Subjective versus objective sleep in men with Klinefelter syndrome.

OBJECTIVES: To investigate sleep among men with Klinefelter syndrome (KS). METHOD: We compared the sleep domains latency, disturbance, and efficiency in 30 men with KS (M age = 36.7 years, SD = 10.6) to 21 age-matched non-KS controls (M age = 36.8 years, SD = 14.4). Actigraphs were used to objectively measure sleep across 7 days and nights. Participants also completed a sleep diary over the same period, and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The mean correlation between the objective and subjective sleep measures was lower for the KS sample (M r = .15) than for controls (M r = .34). Sleep disturbance was significantly larger in the KS sample, as measured by actigraphy (p = .022, d = 0.71) and the PSQI (p = .037, d = 0.61). In regression models predicting sleep domains from KS status, age, educational level, vocational status, IQ, and mental health, KS status was not a significant predictor. Higher age was associated with more actigraphy-measured sleep disturbance. Higher educational level and being employed were associated with better sleep efficiency. CONCLUSIONS: Sleep disturbance may be a particular problem for men with KS and should be measured with complimentary methods.

Peripubertal GnRH and testosterone co-treatment leads to increased familiarity preferences in male sheep.

Chronic gonadotropin-releasing hormone agonist (GnRHa) treatment is effective for the medical suppression of the hypothalamic-pituitary-gonadal axis in situations like central precocious puberty and gender dysphoria. However, its administration during the peripubertal period could influence normal brain development and function because GnRH receptors are expressed in brain regions that regulate emotions, cognition, motivation and memory. This study used an ovine model to determine whether chronic peripubertal GnRHa-treatment affected the developmental shift from preference of familiarity to novelty. Experimental groups included Controls and GnRHa-treated rams. To differentiate between effects of altered GnRH signaling and those associated with the loss of sex steroids, a group was also included that received testosterone replacement as well as GnRHa (GnRHa + T). Preference for a novel versus familiar object was assessed during 5-min social isolation at 8, 28 and 46 weeks of age. Approach behavior was measured as interactions with and time spent near the objects, whereas avoidance behavior was measured by time spent in the entrance zone and attempts to escape the arena via the entry point. Emotional reactivity was measured by the number of vocalizations, escape attempts and urinations. As Control and GnRHa-treated rams aged, their approach behaviors showed a shift from preference for familiarity (8 weeks) to novelty (46 weeks). In contrast, relative to the Controls the GnRHa + T rams exhibited more approach behaviors towards both objects, at 28 and 46 weeks of age and preferred familiarity at 46 weeks of age. Vocalisation rate was increased in GnRHa treated rams in late puberty (28 weeks) compared to both Control and GnRHa + T rams but this effect was not seen in young adulthood (46 weeks). These results suggest that the specific suppression of testosterone during a developmental window in late puberty may reduce emotional reactivity and hamper learning a flexible adjustment to environmental change. The results also suggest that disruption of either endogenous testosterone signalling or a synergistic action between GnRH and testosterone signalling, may delay maturation of cognitive processes (e.g. information processing) that affects the motivation of rams to approach and avoid objects.

Spatial memory is impaired by peripubertal GnRH agonist treatment and testosterone replacement in sheep.

Chronic gonadotropin-releasing hormone agonist (GnRHa) is used therapeutically to block activity within the reproductive axis through down-regulation of GnRH receptors within the pituitary gland. GnRH receptors are also expressed in non-reproductive tissues, including areas of the brain such as the hippocampus and amygdala. The impact of long-term GnRHa-treatment on hippocampus-dependent cognitive functions, such as spatial orientation, learning and memory, is not well studied, particularly when treatment encompasses a critical window of development such as puberty. The current study used an ovine model to assess spatial maze performance and memory of rams that were untreated (Controls), had both GnRH and testosterone signaling blocked (GnRHa-treated), or specifically had GnRH signaling blocked (GnRHa-treated with testosterone replacement) during the peripubertal period (8, 27 and 41 weeks of age). The results demonstrate that emotional reactivity during spatial tasks was compromised by the blockade of gonadal steroid signaling, as seen by the restorative effects of testosterone replacement, while traverse times remained unchanged during assessment of spatial orientation and learning. The blockade of GnRH signaling alone was associated with impaired retention of long-term spatial memory and this effect was not restored with the replacement of testosterone signaling. These results indicate that GnRH signaling is involved in the retention and recollection of spatial information, potentially via alterations to spatial reference memory, and that therapeutic medical treatments using chronic GnRHa may have effects on this aspect of cognitive function.

A reduction in long-term spatial memory persists after discontinuation of peripubertal GnRH agonist treatment in sheep.

Chronic gonadotropin-releasing hormone agonist (GnRHa) administration is used where suppression of hypothalamic-pituitary-gonadal axis activity is beneficial, such as steroid-dependent cancers, early onset gender dysphoria, central precocious puberty and as a reversible contraceptive in veterinary medicine. GnRH receptors, however, are expressed outside the reproductive axis, e.g. brain areas such as the hippocampus which is crucial for learning and memory processes. Previous work, using an ovine model, has demonstrated that long-term spatial memory is reduced in adult rams (45 weeks of age), following peripubertal blockade of GnRH signaling (GnRHa: goserelin acetate), and this was independent of the associated loss of gonadal steroid signaling. The current study investigated whether this effect is reversed after discontinuation of GnRHa-treatment. The results demonstrate that peripubertal GnRHa-treatment suppressed reproductive function in rams, which was restored after cessation of GnRHa-treatment at 44 weeks of age, as indicated by similar testes size (relative to body weight) in both GnRHa-Recovery and Control rams at 81 weeks of age. Rams in which GnRHa-treatment was discontinued (GnRHa-Recovery) had comparable spatial maze traverse times to Controls, during spatial orientation and learning assessments at 85 and 99 weeks of age. Former GnRHa-treatment altered how quickly the rams progressed beyond a specific point in the spatial maze at 83 and 99 weeks of age, and the direction of this effect depended on gonadal steroid exposure, i.e. GnRHa-Recovery rams progressed quicker during breeding season and slower during non-breeding season, compared to Controls. The long-term spatial memory performance of GnRHa-Recovery rams remained reduced (P<0.05, 1.5-fold slower) after discontinuation of GnRHa, compared to Controls. This result suggests that the time at which puberty normally occurs may represent a critical period of hippocampal plasticity. Perturbing normal hippocampal formation in this peripubertal period may also have long lasting effects on other brain areas and aspects of cognitive function.

Behavior Rating Inventory of Executive Function Adult Version in Patients with Neurological and Neuropsychiatric Conditions: Symptom Levels and Relationship to Emotional Distress.

OBJECTIVES: The present study explored the level of self-and informant reported executive functioning in daily living using the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) in a large sample comprising healthy adults and patient cohorts with neurological and neuropsychiatric disorders. The relationship to neuropsychological test performance and self-reported emotional distress was explored, as well as the applicability of U.S. normative data. METHODS: Scores on the self- and informant reported BRIEF-A are presented, along with scores on standardized cognitive tests, and on rating scales of self-reported emotional distress in a Norwegian healthy comparison group (n=115), patients with severe traumatic brain injury (n=125), focal frontal lobe damage (n=29), focal cerebellar lesion (n=24), Parkinson's disease (n=42), attention deficit hyperactivity disorder (n=34), type II bipolar disorder (n=21), and borderline personality disorder (n=18). RESULTS: Strong associations were observed between the BRIEF-A and emotional distress in both the healthy group and in neurological groups, while no or weak relationships with IQ and performance-based tests of executive function were seen. The relationship between BRIEF-A and emotional distress was weaker in the neuropsychiatric patient groups, despite high symptom load in both domains. Healthy participants tended to have BRIEF-A scores 1/2-3/4 SD below the U.S. normative mean of T score=50. CONCLUSIONS: The study demonstrates the need to interpret BRIEF-A results within a broad differential diagnostic context, where measures of psychological distress are included in addition to neuropsychological tests. Uncertainty about the appropriateness of U.S. normative data in non-U.S. countries adds to the need for interpretive caution. (JINS, 2016, 22, 682-694).

Anterior cingulate cortex and cognitive control: neuropsychological and electrophysiological findings in two patients with lesions to dorsomedial prefrontal cortex.

Whereas neuroimaging studies of healthy subjects have demonstrated an association between the anterior cingulate cortex (ACC) and cognitive control functions, including response monitoring and error detection, lesion studies are sparse and have produced mixed results. Due to largely normal behavioral test results in two patients with medial prefrontal lesions, a hypothesis has been advanced claiming that the ACC is not involved in cognitive operations. In the current study, two comparably rare patients with unilateral lesions to dorsal medial prefrontal cortex (MPFC) encompassing the ACC were assessed with neuropsychological tests as well as Event-Related Potentials in two experimental paradigms known to engage prefrontal cortex (PFC). These included an auditory Novelty Oddball task and a visual Stop-signal task. Both patients performed normally on the Stroop test but showed reduced performance on tests of learning and memory. Moreover, altered attentional control was reflected in a diminished Novelty P3, whereas the posterior P3b to target stimuli was present in both patients. The error-related negativity, which has been hypothesized to be generated in the ACC, was present in both patients, but alterations of inhibitory behavior were observed. Although interpretative caution is generally called for in single case studies, and the fact that the lesions extended outside the ACC, the findings nevertheless suggest a role for MPFC in cognitive control that is not restricted to error monitoring.

Executive functions after orbital or lateral prefrontal lesions: neuropsychological profiles and self-reported executive functions in everyday living.

OBJECTIVE: This study examined the effects of chronic focal lesions to the lateral prefrontal cortex (LPFC) or orbitofrontal cortex (OFC) on neuropsychological test performance and self-reported executive functioning in everyday living. METHODS: Fourteen adults with OFC lesions were compared to 10 patients with LPFC injuries and 21 healthy controls. Neuropsychological tests with emphasis on measures of cognitive executive function were administered along with the Behavior Rating Inventory of Executive Functions (BRIEF-A) and a psychiatric screening instrument. RESULTS: The LPFC group differed from healthy controls on neuropsychological tests of sustained mental effort, response inhibition, working memory and mental switching, while the BRIEF-A provided more clinically important information on deficits in everyday life in the OFC group compared to the LPFC group. Correlations between neuropsychological test results and BRIEF-A were weak, while the BRIEF-A correlated strongly with emotional distress. CONCLUSIONS: It was demonstrated that LPFC damage is particularly prone to cause cognitive executive deficit, while OFC injury is more strongly associated with self-reported dysexecutive symptoms in everyday living. The study illustrates the challenge of identifying executive deficit in individual patients and the lack of strong anatomical specificity of the currently employed methods. There is a need for an integrative methodological approach where standard testing batteries are supplemented with neuropsychiatric and frontal-specific rating scales.

ERP indices of resource allocation difficulties in mild head injury.

This study examined the hypothesis that distractibility is a characteristic sequela of mild closed head injury (MHI). The Minnesota Multiphasic Personality Inventory (MMPI-2) was used to study whether comorbid stress-related symptoms are associated with behavioral and electrophysiological indexes of attention. Event-related potentials (ERPs) and performance (reaction time, accuracy) were studied in patients with MHI (n = 20), patients with frontal lesions (n = 14), and healthy controls (n = 20) during a three-tone oddball task. Participants were instructed to detect rare target (2000 Hz) tones, and to withhold responding to equally rare distractor (500 Hz) tones and frequently occurring standard (1000 Hz) tones. All groups distinguished the two classes of deviants as indicated by the larger P3 amplitude to target relative to distractor tones. This indicates that the group with MHI was capable of differential allocation of attentional resources to target and non-target events. However, impaired performance and attenuated ERP amplitudes to both classes of deviants relative to patients with frontal lesions and controls, suggest limited availability, or expenditure of the resources needed for adequate task performance. In the group with MHI, both P3 amplitude and reaction time (RT) were significantly related to subjectively reported distress. The difference in RT disappeared, whereas the P3 amplitude differences between the patient groups remained when adjusting for level of distress.

ERP indicators of disturbed attention in mild closed head injury: a frontal lobe syndrome?

The purpose of the study was to examine the hypothesis that distractibility is a fundamental characteristic of mild closed head injury (MHI). The claim that cognitive symptoms in MHI are due to a mild type of frontotemporal injury was also investigated. Cognitive event-related potentials (ERPs), accuracy and reaction time to target stimuli in a dichotic listening paradigm, and neuropsychological test results were studied in patients with MHI (N = 15), patients with verified frontal lobe damage (N = 10), and healthy controls (N = 13). Information processing reflecting target detection (N2, P3b) and sustained selective attention (processing negativity) was studied. The MHI and frontal patients did not differ on behavioral measures, except that the MHI group had significantly longer reaction times to target stimuli in the ERP task. Both patient groups had deviant ERPs compared with controls, but their ERP patterns differed in important respects. Contrary to expectations, the MHI patients had the most abnormal ERPs. They showed significantly smaller N2 and Nd amplitudes than frontal patients and controls, indicating that the mediating cognitive mechanisms were not equivalent in MHI and frontal injury. The data suggest that MHI patients allocated less processing resources to the task than either the control subjects or the patients with frontal lobe damage.