Cognitive and negative symptoms in schizophrenia : studies of patients and healthy controls using magnetic resonance imaging

Schizophrenia is a severe psychiatric illness. It affects young people and often results in lifelong complications such as a distorted perception of reality, decreased cognitive ability and impairment in the realms of motivation and emotions. There is no effective treatment available for two of the symptom domains: cognitive symptoms and the so - called negative symptoms. In recent years, attention has been drawn to the fact that these are the symptom domains resulting in the greatest functional impairment and which best predict a negative prognosis. The need for increased knowledge of the underlying neurobiological correlate is therefore great. Another aspect of the disease - diagnosis in the new onset phase - is an area also requiring more atten tion, as it is of the utmost importance that a reliable diagnosis be made quickly in order that the correct treatment may be initiated. This thesis describes four studies carried out by myself and my colleagues. Each study addresses different aspects of th ese schizophrenia - related problems. Diagnostic stability (DS) in the new onset phase of schizophrenia and other psychotic disorders was investigated in the first study. The diagnostic development was analyzed in material documenting 146 first episode psych osis patients that were followed prospectively and longitudinally over 3 years. A large variation in DS was found between the various diagnoses and diagnostic groups. Generally, schizophrenia and the schizophrenia spectrum had high DS, while the DS of diag noses such as delusional disorder and schizoaffective disorder was low. On the basis of this it is suggested to be restrictive in the use of specific diagnoses in the early phase of a psychotic disorder. The second study examined whether the network of bra in regions which processes cognitive control activates different circuits depending on whether the distraction to be processed in parallel with solving a task is of a cognitive or affective nature. A group of 11 healthy subjects were asked to perform count ing Stroop (cStroop) and affective counting Stroop (aStroop) during one session while being scanned by a magnetic resonance imaging (MRI) camera. The blood oxygen level dependent (BOLD) functional MRI (fMRI) data shows that this division is present not onl y in the anterior cingulum cortex (ACC) as expected from previous studies, but also in the dorsolateral prefrontal cortex (DLPFC). This implies separate circuits within the cognitive control network for affective and cognitive distractions. The third study was devoted to the neurochemical regulation of the cognitive control network. Pharmaco fMRI technique was used to investigate whether brain regions, as activated by aStroop and cStroop respectively, react differently to the selective serotonin reuptake in hibitor (SSRI) agent escitalopram when it is used as a pharmacological probe. A group of 11 healthy subjects performed aStroop and cStroop while being scanned by an MRI camera. Escitalopram was administered after the first session, and the subjects repeate d the same examination after a period of four hours. It was found that activation in the rostral ACC by aStroop was significantly decreased following intake of escitalopram. The implication is that the ability to pursue goal - oriented behavior while being d isturbed by affective stimuli - an ability which is often impaired in states such as schizophrenia - may be improved on administration of an SSRI. The amygdala’s involvement in the negative symptoms of schizophrenia was examined in the fourth study. The a mygdala is a region in the medial temporal lobe of the brain which is critical to faculties such as assigning value to affective stimuli. It was found that the volume of the amygdala as measured by MRI and the activity of the amygdala during an affect indu cing paradigm called the Face Matching Task paradigm as measured by BOLD fMRI had a negative correlation to the level of negative symptoms in a group of 28 schizophrenia patients. No significant difference was however found in the volume or activity of the amygdala between this group of patients and a group of 28 matched healthy control subjects. We believe this indicates that the amygdala is involved in the neurobiology of negative symptoms

Differential Effects of Single-Dose Escitalopram on Cognitive and Affective Interference during Stroop Task

Background and objective: Our aim was to study the regulatory role of serotonin [(5-hydroxytryptamine (5-HT)] on two key nodes in the cognitive control networks – the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). We hypothesized that increasing the levels of 5-HT would preferentially modulate the activity in ACC during cognitive control during interference by negative affects compared to cognitive control during interference by a superimposed cognitive task. Methods: We performed a functional magnetic resonance imaging investigation on 11 healthy individuals, comparing the effects of the selective 5-HT reuptake inhibitor escitalopram on brain oxygenation level dependent signals in the ACC and the DLPFC using affective and cognitive counting Stroop paradigms (aStroop and cStroop). Results: Escitalopram significantly decreased the activity in rostral ACC during aStroop compared to cStroop (p < 0.05). In the absence of escitalopram, both aStroop and cStroop significantly activated ACC and DLPFC (Z ≥ 2.3, p < 0.05). Conclusion: We conclude that escitalopram in a region and task specific manner modified the cognitive control networks and preferentially decreased activity induced by affective interference in the ACC

Impulsivity in Compulsive Sexual Behavior Disorder and Pedophilic Disorder

Background and aims: Impulsivity is regarded as a risk factor for sexual crime reoffending, and a suggested core feature in Compulsive Sexual Behavior Disorder. The aim of this study was to explore clinical (e.g. neurodevelopmental disorders), behavioral and neurocognitive dimensions of impulsivity in disorders of problematic sexuality, and the possible correlation between sexual compulsivity and impulsivity. Methods: Men with Compulsive Sexual Behavior Disorder (n = 20), and Pedophilic Disorder (n = 55), enrolled in two separate drug trials in a specialized Swedish sexual medicine outpatient clinic, as well as healthy male controls (n = 57) were assessed with the Hypersexual Behavior Inventory (HBI) for sexual compulsivity, and with the Barratt Impulsiveness Scale (BIS) and Connors' Continuous Performance Test-II (CPT-II) for impulsivity. Psychiatric comorbidity information was extracted from interviews and patient case files. Results: Approximately a quarter of the clinical groups had Attention-Deficit/Hyperactivity Disorder (ADHD) or Autism Spectrum Disorder. Both clinical groups reported more compulsive sexuality (r = 0.73-0.75) and attentional impulsivity (r = 0.36-0.38) than controls (P &lt; 0.05). Based on results on univariate correlation analysis, BIS attentional score, ADHD, and Commissions T-score from CPT-II were entered in a multiple linear regression model, which accounted for 15% of the variance in HBI score (P &lt; 0.0001). BIS attentional score was the only independent positive predictor of HBI (P = 0.001). Discussion: Self-rated attentional impulsivity is an important associated factor of compulsive sexuality, even after controlling for ADHD. Psychiatric comorbidity and compulsive sexuality are common in Pedophilic Disorder. Conclusion: Neurodevelopmental disorders and attentional impulsivity - including suitable interventions - should be further investigated in both disorders

Altered Neural and Behavioral Response to Sexually Implicit Stimuli During a Pictorial-Modified Stroop Task in Pedophilic Disorder

Background: Pedophilic disorder (PD) entails sexual attraction to prepubertal children. A risk factor for committing child sexual abuse in PD is impaired cognitive control. However, the underlying neurocognitive mechanisms remain unclear. Methods: We performed a case-control study including 51 self-identified and help-seeking males with PD and 55 matched healthy control subjects. Functional magnetic resonance imaging and a pictorial-modified Stroop task involving computer-generated sexually implicit images were used to measure response time and brain activation. Increases in response time during the pictorial-modified Stroop task are presumably due to image-induced interference in executive functions required for task performance. Results: In PD, during the presentation of images of children compared with adults, we found increased response time (p = .005; 848 ± 92 ms vs. 826 ± 88 ms), and compared with healthy control subjects, we found increased activation in the occipital, temporal (bilateral hippocampus), parietal, frontal, cingulate, and left insular cortices; caudate (bilaterally); thalamus (mediodorsal); and cerebellum. Conclusions: Presentation of child images was associated with response interference in PD and increased engagement of brain regions involved in the processing of sexual stimuli, visual perception, self-referential thought, and executive function. We conclude that processing of child images is associated with functional and behavioral alterations in PD

Pharmacological Treatment for Pedophilic Disorder and Compulsive Sexual Behavior Disorder : A Review

Guidelines for the pharmacological treatment of paraphilic disorders have historically been based on data from forensic settings and on risk levels for sexual crime. However, emerging treatment options are being evaluated for individuals experiencing distress because of their sexual urges and preferences, targeting both paraphilic disorders such as pedophilic disorder (PeD) and the new diagnosis of compulsive sexual behavior disorder (CSBD) included in the International Classification of Diseases, 11th Revision (ICD-11). As in other mental disorders, this may enable individualized pharmacological treatment plans, taking into account components of sexuality (e.g. high libido, compulsivity, anxiety-driven/sex as coping), medical and psychiatric comorbidity, adverse effects and patient preferences. In order to expand on previous reviews, we conducted a literature search focusing on randomized controlled trials of pharmacological treatment for persons likely to have PeD or CSBD. Our search was not restricted to studies involving forensic or criminal samples. Twelve studies conducted between 1974 and 2021 were identified regardless of setting (outpatient or inpatient), with only one study conducted during the last decade. Of a total of 213 participants included in these studies, 122 (57%) were likely to have PeD, 34 (16%) were likely to have a CSBD, and the remainder had unspecified paraphilias (40, 21%) or sexual offense (17, 8%) as the treatment indication. The diagnostic procedure for PeD and/or CSBD, as well as comorbid psychiatric symptoms, has been described in seven studies. The studies provide some empirical evidence that testosterone-lowering drugs reduce sexual activity for patients with PeD or CSBD, but the body of evidence is meager. There is a need for studies using larger samples, specific criteria for inclusion, longer follow-up periods, and standardized outcome measures with adherence to international reporting guidelines

Effects of internet-delivered cognitive behavioral therapy on use of child sexual abuse material: A randomized placebo-controlled trial on the Darknet

Introduction: The use of child sexual abuse material (CSAM) is an international public health and child protection challenge.Objective: To investigate whether Prevent It, a therapist-supported, internet-delivered, eight-week, cognitive behavioral therapy, reduces CSAM viewing among users.Methods: We conducted a global online single-blind (participants), parallel-group, superiority, randomized, psychological placebo-controlled trial with a one-month follow-up, 2019-2021 (ISRCTN76841676). We recruited anonymous participants, mainly from Darknet forums. Inclusion criteria: age 18+ years, past week CSAM use, and sufficient English language skills; exclusion criteria: severe psychiatric illness or non-serious intent to participate. The main outcome was change in self-reported, weekly viewing time from pre-to post-treatment, according to the Sexual Child Molestation Risk Assessment+.Results: A total of 160 participants (157 male, 2 non-binary, and 1 not reporting gender) from all world regions (age intervals [%]: 18-29 [49]; 30-39 [30]; 40-49 [15]; 50-59 [6]) were randomized (1:1) to Prevent It (N = 80) or Placebo (N = 80). Between-group, intention-to-treat analyses suggested a significantly larger decrease in viewing time in Prevent It participants vs. controls pre-to post-treatment (Prevent It: N = 76, Placebo: N = 78, estimate-0.25, 95 % CI,-0.46 to-0.04, p = .017, Cohens d 0.18). Negative side effects from treatment were fewer in Prevent It compared to control participants and neither group reported severe adverse events.Conclusion: We provide initial support for the feasibility, efficacy, and safety of Prevent It to reduce CSAM viewing among motivated users. Further research is needed to validate these findings