Next-generation sequencing of patients with congenital anosmia.

We performed whole exome or genome sequencing in eight multiply affected families with ostensibly isolated congenital anosmia. Hypothesis-free analyses based on the assumption of fully penetrant recessive/dominant/X-linked models obtained no strong single candidate variant in any of these families. In total, these eight families showed 548 rare segregating variants that were predicted to be damaging, in 510 genes. Three Kallmann syndrome genes (FGFR1, SEMA3A, and CHD7) were identified. We performed permutation-based analysis to test for overall enrichment of these 510 genes carrying these 548 variants with genes mutated in Kallmann syndrome and with a control set of genes mutated in hypogonadotrophic hypogonadism without anosmia. The variants were found to be enriched for Kallmann syndrome genes (3 observed vs. 0.398 expected, p = 0.007), but not for the second set of genes. Among these three variants, two have been already reported in genes related to syndromic anosmia (FGFR1 (p.(R250W)), CHD7 (p.(L2806V))) and one was novel (SEMA3A (p.(T717I))). To replicate these findings, we performed targeted sequencing of 16 genes involved in Kallmann syndrome and hypogonadotrophic hypogonadism in 29 additional families, mostly singletons. This yielded an additional 6 variants in 5 Kallmann syndrome genes (PROKR2, SEMA3A, CHD7, PROK2, ANOS1), two of them already reported to cause Kallmann syndrome. In all, our study suggests involvement of 6 syndromic Kallmann genes in isolated anosmia. Further, we report a yet unreported appearance of di-genic inheritance in a family with congenital isolated anosmia. These results are consistent with a complex molecular basis of congenital anosmia.

Olfactory function and alternation learning in eating disorders.

Orbitofrontal dysfunction is a prominent feature of obsessive compulsive disorder (OCD). In the present study we assessed orbitofrontal functioning in eating disorders (EDs) which share many features with OCD. For this purpose we studied female adolescent inpatients with anorexia nervosa restricting type (n=40), anorexia nervosa binge/purge type (n=23), a normal weight group including patients with either bulimia nervosa or eating disorder not otherwise specified-purging type (n=33), and 20 non-ED control females. Patients were assessed at admission, and when achieving weight restoration and symptom stabilization at discharge, for depression, non-ED, and ED-related OC symptoms. Orbitofrontal functioning was assessed with an alternation learning task, and with a battery assessing olfactory threshold and discrimination. Control females were assessed once. ED patients of all subtypes performed better on olfactory threshold and discrimination, but not on alternation learning, in comparison to healthy controls. More favorable orbitofrontal functioning was associated with greater ED-related obsessionality. No changes were found in olfactory threshold and discrimination between acutely-ill and symptomatically-stabilized patients. The improvement shown in alternation learning from admission to discharge was suggested to reflect a learning effect rather than being an actual change. Our findings suggest that the better orbitofrontal functioning of ED patients in comparison to healthy controls may represent a core feature of the ED that is independent of malnutrition and deranged eating behaviors, but is associated with ED-related obsessionality.

Alternation learning in pathological gamblers: an fMRI Study.

OBJECTIVES: We have previously reported that pathological gamblers have impaired performance on the Stroop color word naming task, go-no-go task and speed accuracy tradeoff performance, tasks used to assess executive function and interference control. The aim of the present neuroimaging study was to explore the relationship between frontal cortex function and gambling severity in pathological gamblers. MATERIALS AND METHODS: Functional MRI (fMRI) was used to estimate brain activity of ten male medication-free pathological gamblers during performance of an alternation learning task. Performance of this task has been shown to depend on the function of regions in the frontal cortex. RESULTS: The executive functions needed to perform the alternation learning task were expressed as brain activation in lateral and medial frontal as well as parietal and occipital regions. By correlating the level of local brain activation to task performance, parietal regions and lateral frontal and orbitofrontal regions were demonstrated. A higher score in SOGS was associated with intrusion on the task-specific activation in the left hemisphere, to some extant in parietal regions and even more pronouncedly in left frontal and orbitofrontal regions. CONCLUSIONS: Our preliminary data suggests that pathological gambling may be characterized by specific neuro-cognitive changes related to the frontal cortex.

Alteration learning in social anxiety disorder: an fMRI study.

The present study attempts to challenge the orbitofrontal cortex by using a learning paradigm which is specifically subserved by this cortical region. We implemented a version of alternation learning specifically designed for fMRI and assessed the cognitive performance and fMRI response in wide range of social anxiety disorder (SAD) severity (n=15). The main regions that were activated by the alternation learning task included portions of frontal and orbitofrontal cortex as well as the calcarine fissure. Correlations between brain activation and performance of the alternation learning task were found, among other regions, in the left and right orbitofrontal cortex. Highest correlations between degree of activation and the anxiety scores as assessed by the Leibovitch Social Anxiety Scale (LSAS) were obtained in the left temporal region as well as orbitofrontal cortex. This study supports the involvement of the orbitofrontal cortex in emotion and cognitive regulation in SAD.

Zolmitriptan compared to propranolol in the treatment of acute neuroleptic-induced akathisia: a comparative double-blind study.

Neuroleptic-induced akathisia (NIA) is a common, sometimes incapacitating adverse effect of anti-psychotic medication. Zolmitriptan is a selective 5-HT(1D) agonist. We aimed to determine its anti-NIA efficacy in comparison to propranolol. Thirty-three neuroleptic-treated patients were randomly allocated in a double-blind design to receive either 7.5 mg/d of zolmitriptan or 120 mg/d of propranolol for 3 consecutive days, followed by 3 days without any anti-NIA treatment. Patients were assessed at baseline and on days 3 and 7 by the Barnes Akathisia Rating Scale (BARS), PANSS, HAMD, HAMA, Pulse, and Blood Pressure. Both groups showed improvement of akathisia (BARS) along the treatment period, with significant effect for time but not for group. No significant differences were found between the groups in all other measurements. Taken together, zolmitriptan was found to be as effective as propranolol for the treatment of NIA. Further placebo-controlled studies are warranted.

In vivo occipital-frontal temperature-gradient in schizophrenia patients and its possible association with psychopathology: a magnetic resonance spectroscopy study.

BACKGROUND: Accumulating data suggest that schizophrenia patients' mental status might be modulated by their core/brain temperature. Hence, we intended to assess in vivo brain temperature (Tb) of schizophrenia patients vs. healthy subjects and to evaluate its potential association with patients' mental status. METHODS: Absolute values of Tb were measured in 9 neuroleptic-treated schizophrenia patients and 10 healthy comparison subjects using 1H magnetic resonance spectroscopy (MRS). Values were extracted by measuring the chemical shift between the peaks of water and N-acetyl-aspartate in the 1H MRS spectra. RESULTS: A substantial (about 1.1 degrees C) and significantly higher occipital-frontal temperature-gradient was found in the schizophrenia patients compared to the healthy controls (1.27 degrees C vs. 0.18 degrees C; p=0.032). Furthermore, a trend was found between the above mentioned occipital-frontal temperature-gradient in the schizophrenia patients and the severity of their psychopathology, as assessed by the total Positive and Negative Syndrome Scale (PANSS) scores (r=0.61; p=0.08). CONCLUSIONS: Our findings corroborate previous results indicating putative correlation between core/brain temperature and the mental status of schizophrenia patients, emphasizing the possible role of within patients decreased frontal temperature and a significant occipital-frontal temperature-gradient as modulators of psychopathology. In addition, the MRS technique used for brain temperature assessment seems to be a potential non-invasive method to assess in vivo absolute Tb in schizophrenia.

Spatial attention and neural asymmetry in obsessive-compulsive disorder.

Patterns of lateralized dysfunction in obsessive-compulsive disorder (OCD) were examined using the Posner spatial attention paradigm. While controls responded faster to left visual field targets than to right, patients lacked this asymmetry. The difference in asymmetry patterns was significant for the invalid cue condition, but not for the valid cue condition. Reversal of normal asymmetry was correlated with obsession severity. Findings support aberrant hemispheric balance in OCD.

Mutations in olfactory signal transduction genes are not a major cause of human congenital general anosmia.

Anosmia affects the western world population, mostly the elderly, reaching to 5% in subjects over the age of 45 years and strongly lowering their quality of life. A smaller minority (about 0.01%) is born without a sense of smell, afflicted with congenital general anosmia (CGA). No causative genes for human CGA have been identified yet, except for some syndromic cases such as Kallman syndrome. In mice, however, deletion of any of the 3 main olfactory transduction components (guanidine triphosphate binding protein, adenylyl cyclase, and the cyclic adenosine monophosphate-gated channel) causes profound reduction of physiological responses to odorants. In an attempt to identify human CGA-related mutations, we performed whole-genome linkage analysis in affected families, but no significant linkage signals were observed, probably due to the small size of families analyzed. We further carried out direct mutation screening in the 3 main olfactory transduction genes in 64 unrelated anosmic individuals. No potentially causative mutations were identified, indicating that transduction gene variations underlie human CGA rarely and that mutations in other genes have to be identified. The screened genes were found to be under purifying selection, suggesting that they play a crucial functional role not only in olfaction but also potentially in additional pathways.

Adjustment disorder: a review of diagnostic pitfalls.

Adjustment disorder is a common diagnosis in psychiatric settings and carries a significant rate of morbidity and mortality. However, both current and previous diagnostic criteria are vague and lead to many difficulties in terms of validity and reliability. This review is based on a thorough literature search and a systematic evaluation of the empiric and theoretic data. The various pitfalls inherent in the process of diagnosing this disorder are discussed in light of the diagnostic criteria for the disorder.

Nasal airflow and olfactory function after the repair of cleft palate (with and without cleft lip).

OBJECTIVE: The objective of this study was to examine nasal airflow and olfactory functions in patients with repaired cleft palate compared with matching normal controls. STUDY DESIGN: The all-cleft group consisted of 25 patients with hard palate cleft comprising 15 patients with unilateral cleft palate and lip (UCLP); 2 with CP but no cleft lip (UCLP subgroup) and 8 patients with bilateral cleft lip and palate (BCLP subgroup). All had had surgical correction of the palate in infancy. The control group consisted of 20 nonaffected orthodontic patients. The median age of both groups was 14 years. The tests included the following: (1) nasal airflow measured by anterior rhinomanometry, (2) smell threshold for isoamyl-acetate determined using a 3-way forced choice method, (3) a self-administered questionnaire regarding the subjective perception of smell sense function, and (4) orthonasal and retronasal smell identification (correct/incorrect) and hedonics using visual analog scale (VAS). RESULTS: The respective test results follow. (1) When compared with the control group, the total airflow in the UCLP subgroup was significantly lower especially on the affected side; while in the BCLP subgroup it was lower than in the control group bilaterally. No significant difference was found between the cleft side of UCLP and BCLP subgroups. (2) The smell threshold of the UCLP subgroup was significantly higher than that of the control group and BCLP subgroup. No significant differences were found between right and left nostrils within the BCLP patients and between them and the control group. (3) No difference was found between the groups regarding the subjective perception of smell. (4) No significant differences were found between the UCLP and BCLP subgroups and between the all-cleft group and the control group, except for one item, regarding orthonasal and retronasal smell identification and hedonics. CONCLUSION: Although nasal airflow is significantly lower and the smell threshold higher on the cleft side, the day-to-day function of the sense of smell of cleft patients is similar to that of normal controls.

Corneal temperature in schizophrenia patients.

Most data imply that dopaminergic transmission is essential for proper hypothalamic-mediated core temperature regulation. Altered central dopaminergic transmission is suggested to be involved in the pathophysiology of schizophrenia. Thus, hypothetically, schizophrenia patients might be at increased risk of developing thermoregulatory dysregulation manifested by alterations in core temperature, as well as in peripheral tissue, the temperature of which has been shown to correlate with core temperature (e.g. cornea). Previous small pilot studies of ours showed that schizophrenia patients may exhibit corneal temperature abnormalities. Hence, we assessed corneal temperature in a controlled sample of drug-free ( n =11) and medicated ( n =28) schizophrenia patients compared to healthy comparison subjects ( n =9), using a FLIR thermal imaging camera. Drug-free schizophrenia patients exhibited significantly higher corneal temperature compared to healthy subjects, typical antipsychotic drug (APD)-treated patients ( n =16) and atypical APD-treated patients ( n =12) (37.08+/-1.46 degrees C vs. 33.37+/-2.51 degrees C, 31.08+/-1.43 degrees C and 31.67+/-0.44 degrees C respectively, p <0.0001; p <0.001 vs. each group separately). The healthy comparison subjects and the atypical APD-treated patients exhibited comparable corneal temperatures and these two groups exhibited higher corneal temperatures compared to the typical APD-treated patients ( p <0.01 and p =0.051 respectively). In conclusion, this study indicates that drug-free schizophrenia patients exhibit substantially higher corneal temperature compared to healthy comparison subjects or medicated patients, and that APDs may decrease corneal temperature either to normal (atypical APD) or to subnormal (typical APD) values. The relevance of these phenomena to the pathophysiology of schizophrenia, the biological mechanism underlying drug-induced corneal temperature alterations, the possible role of temperature-lowering drugs (neuroleptics or non-neuroleptics) on schizophrenic psychosis as well as the role of corneal temperature as a tool to evaluate adherence to APD treatment merit further investigation via larger samples of both medicated and drug-free schizophrenia patients compared to matched controlled subjects.

Impaired procedural learning in obsessive-compulsive disorder and Parkinson's disease, but not in major depressive disorder.

The striatum has been consistently implicated in the pathophysiology of obsessive-compulsive disorder (OCD), yet, studies assessing the performance of OCD patients in procedural learning tasks, assumed to rely on the intact functioning of the striatum, have yielded inconsistent results. Recently, Rauch et al. [Rauch SL, Savage CR, Alpert NM, Dougherty D, Kendrick A, Curran T, et al. Probing striatal function in obsessive-compulsive disorder: a PET study of implicit sequence learning. J Neuropsychiatry Clin Neurosci 1997;9:568-73] have obtained evidence suggesting that seemingly intact performance of OCD patients in such tasks may be achieved by recruiting systems which in normal subjects are reserved for explicit or declarative, rather than implicit or procedural, processing. The present study assessed procedural learning in OCD patients using a card betting task in which explicit processing impairs, rather than assists, acquisition. In addition, we tested a group of Parkinson's disease (PD) patients, in order to better establish the dependence of the task on procedural learning, and a group of major depressive disorder (MDD) patients, in order to test the possibility that impaired learning in the card betting task may be a result of concurrent depression. The majority of OCD (15/18) and PD patients (14/16) did not acquire the task, whereas MDD patients acquired the task similarly to normal control subjects. These results demonstrate that OCD patients are impaired on a procedural learning task in which explicit processing impairs acquisition. Two different interpretations are suggested: that the striatal system is dysfunctional in OCD, or that inappropriate explicit processing in OCD interferes with the functioning of the striatal system.

The 5-HT1D receptor agonist zolmitriptan for neuroleptic-induced akathisia: an open label preliminary study.

Neuroleptic-induced akathisia (NIA) is a common, sometimes incapacitating, adverse side-effect of antipsychotic drugs (APDs). Several non-selective post-synaptic 5-HT2 blockers have shown a beneficial antiakathisic effect. We hypothesized that selective stimulation of the presynaptic 5-HT1D serotonergic inhibitory autoreceptor could also be beneficial in NIA. The study group included eight schizophrenia inpatients with acute or chronic NIA who were treated with unchanged doses of APDs. Participants received, in an open-labelled design, 7.5 mg/day of zolmitriptan (selective 5-HT1D agonist) for 3 consecutive days. Positive and Negative Syndrome Scale and Barnes akathisia scale (BAS) scores were monitored before and at the end of the study. BAS score decreased by 5.25 points following zolmitriptan administration (9.0+/-2.27 to 3.75+/-2.55, t=6.1, d.f.=7, P=0.0005). In one case, the BAS score dropped from a 3-year score >or=9 points (while relatively non-responsive to numerous antiakathisic agents) to 4 points at endpoint. In conclusion, zolmitriptan appears to exert significant and rapid beneficial antiakathisic effect, even in chronic and resistant NIA. Larger, long-term, double-blind, placebo- and comparator- (e.g. propranolol) controlled studies are required to substantiate the efficacy, safety and tolerability of zolmitriptan, as well as the role of serotonergic neurotransmission in NIA.

Serotonergic dissection of obsessive compulsive symptoms: a challenge study with m-chlorophenylpiperazine and sumatriptan.

We have conducted a pharmacological challenge experiment in 10 medication-free obsessive compulsive (OC) disorder (OCD) patients. We used a placebo-controlled paradigm for m-chlorophenylpiperazine (mCPP) and sumatriptan challenges. Endocrine, physiological and behavioral variables were assessed at baseline and over a 3-hour period after the challenge. Both cortisol and prolactin were significantly elevated in OCD patients following mCPP administration. Both mCPP and sumatriptan caused significant OC symptom exacerbation with the response to sumatriptan being more robust. We conclude that the 5-HT(1Dbeta) receptor may play a role in the pathophysiology of OCD.

Musical hallucinations: prevalence in psychotic and nonpsychotic outpatients.

BACKGROUND: Musical hallucinations have been considered a rare manifestation of psychotic states or brain and hearing abnormalities. However, an obsessive-compulsive disorder (OCD) assessment tool refers to musical hallucinations and our preliminary study showed that about one third of OCD patients experienced musical hallucinations. AIMS: To elucidate the lifetime prevalence of musical hallucinations among psychotic and nonpsychotic psychiatric outpatients. METHODS: Lifetime experience of musical hallucinations was examined with a specially designed structured interview in 190 consecutive outpatients with diagnoses of anxiety, affective, and schizophrenia disorders. RESULTS: Musical hallucinations occurred in more than one fifth of all diagnoses. The prevalence of musical hallucinations was highest in OCD patients (41%). Musical hallucinations were significantly more frequent with more comorbid disorders, and logistic regression revealed that this finding was mainly due to OCD combined with either social phobia or schizophrenia. CONCLUSION: Musical hallucinations are more common among psychiatric patients than previously reported and are more suggestive of OCD than of other mental disorders.

Neuroimaging communality between schizophrenia and obsessive compulsive disorder: a putative basis for schizo-obsessive disorder?

Four major brain regions have been repeatedly implicated in the pathophysiology of obsessive compulsive disorder (OCD) in in vivo neuroimaging studies: the caudate nucleus, the orbitofrontal cortex, the anterior cingulate gyrus and the mediodorsal thalamic nucleus. The present review describes the neuroimaging studies on schizophrenia, pertaining to these brain regions. Our working hypothesis is that such common brain regions, if dysfunctional in schizophrenic patients, would be candidates for a neural network subserving the newly emerging syndrome of schizo-obsessive disorder. Findings, though, are controversial. We conclude that further studies, aimed at specific monitoring of these brain regions, in patients suffering from the schizo-obsessive syndrome are warranted.

Alternation learning in OCD/schizophrenia patients.

In continuation of our previous studies on orbitofrontal cortex function in obsessive compulsive disorder (OCD) we studied a group of OCD patients with schizophrenia in comparison with a group of schizophrenia patients. In order to test orbitofrontal cortex function we again used an alternation learning task. We found no difference between the two groups in the performance of this task. The relationship between severity of OC symptoms and alternation learning was curvilinear. Thus, in the low range of symptom severity the correlation between alternation learning and symptom severity was negative, while in the high range it was positive. The positive correlation in the severely affected patients is essentially the same as that found in severe "pure" OCD patients, which we have previously reported. We conclude that the data indicate independent orbitofrontal cortex function in OCD, irrespective of comorbidity.