to reduced volume of medial temporal structures in several neurological and psychiatric populations, including schizophrenic patients. Impairments in verbal memory have been proposed to be a marker of risk for schizophrenia. Recently, relatives of schizophrenic patients have been reported to have reduced volume of the amygdala-hippocampal complex. In this study, we evaluate the possibility that amygdala-hippocampal volume reductions may constitute one neural substrate of verbal memory deficits in first-degree relatives. Subjects were 20 healthy first-degree relatives of schizophrenic patients and 14 demographically similar controls. Verbal memory was assessed with the Logical Memory Test. Subjects were scanned with high-resolution MRI and the images were transformed into Talairach space. Volumes of interest were amygdala-anterior hippocampus and posterior hippocampus. Relatives of schizophrenic patients had intact immediate verbal memory but significantly poorer delayed verbal memory than controls. Relatives also had significantly reduced amygdala-anterior hippocampus volumes. Across all subjects, delayed verbal memory was significantly correlated with amygdala-anterior hippocampus volume. The magnitude of the correlation did not differ between the groups. These data provide an empirical link between memory performance and volumetric abnormalities in the amygdala-hippocampal complex in the relatives of schizophrenic patients.

Adolescent↗
PubMed2001

Clinical and neurochemical effect of acute tryptophan depletion in unaffected relatives of patients with bipolar affective disorder.

BACKGROUND: The lowering of mood induced by an acute tryptophan depletion (ATD) has been proposed as a candidate endophenotype for the vulnerability to manic-depressive illness. This study tests this hypothesis in relatives of probands from well-characterized multiplex families affected with bipolar affective disorder (BAD). METHODS: In a double-blind, crossover design, 20 unaffected relatives (URs) and 19 control subjects received either a 100-g amino acid (AA) drink devoid of tryptophan or a placebo, respectively. Clinical and biochemical effects of ATD were compared between unaffected relatives of BAD probands and age- and sex-matched control subjects. RESULTS: At 5 hours after AA drink ingestion, relative to the placebo, ATD resulted in 74% and 84% decreases in total plasma tryptophan concentrations in control subjects and relatives of patients with BAD, respectively. Unlike control subjects unaffected relatives experienced a lowering of mood during ATD but not with the placebo. Furthermore, URs tended to show increased impulsivity in the ATD condition. Measurements obtained before ingestion of the AA drink indicated that, relative to control subjects URs exhibited lower serotonin platelet concentrations, lower affinity, and fewer binding sites of the serotonin transporter for imipramine; these differences were unaffected by ATD. CONCLUSION: These results replicate and extend previous findings suggesting that URs of patients with BAD are more susceptible to low tryptophan availability. This finding may bear significance in the purported role of serotonergic mechanisms in the vulnerability to depressive syndrome and/or illness.

Acute Disease↗
PubMed2001

TPH and suicidal behavior: a study in suicide completers.

An association between the gene that codes for tryptophan hydroxylase (TPH)-the rate-limiting enzyme in the synthesis of serotonin-and suicidal behavior has been investigated with some detail in samples of living subjects who attempted suicide. In this study, we investigated TPH and suicide completion, the most severe form of suicidal behavior. A relatively large sample of suicide completers (n = 101) was genotyped at three TPH loci (two polymorphisms in the promoter region, A-6526G and G-5806T, and one in intron 7, A218C) and compared to psychiatrically normal living controls (n = 129). Although no significant differences were found between groups for genetic variation at single loci, haplotype analysis revealed that one haplotype (-6526G -5806T 218C) was significantly more frequent among suicide cases than in normal controls (chi(2) = 11.30, df = 2, P = 0.0008; OR = 2.0 CI: 1.30-3.6). Further analyses suggested that this haplotype is particularly more frequent among subjects who committed suicide using violent methods. Similar results were observed in recent haplotype analyses in suicide attempters, which found that the equivalent of haplotype -6526G -5806T 218C was more frequent in impulsive attempters (Rotondo et al, Mol Psychiatry 1999; 4: 360-368). Our results replicate in suicide completers previous data observed in suicide attempters. These and other results continue to point to the substantial role that the gene that codes for TPH may play in the neurobiology of suicidal behavior.

Genetic Predisposition to Disease↗
PubMed2001

Brain Regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder.

OBJECTIVE: Neurotransmission of serotonin (or 5-hydroxytryptamine [5-HT]) is thought to be disturbed in patients exhibiting impulsive behaviors. However, until recently it has not been possible to test this hypothesis in the brains of living humans. METHOD: Unidirectional trapping of the 5-HT precursor analog alpha-[(11)C]methyl-L-tryptophan (alpha-[(11)C]MTrp) has been proposed as an index of 5-HT synthesis capacity. The authors measured brain regional alpha-[(11)C]MTrp trapping with positron emission tomography in medication-free subjects with borderline personality disorder (N=13) and a healthy comparison group (N=11). Impulsivity was assessed by using a laboratory measure of behavioral disinhibition, go/no-go commission errors. RESULTS: Compared to healthy men, the men with borderline personality disorder had significantly lower alpha-[(11)C]MTrp trapping in corticostriatal sites, including the medial frontal gyrus, anterior cingulate gyrus, superior temporal gyrus, and corpus striatum. In the women with borderline personality disorder, significantly lower alpha-[(11)C]MTrp trapping was seen in fewer regions, but in both men and women, negative correlations with impulsivity scores were identified in the medial frontal gyrus, anterior cingulate gyrus, temporal gyrus, and striatum. CONCLUSIONS: Low 5-HT synthesis capacity in corticostriatal pathways may contribute to the development of impulsive behaviors in persons with borderline personality disorder.

Adult↗
PubMed2001

[Coronary surgery of the beating heart. First year of experience in a series of 317 non-selected coronary patients].

From May 1999 to May 2000, 317 unselected patients, representing 92.7% of all coronary artery surgery procedures, underwent open heart surgery of the beating heart by median sternotomy with the aid of a cardiac stabilising device. The main preoperative characteristics were: mean age = 66.1 years; men = 78.9%; left main stem disease = 31.8%; mean left ventricular ejection fraction = 54.1%; mean Parsonnet index = 16.9. These 317 patients were compared with a group of 303 patients who underwent coronary bypass surgery the year before by the same surgical team with cardiopulmonary bypass (CPB) and cardiac standstill. Seven hundred and eighty-six distal anastomoses were carried out in the beating heart group (2.48 grafts per patient) compared with 2.91 in the CPB group: p < 0.001). There were 10.1% single bypass, 37.5% double bypass, 47.3% triple bypass and 5% quadruple bypass procedures. A cardiopulmonary bypass was required in 13 patients (4.1%). The mortality at 30 days was 3.1% versus 4.6% in the CPB group (p = NS). The need for blood transfusion was reduced by nearly 40% in the beating heart group (23.7% versus 39.9%, p < 0.001). The incidence of cerebrovascular complications was reduced from 3% in the CPB group to 0.6% in the beating heart group (p = 0.06). The peak postoperative troponine I levels were much lower in the beating heart group (2.5 versus 6.4 ng/ml, p < 0.001). The authors conclude that surgery on the beating heart is feasible in most patients. Compared with conventional surgery under CPB, there seems to be less requirement for blood transfusion and a tendency to reduce the cerebral risk. Nevertheless, a large prospective randomised trial is required to validate the potential advantages and limitations of this technique with respect to conventional surgery and to determine the optimal indications of surgery on the beating heart.

Adult↗
PubMed2000

Functional neuroanatomy of smooth pursuit and predictive saccades.

We used PET to study differences in cerebral blood flow (CBF) in smooth pursuit, predictive saccades and fixation. Eye movements were monitored in the scanner. Compared with fixation, pursuit and predictive saccades activated a network of highly similar areas, including frontal eye fields, supplementary eye fields, V5 and medial cuneus. Our findings are consistent with non-human primate studies that suggest that pursuit and saccades are controlled by similar and adjacent neural areas. Pursuit was associated with greater activation of caudate than saccades, suggesting a role for basal ganglia in pursuit that is consistent with studies of neurological populations. Saccades were associated with greater activation of cerebellum and frontal eye fields. A frontal-cerebellar loop may be important in coordinating the preparation and timing of saccades in predictive tracking.

Adult↗
PubMed2000

Effects on mood of acute phenylalanine/tyrosine depletion in healthy women.

Catecholamines have been implicated in the etiology and pathophysiology of mood and anxiety disorders. In the present study, we investigated the effects of experimentally reducing catecholamine neurotransmission by means of acute phenylalanine/tyrosine depletion (APTD). Healthy female volunteers ingested: (1) a nutritionally balanced amino acid (AA) mixture (n = 14); (2) a mixture deficient in the serotonin precursor, tryptophan (n = 15); or (3) one deficient in the catecholamine precursors, phenylalanine and tyrosine (n = 12). Mood was measured at three times: at baseline and both immediately before and after an aversive psychological challenge (public speaking and mental arithmetic) conducted 5 hours after AA mixture ingestion. Acute tryptophan depletion (ATD) lowered mood and energy and increased irritability scores. These effects were statistically significant only after the psychological challenge. The effect of APTD on mood was similar to that of ATD. APTD did not attenuate the anxiety caused by the psychological challenge. These findings suggest that, in healthy women, reduced serotonin and/or catecholamine neurotransmission increases vulnerability to lowered mood, especially following exposure to aversive psychological events.

Adult↗
PubMed2000

Association between the methylenetetrahydrofolate reductase 677C-->T missense mutation and schizophrenia.

The schizophrenia phenotype is heterogeneous with respect to clinical presentation, long-term response to medication, and outcome, possibly reflecting genetic heterogeneity and/or the presence of modifier genes. Compared to non-responders, schizophrenic patients who are responders to neuroleptic medications are characterized by a high female/male ratio, a better long-term outcome and more frequently disturbed dopamine neurotransmission. In this study, we compared two groups of schizophrenic patients selected on the basis of their long-term response to neuroleptics (excellent responders and non-responders) and a group of healthy volunteers, with regard to a missense mutation (677C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene. This polymorphism was chosen because it is functional and was previously associated with schizophrenia. The present study revealed a significant association between schizophrenia and allele T of this gene. This association was entirely due to an over-representation of allele T in responder patients compared to controls; nonresponder patients did not differ from controls. Genotype TT was more frequent in responder patients compared to controls, thus replicating the findings of Arinami et al. These results strongly suggest that the MTHFR gene is involved in the pathogenesis of schizophrenia characterized by a rapid and sustained therapeutic response to typical neuroleptics and/or a good long-term prognosis/favorable therapeutic outcome.

Adult↗
PubMed2000

Depressive relapse following acute tryptophan depletion in patients with major depressive disorder.

Acute tryptophan depletion (ATD) lowers serotonin synthesis and elicits depressive symptoms in some, though not all, remitted patients with major depressive disorder (MDD). In the present study, eight medication-free remitted patients with MDD, seasonal pattern, were tested twice, once following the ingestion of a tryptophan-containing mixture, once following ATD. ATD significantly increased Hamilton depression scores (p < 0.001). Four of the patients had a family history of psychiatric disorders: substance abuse (n = 4), mood disorders (n = 3) or Cluster B personality disorders (n = 3). The mood-lowering response to ATD was significantly greater in those patients with, than without, affected relatives (p < 0.001). These preliminary findings (1) support the hypothesis that depressed states are related to disturbed serotonin neurotransmission and (2) suggest that depressive symptoms following ATD might identify a subgroup of patients at high genetic risk for disorders associated with affective lability and dysregulated impulse-control, conditions thought to be related to low serotonin neurotransmission.

Adult↗