Impulsivity in Parkinson's disease patients treated with subthalamic nucleus deep brain stimulation-An exploratory study.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a recognized treatment in Parkinson's disease (PD). Knowledge is still limited regarding the possible impact of STN-DBS on personality traits and the personality characteristics of PD patients who undergo surgery. METHODS: To assess personality traits in relation to STN-DBS we did an ancillary protocol as part of a prospective randomized study that compared two surgical strategies. Patients were assessed with the Temperament and Character Inventory (TCI), the Urgency, Premeditation, Perseverance and Sensation Seeking impulse behavior scale, the Eysenck Personality Questionnaire (EPQ) and the Toronto Alexithymia Scale preoperatively and after one year of STN-DBS. EPQ and TCI baseline scores were compared with mean scores of healthy reference populations. RESULTS: After 12-months of STN-DBS, there was a significant decline in Persistence compared to baseline. Preoperatively, the STN-DBS patients had significantly lower Persistence and Self-Transcendence scores, and significantly higher scores on Novelty-Seeking, Self-Directedness, Cooperativeness and on Social Conformity than referenced populations. No difference was found in Neuroticism or Harm-Avoidance scores. The baseline prevalence of alexithymia was low and at 1-year follow-up there was no significant change in alexithymia scores. CONCLUSIONS: We found a higher baseline level of impulsivity in PD patients who underwent STN-DBS. After one year of STN-DBS, our results indicated that the treatment may affect the patients' personality by increasing certain aspects of impulsivity. There was no effect on alexithymia. The preoperative personality profile of PD patients might influence the outcome of STN-DBS.

Mechanisms of change and heterogeneous treatment effects in psychodynamic and cognitive behavioural therapy for patients with depressive disorder: a randomized controlled trial.

BACKGROUND: Major depressive disorder (MDD) is a prevalent psychiatric condition associated with significant disability, mortality and economic burden. Cognitive behavioral therapy (CBT) and psychodynamic psychotherapy (PDT) are found to be equally effective for patients with depression. However, many patients do not respond sufficiently to either treatment. To offer individualized treatment, we need to know if some patients benefit more from one of the two therapies. At present little is known about what patient characteristics (moderators) may be associated with differential outcomes of CBT and PDT, and through what therapeutic processes and mechanisms (mediators) improvements occur in each therapy mode. Presently only theoretical assumptions, sparsely supported by research findings, describe what potentially moderates and mediates the treatment effects of CBT and PDT. The overall aim of this study is to examine theoretically derived putative moderators and mediators in CBT and PDT and strengthen the evidence base about for whom and how these treatments works in a representative sample of patients with MDD. METHODS: One hundred patients with a diagnosis of MDD will be randomized to either CBT or PDT. Patients will be treated over 28 weeks with either CBT (one weekly session over 16 weeks and three monthly booster sessions) or PDT (one weekly session over 28 weeks). The patients will be evaluated at baseline, during the course of therapy, at the end of therapy, and at follow-up investigations 1 and 3 years post treatment. A large range of patient and observer rated questionnaires (specific preselected putative moderators and mediators) are included. DISCUSSION: The clinical outcome of this study may better guide clinicians when deciding what kind of treatment any individual patient should be offered. Moreover, the study aims to further our knowledge of what mechanisms lead to symptom improvement and increased psychosocial functioning. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03022071.

Differences in course of illness between patients with bipolar II disorder with and without epileptiform discharges or other sharp activity on electroencephalograms: a cross-sectional study.

BACKGROUND: A diagnosis of bipolar II disorder requires that the symptoms cannot be better explained by a medical condition. Epilepsy is in some cases associated with an affective syndrome mimicking an unstable bipolar II disorder. Epileptiform discharges on electroencephalograms (EEGs) are typical, but not pathognomonic, for epilepsy. A previous study has found a high frequency of epileptiform discharges and other sharp activity among patients with bipolar disorder. The aim of the study was to identify if epileptic discharges or other sharp activity per se are associated with an altered course of illness among patients with bipolar II disorder. METHODS: Eighty six patients diagnosed with bipolar II disorder at two psychiatric departments were interviewed about prior course of illness and assessed with EEGs. The patients were split into two groups based on the presence (n = 12) or absence (n = 74) of epileptiform discharges or other sharp activity. Wilcoxon rank sum test, Fisher's exact test, and Pearson's chi squared test were used to assess differences between the groups on six variables of course of illness. RESULTS: Patients with epileptiform discharges or other sharp activity had a history of more hypomanic episodes per year (median (interquartile range (IQR)) 1.5 (3.2) vs. 0.61 (1.1), p = 0.0090) and a higher hypomania:depression ratio (median (IQR) 3.2 (16) vs. 1.0 (1.0), p = 0.00091) as compared to patients without. None of the patients with epileptiform discharges or other sharp activity had self-reported epileptic seizures in their history. CONCLUSIONS: Epileptiform discharges or other sharp activity on EEGs are associated with more hypomanic episodes and an increased hypomania:depression ratio. Our results warrant replication in prospective studies, but suggest that EEG findings could be of prognostic importance for patients diagnosed with bipolar II disorder in psychiatric care. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT00201526 ).

Borderline patients have difficulties describing feelings; bipolar II patients describe difficult feelings. An alexithymia study.

OBJECTIVE: Apparent similarities between borderline personality disorder (BPD) and bipolar II disorder (BIP-II) contribute to clinical difficulties in distinguishing between the disorders. Here, we aimed to explore how subjective Difficulties with the Identification and Description of Feelings (DIDF), a major constituent of the alexithymia construct and assessed as a part of the Toronto Alexithymia Scale (TAS), are related to relationship problems and health complaints in these groups. METHODS: Twenty-two patients with BPD; 22 patients with BIP-II; and 23 healthy controls (HC) completed TAS. Health complaints, including symptoms associated with mood swings, were assessed with the Giessener Subjective Complaints List (Giessener Beschwerdebogen-GBB), and relationship problems with the Health of the Nation Outcome scale, Relationship item (HoNOSR). Bivariate correlations were run. RESULTS: Both patient groups had high DIDF and GBB scores. In BPD only, there was a significant positive correlation between DIDF and HoNOSR. In BIP-II only, there was a significant positive correlation between DIDF and GBB total score. In BIP-II, DIDF correlated highly with those GBB subscales assessing symptoms typically occurring during bipolar mood swings (cardiovascular and gastrointestinal symptoms, exhaustion). CONCLUSION: Our results suggest that in BPD, high DIDF scores represent genuine problems with identifying and describing emotions which are expected to correlate with relationship problems. In BIP-II, high DIDF scores could potentially represent difficulties with understanding the unpredictable symptoms of bipolar mood swings. The findings suggest that difficulties with identifying and describing feelings in patients should be carefully explored to increase the validity of the diagnostic evaluation.

Patterns of altered regional brain glucose metabolism in borderline personality disorder and bipolar II disorder.

OBJECTIVE: The relationship between borderline personality disorder (BPD) and bipolar II disorder (BIP-II) is disputed but understudied. Here, we investigated brain glucose metabolism in these patient groups and healthy control subjects (HCs). METHODS: Sixty-five subjects, 22 BPD (19 females), 22 BIP-II (17 females), and 21 HC (14 females), were examined using 2-deoxy-2[18F]-fluoro-d-glucose positron-emission tomography (PET) scanning. Only patients without reciprocal comorbidity were recruited; BPD participants without bipolar spectrum pathology; BIP-II participants without cluster A/B personality pathology. Groups were compared pairwise. Associations with mood state and childhood trauma were analyzed. RESULTS: Both patient groups exhibited hypometabolism compared with HCs in insula, brainstem, and frontal white matter. Additionally, BPD patients showed hypometabolism in hypothalamus, midbrain, and striatum; BIP-II patients in cerebellum. Uncorrected analyses showed cortical areas of higher metabolism in BIP-II than BPD, and associations with clinical variables differed between the groups. CONCLUSION: Reduced metabolism in the insula regions was shown in both disorders, suggesting shared pathophysiological mechanisms. The observed patterns of altered metabolism specific to each patient group, as well as the uncorrected results, may also suggest differential pathophysiology. However, these latter findings must be interpreted cautiously given the non-significant corrected results in the direct comparison between the disorders.

Cortical abnormalities in bipolar disorder: an MRI analysis of 6503 individuals from the ENIGMA Bipolar Disorder Working Group.

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Subcortical volumetric abnormalities in bipolar disorder.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10-7) and thalamus (d=-0.148; P=4.27 × 10-3) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10-5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

Somatic and cognitive symptoms as indicators of potential endophenotypes in bipolar spectrum disorders: an exploratory and proof-of-concept study comparing bipolar II disorder with recurrent brief depression and healthy controls.

BACKGROUND: We examined whether somatic symptoms reported by patients with bipolar spectrum disorder (BSD), in this study defined as bipolar II (BD-2) or recurrent brief depression with (RBD-H) or without (RBD-O) a history of hypomanic symptoms might point to the possible underlying disease markers (endophenotypes). We hypothesized that somatic symptoms that are possible indirect indicators of endophenotypes should be more prevalent among patients than among healthy controls; should not correlate with neuroticism; should not correlate with the severity of current mental status (e.g., anxiety, depression); and should not correlate with the use of psychotropic drugs including antiepileptics or be explained by co-morbid medical diseases. METHODS: Sixty-one patients (BD-2: n=21; RBD-H: n=19; RBD-O: n=21) were compared with 21 healthy controls. Assessments included a 123-item somatic symptom checklist; assessments for neuroticism, anxiety and depression. Candidate somatic symptoms were selected using a 4-step inclusion/exclusion procedure. RESULTS: Seven symptoms survived in all three groups: general (fatigue, feeling exhausted); sensory (leaden sensation in legs, pain in the body, impaired sense of smell); cognitive (loss of memory) and autonomic (excessive perspiration). In addition 15 symptoms survived in one or two groups (examples: impaired hearing, hypersensitivity to sound, inability to find words). LIMITATIONS: Possible selection bias and small sample size precludes firm conclusions with regards to specific symptoms. CONCLUSION: Our approach identified symptoms for which an association with BSDs has been suggested previously, as well as symptoms not commonly associated with BSDs. The findings support the feasibility and validity of using assessment of somatic symptoms as an approach to identify potential endophenotypes in BSDs.

Regional cortical thinning may be a biological marker for borderline personality disorder.

OBJECTIVE: We investigated cerebral cortical thickness and its relation to measurements of difficulties with identifying and describing emotions in patients with borderline personality disorder (BPD). METHOD: Eighteen SCID-II-diagnosed female patients with BPD and 21 healthy female controls underwent magnetic resonance imaging and completed the Toronto Alexithymia Scale (TAS). First, regional cortical thickness across the cerebral surface was compared between patients and healthy controls. Then, analyses of the association between cortical thickness and TAS subscales were performed in patients. RESULTS: Compared with controls, patients exhibited clusters of significantly reduced cortical thickness in the left medial and lateral prefrontal cortex, left temporoparietal junction, bilateral temporal poles, and bilateral paracentral lobules. Significant negative associations were observed between cortical thickness and the 'Difficulties Describing Feelings' TAS subscale (DDF) scores in patients. The anatomical distribution of these associations was highly overlapping with the group differences in cortical thickness. CONCLUSION: The pattern of regions exhibiting cortical thinning in patients resembles a network of cortical structures repeatedly shown to be involved in social cognition. The results of the DDF analyses suggest that the thinning may partly be related to interpersonal dysfunction in patients with BPD. The pattern of thinning may represent a potential biological marker for BPD.

Temperament and character in patients with bipolar II disorder and recurrent brief depression.

OBJECTIVES: We compared the temperament and character profiles of 21 patients with bipolar II disorder, 40 patients with recurrent brief depression (RBD; at least monthly depressive episodes meeting the diagnostic criteria for major depressive episode except for duration that is less than 2 weeks, typically 2-3 days, without fixed relation to menstrual cycle) of which 21 had no history of hypomania and 19 had experienced hypomanic episodes, and 21 age- and sex-matched controls. METHODS: Assessments included the Montgomery-Åsberg Depression Rating Scale, Hypomania Checklist, and Temperament and Character Inventory-125. Patients with cluster A and B personality disorders were excluded. RESULTS: Bipolar II and RBD patients had higher harm avoidance (HA) and lower self-directedness (SD) compared with controls. Excluding panic disorder comorbidity effaced this difference in HA and SD (bipolar II only) and harm avoidance. No other differences were found. CONCLUSIONS: In this first study comparing personality profiles of patients with bipolar II vs RBD, when controlling for confounders, neither bipolar II nor RBD patients differed significantly from healthy controls. The lower SD scores among RBD patients may reflect sampling bias (a higher rate of Axis 2 cluster C disorders).

Identification of T cell ligands in a library of peptides covalently attached to HLA-DR4.

While T cells have been clearly implicated in a number of disease processes including autoimmunity, graft rejection, and atypical immune responses, the precise Ags recognized by the pathogenic T cells have often been difficult to identify. This has particularly been true for MHC class II-restricted CD4+ T cells. Although such cells can be demonstrated to have undergone clonal expansion at sites of pathology, they are frequently difficult to establish as stable T cell clones. Furthermore, in general, larger peptides in higher concentrations are required to stimulate CD4+ T cells than CD8+ T cells, which makes some of the techniques developed to identify CD8+ T cell Ags impractical. To circumvent some of these problems, we developed a model system consisting of two parts. The first part involves the construction of an indicator T cell hybridoma expressing a chimeric TCR comprised of murine constant regions and human variable regions specific for influenza hemagglutinin 307-319 presented by DR4. The second part consists of a library of fibroblasts each expressing multiple peptides as amino terminal covalent extensions of the beta-chain of HLA-DR4 (DRA1*0101, DRB1*0401). Using this model system, we screened approximately 100, 000 peptides and identified three novel peptides stimulatory for the HA1.7 TCR. While there is some convergence at residues known to be important for T cell recognition, all three peptides differ markedly from each other and bear little resemblance to wild-type hemagglutinin 307-319.

Delineation by use of specific monoclonal antibodies of the T-cell receptor and major histocompatibility complex interaction sites on the superantigen toxic shock syndrome toxin 1.

Murine monoclonal antibodies (MAbs) specific for toxic shock syndrome toxin 1 (TSST-1), a bacterial superantigen, showed the ability either to detect TSST-1 bound to histocompatibility locus antigen (HLA)-DR molecules or to inhibit TSST-1 binding to HLA-DR. A MAb capable of detecting DR-bound TSST-1 could also inhibit the toxin-induced activation of a T-cell receptor Vbeta15-expressing murine T-cell hybridoma. Alternatively, MAbs with specificity for the HLA-DR association site could present TSST-1 in vitro, stimulating CD4+ human T cells to proliferate. These functional activities correlated directly with with MAb specificity for HLA-DR versus T-cell receptor Vbeta interaction sites on TSST-1 as determined by reactivity with a panel of recombinant TSST-1 mutant molecules. Therefore, these MAbs discriminate the superantigen functional sites on the TSST-1 molecule and constitute reagents with the property of being potent modulators of the toxic activity of TSST-1.

Direct binding of progesterone receptor to nonconsensus DNA sequences represses rat GnRH.

The mechanisms by which steroid receptors repress gene expression are not well understood. In this report, we show that progesterone receptor (PR), in the presence of progesterone (P) directly represses rat gonadotropin releasing hormone (rGnRH) gene transcription. Deletion analysis studies using transient transfection assays in GT1-7 neuronal cells mapped the effects of P to sequences in the proximal rGnRH promoter between -171 and -73. This DNA sequence lacks any consensus steroid response element binding sites. Cotransfection of a mutant progesterone receptor that lacks a functional DNA binding region (hPRcys) abolished repression of the rGnRH promoter by P. Gel mobility shift assays confirmed that PR directly binds to the DNA fragments -171/-126, -126/-73, and -111/-73, which encompass the negative progesterone response element (nPRE) of the rGnRH promoter. Mutagenesis of the rGnRH nPRE -171/-126 DNA fragment resulted in a loss of PR binding. Thus, direct DNA binding of PR to nonconsensus elements in the proximal rGnRH promoter inhibits rGnRH gene expression.

Identification of class II major histocompatibility complex and T cell receptor binding sites in the superantigen toxic shock syndrome toxin 1.

Superantigens, in association with class II major histocompatibility complex (MHC) molecules, activate T cells bearing particular beta chain variable domains of the T cell receptor (TCR). Unlike conventional peptide antigens, superantigens bind as intact proteins to TCR and MHC molecules outside their peptide binding sites. To characterize these interactions at the molecular level, random point mutations were generated in the gene encoding toxic shock syndrome toxin 1, a bacterial superantigen associated with toxic shock syndrome. Functionally impaired mutants were identified based on their lack of murine and human T cell stimulatory activities, and experiments analyzing binding to human histocompatibility leukocyte antigen-DR molecules differentiated residues involved in MHC from TCR binding. The results showed that the great majority of mutations are clustered in two distinct regions of the toxic shock syndrome toxin 1 molecule. The class II MHC binding site is located in the hydrophobic region of the NH2-terminal domain, and the TCR binding site is primarily in the major central groove of the COOH-terminal domain. These studies provide insight into the interactions necessary for superantigen-mediated disease in humans.