Happy Birthday "One Flew Over the Cuckoo's Nest": A Momentous Tale in the Quest for an Effective and Ethical Approach to Psychosurgery.

The anniversary of the publication of 'One Flew Over the Cuckoo's Nest' by Ken Kesey offers an opportunity for reflection on the use of neurosurgery in psychiatry. We used a narrative, historical and dialectical method to deliver an account of the controversial subject. A balanced representation of the negative and positive aspects, acknowledging some of the questionable ethical practices while describing well-reasoned applications is provided. It includes neurosurgeons, psychiatrists who have embraced these procedures with unwarranted enthusiasm and those who have opposed. Neurosurgical techniques for the treatment of severe mental disorders have evolved from rudimentary procedures which were used to 'correct' unwanted behaviours associated with a wide range of severe mental disorders to more refined and selective approaches used as a last resort to treat specific mental health conditions. In the absence of specific aetiological models to guide ablative surgical targets, non-ablative, stimulatory techniques have more recently been developed to allow reversibility when surgical treatment fails to obtain a sizeable improvement in quality of life. The subject is concretely illustrated by two eloquent clinical images: one on a series of brain computed tomography scans carried out on a Canadian population of subjects, who underwent leukotomy decades ago, and the other more contemporary on an implantation surgery to epidural stimulation. Alongside technical advances in psychosurgery, a regulatory framework has gradually developed to ensure vigilance in the appropriateness of patients' selection. Nevertheless, harmonisation of protocols around the world is necessary to ensure consistency in obtaining and maintaining the highest possible ethical standards for the benefit of patients. If the neurosciences promise today, in their new, better framed, and reversible applications, to provide answers to unmet therapeutic needs, we still must remain attentive to drifts linked the introduction of intrusive technologies for purposes of domination or behaviour modification that would impede our individual freedom.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

Short-term and long-term measures of cortisol in saliva and hair in atypical and non-atypical depression.

BACKGROUND: Atypical depression may show lowered rather than raised short-term cortisol levels. Atypical major depressive episodes (A-MDE) may also be more closely linked to environmental factors and show overlap with somatic symptom disorders. Hair specimens allow measuring long-term cortisol levels. METHODS: Twenty-seven A-MDE and 44 NA-MDE patients and 40 matched controls were tested. Measures of hair cortisol concentration [HCC] covering the previous 3 months and short-term cortisol parameters (six saliva specimens to assess the cortisol awakening response [CAR] and total daily cortisol output calculated as the area under the curve [AUCg]) were taken alongside measures of environmental factors and clinical variables. RESULTS: There were no differences in HCC between the three groups (P = 0.8), and no difference in the CAR (P = 0.95). However, A-MDE showed lowered short-term cortisol output (AUCg) compared to controls (P = 0.04). A-MDE patients also reported a higher number of daily hassles, and higher levels of fatigue and impaired concentration than NA-MDE. CONCLUSIONS: Normal long-term (HCC) and reduced short-term (AUCg) cortisol levels in A-MDE could suggest a disrupted long-term cortisol rhythm, perhaps affected by environmental factors or by certain symptoms, such as mid-nocturnal insomnia. However, other underlying explanations for these findings should also be investigated in the future.

A morphometric signature of depressive symptoms in unmedicated patients with mood disorders.

OBJECTIVE: A growing literature indicates that unipolar depression and bipolar depression are associated with alterations in grey matter volume. However, it is unclear to what degree these patterns of morphometric change reflect symptom dimensions. Here, we aimed to predict depressive symptoms and hypomanic symptoms based on patterns of grey matter volume using machine learning. METHOD: We used machine learning methods combined with voxel-based morphometry to predict depressive and self-reported hypomanic symptoms from grey matter volume in a sample of 47 individuals with unmedicated unipolar and bipolar depression. RESULTS: We were able to predict depressive severity from grey matter volume in the anteroventral bilateral insula in both unipolar depression and bipolar depression. Self-reported hypomanic symptoms did not predict grey matter loss with a significant degree of accuracy. DISCUSSION: The results of this study suggest that patterns of grey matter volume alteration in the insula are associated with depressive symptom severity across unipolar and bipolar depression. Studies using other modalities and exploring other brain regions with a larger sample are warranted to identify other systems that may be associated with depressive and hypomanic symptoms across affective disorders.

Resting-state brain alteration after a single dose of SSRI administration predicts 8-week remission of patients with major depressive disorder.

BACKGROUND: The present study investigated alteration of brain resting-state activity induced by antidepressant treatment and attempted to investigate whether treatment efficacy can be predicted at an early stage of pharmacological treatment. METHOD: Forty-eight first-episode medication-free patients diagnosed with major depression received treatment with escitalopram. Resting-state functional magnetic resonance imaging was administered prior to treatment, 5 h after the first dose, during the course of pharmacological treatment (week 4) and at endpoint (week 8). Resting-state activity was evaluated in the course of the 8-week treatment and in relation to clinical improvement. RESULTS: Escitalopram dynamically modified resting-state activity in depression during the treatment. After 5 h the antidepressant induced a significant decrease in the signal in the occipital cortex and an increase in the dorsolateral and dorsomedial prefrontal cortices and middle cingulate cortex. Furthermore, while remitters demonstrated more obvious changes following treatment, these were more modest in non-responders suggesting possible tonic and dynamic differences in the serotonergic system. Changes after 5 h in the caudate, occipital and temporal cortices were the best predictor of clinical remission at endpoint. CONCLUSIONS: This study revealed the possibility of using the measurement of resting-state neural changes a few hours after acute administration of antidepressant to identify individuals likely to remit after a few weeks of treatment.

State-dependent changes in hippocampal grey matter in depression.

Reduced hippocampal volume has been reported in depression and may be involved in the aetiology of depressive symptoms and vulnerability to depressive relapse. Neuroplasticity following antidepressant drug treatment in the hippocampus has been demonstrated in animal models but adaptive changes after such treatment have not been shown in humans. In this study, we determined whether grey matter loss in the hippocampus in depression (1) is present in medication-free depressed (2) changes in response to antidepressant treatment and (3) is present as a stable trait in medication-free remitted patients. Sixty-four medication-free unipolar depressed patients: 39 currently depressed and 25 in remission, and 66 healthy controls (HC) underwent structural magnetic resonance imaging in a cross-sectional and longitudinal design. Thirty-two currently depressed participants were then treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring plasma citalopram concentration. We measured regional variation in grey matter concentration by using voxel-based morphometry-Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra. Patients with current depression had bilaterally reduced grey matter in the hippocampus compared with HC and untreated patients in stable remission with the latter groups not differing. An increase in grey matter was observed in the hippocampus following treatment with citalopram in currently depressed patients. Grey matter reduction in the hippocampus appears specific to the depressed state and is a potential biomarker for a depressive episode.

Interaction between a history of depression and rumination on neural response to emotional faces.

BACKGROUND: Both past depressive episodes and the personality trait of depressive rumination are strong risk factors for future depression. Depression is associated with abnormal emotional processing, which may be a neurobiological marker for vulnerability to depression. A consistent picture has yet to emerge as to how a history of depression and the tendency to ruminate influence emotional processing. The aim of this study was to investigate the relationship between rumination, past depression and neural responses when processing face emotions. METHOD: The Ruminative Responses Scale (RRS) was completed by 30 remitted depressives and 37 controls who underwent functional magnetic resonance imaging (fMRI) scanning while viewing happy, sad, fearful and neutral faces. RESULTS: The remitted depressives showed overall reductions in neural responses to negative emotions relative to the controls. However, in the remitted depressives, but not the controls, RRS scores were correlated with increased neural responses to negative emotions and decreased responses to happiness in limbic regions. CONCLUSIONS: Automatic emotion processing biases and rumination seem to be correlated to aspects of vulnerability to depression. However, remission from depression may be maintained by a general suppression of limbic responsiveness to negative emotion.

Autism, ethnicity and maternal immigration.

BACKGROUND: A growing number of European studies, particularly from Nordic countries, suggest an increased frequency of autism in children of immigrant parents. In contrast, North American studies tend to conclude that neither maternal ethnicity nor immigrant status are related to the rate of autism-spectrum disorders. AIMS: To examine the hypotheses that maternal ethnicity and/or immigration are linked to the rate of childhood autism-spectrum disorders. METHOD: Retrospective case-note analysis of all 428 children diagnosed with autism-spectrum disorders presenting to the child development services in two centres during a 6-year period. RESULTS: Mothers born outside Europe had a significantly higher risk of having a child with an autism-spectrum disorder compared with those born in the UK, with the highest risk observed for the Caribbean group (relative risks (RRs) in the two centres: RR = 10.01, 95% CI 5.53-18.1 and RR = 8.89, 95% CI 5.08-15.5). Mothers of Black ethnicity had a significantly higher risk compared with White mothers (RR = 8.28, 95% CI 5.41-12.7 and RR = 3.84, 95% CI 2.93-5.02). Analysis of ethnicity and immigration factors together suggests the increased risk is predominately related to immigration. CONCLUSIONS: Maternal immigration is associated with substantial increased risk of autism-spectrum disorders with differential risk according to different region of birth and possibly ethnicity.

Detection of tulobuterol crystal in transdermal patches using terahertz pulsed spectroscopy and imaging.

Applicability of a Terahertz Pulsed Spectroscopy (TPS) and a Terahertz Pulsed Imaging (TPI) for detection of tulobuterol (TBR) crystals in transdermal patches was investigated. Because TBR has high permeability in dermis, crystalline TBR in patch matrices contributes to controlling the release rate of TBR from a matrix. Therefore, crystalline TBR is one of the important factors for quality control of TBR transdermal tapes. A model tape that includes 5 w/w%, 10 w/w%, 20 w/w% or 30 w/w% of TBR was measured by TPS/TPI. TBR crystals in the matrices were successfully detected by TPI. Identification of TBR in an image of a crystal-like mass was done by comparison between the spectra of tapes and a TBR standard substance. These results indicate that TPS and TPI are applicable to identifying crystalline lumps of an active drug in tapes for quality control.

Meta-analysis of magnetic resonance imaging studies of the corpus callosum in schizophrenia.

OBJECTIVES: The corpus callosum plays a pivotal role in inter-hemispheric transfer and integration of information. Magnetic resonance studies have reported callosal abnormalities in schizophrenia but findings have been inconsistent. Uncertainty has persisted despite a meta-analytic evaluation of this structure several years ago. We set out to perform a further meta-analysis with the addition of the numerous reports published on the subject to test the hypothesis that the corpus callosum is abnormal in schizophrenia. METHOD: A systematic search was carried out to identify suitable magnetic resonance studies which reported callosal areas in schizophrenia compared to controls. Results from the retrieved studies were compared in a meta-analysis whilst the influence of biological and clinical variables on effect size was ascertained with meta-regression analysis. RESULTS: Twenty-eight studies were identified. Corpus callosum area was reduced in schizophrenia in comparison to healthy volunteers. This effect was larger in first episode patients. Similarly, heterogeneity detected among the studies was associated with course of illness indicating that chronic subjects with schizophrenia showed larger callosal areas. There was no evidence of publication bias. CONCLUSIONS: This study confirms the presence of reduced callosal areas in schizophrenia. The effect is of a larger magnitude at first presentation and less so in subjects with a chronic course generally medicated with antipsychotics.

Meta-analysis of magnetic resonance imaging studies of the corpus callosum in bipolar disorder.

OBJECTIVE: The corpus callosum (CC) plays a pivotal role in inter-hemispheric transfer and integration of information and is a relatively understudied structure in bipolar disorder (BD). Magnetic resonance imaging (MRI) studies have reported callosal abnormalities in this condition but findings have been inconsistent. Structural changes affecting the CC may underlie functional abnormalities in BD and could contribute to, or explain the pathophysiology of, the condition. METHOD: A systematic review was carried out to identify, appraise and summarize MRI studies which compared callosal areas in BD with an unrelated control group. The findings were then synthesized using random effects meta-analysis. Consideration was given to a number of variables to explain heterogeneity. RESULTS: Five case-control studies were identified. Bipolar patients showed reduced callosal areas in comparison with healthy volunteers with no evidence of heterogeneity or publication bias. CONCLUSION: Findings from this study indicate that callosal areas are reduced in BD and suggest that a failure to integrate information across the hemispheres may contribute to the pathophysiology of the disorder. Further research is necessary to clarify the underlying cellular changes leading to these morphometric differences.

The effects of serotonin modulation on medial prefrontal connectivity strength and stability: A pharmacological fMRI study with citalopram.

BACKGROUND: Static and dynamic functional connectivity are being increasingly used to measure the effects of disease and a range of different interventions on brain networks. While preliminary evidence suggests that static connectivity can be modulated by chronic antidepressants administration in healthy individuals and in major depression, much less is known about the acute effects of antidepressants especially on dynamic functional connectivity changes. Here we examine acute effects of antidepressants on dynamic functional connectivity within the default mode network. The default mode network is a well described network with many functions in which the role of serotonin is not clear. METHODS: In this work we measured acute pharmacological effects of an infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram (10 mg) in a sample of thirteen healthy volunteers randomised to receive on two occasions the active compound or placebo in a cross over dosing. RESULTS: Acute citalopram administration relative to placebo increased static connectivity between the medial prefrontal cortex and right dorsolateral prefrontal cortex and posterior cingulate cortex. The SSRI also induced a reduction in variability of connectivity with the medial prefrontal cortex in the precuneus and posterior cingulate cortex. DISCUSSION: The measured changes are compatible with modified serotonin cortical availability.

Instability of default mode network connectivity in major depression: a two-sample confirmation study.

Major depression is associated with altered static functional connectivity in various brain networks, particularly the default mode network (DMN). Dynamic functional connectivity is a novel tool with little application in affective disorders to date, and holds the potential to unravel fluctuations in connectivity strength over time in major depression. We assessed stability of connectivity in major depression between the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), key nodes in the DMN that are implicated in ruminative cognitions. Functional connectivity stability between the mPFC and PCC over the course of a resting-state functional magnetic resonance imaging (fMRI) scan was compared between medication-free patients with major depression and healthy controls matched for age, sex and handedness. We tested replicability of the results in an independent sample using multi-echo resting-state fMRI. The primary sample included 20 patients and 19 controls, while the validation sample included 19 patients and 19 controls. Greater connectivity variability was detected in major depression between mPFC and PCC. This was demonstrated in both samples indicating that the results were reliable and were not influenced by the fMRI acquisition approach used. Our results demonstrate that alterations within the DMN in major depression go beyond changes in connectivity strength and extend to reduced connectivity stability within key DMN regions. Findings were robustly replicated across two independent samples. Further research is necessary to better understand the nature of these fluctuations in connectivity and their relationship to the aetiology of major depression.

Inflammation and clinical response to treatment in depression: A meta-analysis.

The depressive state has been characterised as one of elevated inflammation, which holds promise for better understanding treatment-resistance in affective disorders as well as for future developments in treatment stratification. Aiming to investigate alterations in the inflammatory profiles of individuals with depression as putative biomarkers for clinical response, we conducted meta-analyses examining data from 35 studies that investigated inflammation before and after treatment in depressed patients together with a measure of clinical response. There were sufficient data to analyse IL-6, TNFα and CRP. Levels of IL-6 decreased with antidepressant treatment regardless of outcome, whereas persistently elevated TNFα was associated with prospectively determined treatment resistance. Treatment non-responders tended to have higher baseline inflammation, using a composite measure of inflammatory markers. Our findings suggest that elevated levels of inflammation are contributory to treatment resistance. Combining inflammatory biomarkers might prove a useful tool to improve diagnosis and detection of treatment refractoriness, and targeting persistent inflammation in treatment-resistant depression may offer a potential target for the development of novel intervention strategies.

The relationship between cortisol, stress and psychiatric illness: New insights using hair analysis.

BACKGROUND: Stress is an established important contributor to the development of mental illness and stress related disorders. The biology implicated in the homeostasis of pathological stress mechanisms is not fully established. One of the difficulties with current techniques is the limitation in capturing chronic levels of cortisol as an expression of stress levels in humans. Hair samples can be used to evaluate cortisol levels averaged over relatively long periods of time, therefore providing a more valid measure of chronic levels of this hormone. A highly replicable technique to measure long-term cortisol could prove pivotal in improving our understanding of the role of stress in psychiatric disorders. METHODS: This review synthesises all the published studies relating hair cortisol concentration (HCC) to stress and to psychiatric disorders. It describes and summarises their findings with the aim of providing a summary picture of the current state of this line of research. RESULTS: The strongest finding to date is the replicable increases in hair cortisol associated with stressful life events. Findings in psychiatric disorders are more sparse and inconsistent. There is some support for the presence of raised HCC in major depressive disorders, and for lowered HCC in posttraumatic stress disorder, suggesting chronic hypercortisolaemia and hypocortisolaemia respectively. CONCLUSIONS: HCC is a promising methodology to study chronic cortisol levels with the potential to help characterise psychiatric and stress related disorders. The combination of chronic and acute cortisol measurements has the potential for more accurately determining different aspects of the stress response, and ultimately for the development of a biological marker to aid diagnosis and response to treatment.

Acute dystonic reaction in an elderly patient with mood disorder after titration of paroxetine: possible mechanisms and implications for clinical care.

The administration of a serotonin reuptake inhibitor may lead to extra pyramidal signs, as reported in the literature. The risk seems to be increased in elderly people. We describe a case of acute dystonic reaction to paroxetine treatment in an elderly patient, who presented with a bipolar affective disorder. The underlying mechanism, possibly generated in the subcortical motor areas, is linked to changes that occur in the pharmacokinetic variables, the decreased neuroplasticity of ageing neurones and to previous exposure to neuroleptic medications.

The use of Fourier-transform infrared spectroscopy for the quantitative determination of glucose concentration in whole blood.

Fourier-transform infrared transmission spectroscopy has been used for the determination of glucose concentration in whole blood samples from 28 patients. A 4-vector partial least-squares calibration model, using the spectral range 950-1200 cm(-1), yielded a standard-error-of-prediction of 0.59 mM for an independent test set. For blood samples from a single patient, we found that the glucose concentration was proportional to the difference between the values of the second derivative spectrum at 1082 cm(-1) and 1093 cm(-1). This indicates that spectroscopy at these two specific wavenumbers alone could be used to determine the glucose concentration in blood plasma samples from a single patient, with a prediction error of 0.95 mM.

Using Terahertz pulse spectroscopy to study the crystalline structure of a drug: a case study of the polymorphs of ranitidine hydrochloride.

We describe the application of Terahertz pulse spectroscopy to polymorph identification. The particular compounds investigated were the different crystalline Forms 1 and 2 of ranitidine hydrochloride, both in the pure form and also obtained as a marketed pharmaceutical product. Identification was clear. The technique has advantages that excitation is not via a powerful laser source, as used in Raman spectroscopy, so phase changes or photochemical reactions in polymorphs do not occur. Terahertz absorption spectral interpretation and instrumentation are similar to basic Fourier transform infrared (FTIR) spectroscopy and therefore easy to understand. The sample preparation techniques used are the same as those used in FTIR and Raman spectroscopies. The data obtained is complementary to Raman Spectroscopy. As the selection rules are different between the two techniques, we are able to obtain new data set directly related to crystalline structure adding to that obtained by Raman spectroscopy. Terahertz pulse spectroscopy provides information on low-frequency intermolecular vibrational modes; these are difficult to assess in Raman spectroscopy due to the proximity of the laser exciting line. It is concluded that the method has a wide range of applications in pharmaceutical science including formulation, high throughput screening, and inspection in storage.

[Multiple pterygium syndrome: description of a new clinical case]. / Sindrome dello pterigio multiplo: descrizione di un nuovo caso clinico.

Multiple Pterygium Syndrome is a rare autosomal recessive disorder characterized by short stature, multiple pterygium, joint contractures, vertebral fusions and minor facial anomalies. Due to the extreme phenotypic variability of this syndrome many mild cases may be misdiagnosed or not recognized. The importance of an early diagnosis is to provide an adequate follow-up of these children in order to try to prevent many of the clinical problems they may encounter in their life-time.

[Dyggve-Melchior-Clausen syndrome: description of 2 further cases]. / La sindrome di Dyggve-Melchior-Clausen: descrizione di due nuovi casi clinici.

In this paper we describe the clinical and radiographic features of a spondylo-epi-methaphyseal dysplasia. Dyggve-Melchior-Clausen syndrome. In these two new cases, without severe mental retardation, we have highlighted the clinical and radiological findings, progression of the skeletal changes that have allowed us to make a diagnosis.