Novel insights into maladaptive behaviours in Prader-Willi syndrome: serendipitous findings from an open trial of vagus nerve stimulation.

BACKGROUND: We report striking and unanticipated improvements in maladaptive behaviours in Prader-Willi syndrome (PWS) during a trial of vagus nerve stimulation (VNS) initially designed to investigate effects on the overeating behaviour. PWS is a genetically determined neurodevelopmental disorder associated with mild-moderate intellectual disability (ID) and social and behavioural difficulties, alongside a characteristic and severe hyperphagia. METHODS: Three individuals with PWS underwent surgery to implant the VNS device. VNS was switched on 3 months post-implantation, with an initial 0.25 mA output current incrementally increased to a maximum of 1.5 mA as tolerated by each individual. Participants were followed up monthly. RESULTS: Vagal nerve stimulation in these individuals with PWS, within the stimulation parameters used here, was safe and acceptable. However, changes in eating behaviour were equivocal. Intriguingly, unanticipated, although consistent, beneficial effects were reported by two participants and their carers in maladaptive behaviour, temperament and social functioning. These improvements and associated effects on food-seeking behaviour, but not weight, indicate that VNS may have potential as a novel treatment for such behaviours. CONCLUSIONS: We propose that these changes are mediated through afferent and efferent vagal projections and their effects on specific neural networks and functioning of the autonomic nervous system and provide new insights into the mechanisms that underpin what are serious and common problems affecting people with IDs more generally.

Hypothalamic-pituitary-adrenal (HPA) axis activity in adults with intellectual disabilities: a preliminary investigation.

BACKGROUND: Cortisol is a marker of physiological arousal, exhibiting a characteristic pattern of diurnal activity. The daily cortisol profile has been xamined extensively and is atypical in a number of clinical disorders. However, there are very few studies focussing on the cortisol profile in adults with intellectual disabilities (ID). This paper reports a preliminary investigation into the nature of the cortisol profile in adults with mild or moderate ID and provides reflections on the challenges of psychophysiological research in this population. METHODS: On two consecutive days, 39 adults with mild or moderate ID each donated saliva samples for cortisol analysis, at multiple times between waking and evening. A comparison between these data and the published literature permitted a descriptive assessment of the cortisol awakening response (CAR) and diurnal profile. A variety of psychometric measures and an assessment of behavioural history were also collected in order to describe aspects of the participants' emotional and behavioural states. RESULTS: Individuals with ID exhibit a diurnal cortisol secretion profile, qualitatively similar to that of the typical, healthy, adult population. However, the findings also suggested a blunted CAR, warranting further investigation. There was also some evidence that cortisol secretion was affected by anxiety and a recent history of aggression. CONCLUSION: While further work is required to characterise the CAR fully, there was no indication that the diurnal cortisol profile among people with ID differs from that of the typical population. This study also demonstrates that, although challenging, it is feasible, and acceptable to participants, to collect repeated physiological measures from men and women with mild and moderate ID.

Dopamine transporter binding in Gilles de la Tourette syndrome: a [123I]FP-CIT/SPECT study.

OBJECTIVE: To investigate dopamine transporter binding in Gilles de la Tourette syndrome (GTS) with SPECT and [123I]FP-CIT. METHOD: Ten neuroleptic naïve/free patients with GTS, and 10 age- and gender-matched normal volunteers were studied. Subjects were clinically evaluated. GTS severity and affective symptoms were measured and the presence of GTS-related behaviours were recorded. RESULTS: The GTS group showed significantly higher binding in both caudate and putamen nuclei than the controls. No associations were found between striatal binding ratios and measures of affect or GTS-related behaviours. CONCLUSION: Patients with GTS show higher striatal binding of FP-CIT to the striatum in comparison with age- and gender-matched control subjects, indicating that dopamine transporter abnormalities are involved in the pathophysiology of GTS. These abnormalities appear to be distributed across both caudate and putamen.

Neuropsychiatry of the basal ganglia.

This review aims to relate recent findings describing the role and neural connectivity of the basal ganglia to the clinical neuropsychiatry of basal ganglia movement disorders and to the role of basal ganglia disturbances in "psychiatric"' states. Articles relating to the relevant topics were initially collected through MEDLINE and papers relating to the clinical conditions discussed were also reviewed. The anatomy and connections of the basal ganglia indicate that these structures are important links between parts of the brain that have classically been considered to be related to emotional functioning and brain regions previously considered to have largely motor functions. The basal ganglia have a role in the development and integration of psychomotor behaviours, involving motor functions, memory and attentional mechanisms, and reward processes.

A SPECT study of the effect of vagal nerve stimulation on thalamic activity in patients with epilepsy.

The mechanism by which vagal nerve stimulation (VNS) exerts an anticonvulsant effect in humans is unknown. This study used (99m)Tc-HMPAO single photon emission tomography (SPECT) to examine the effects of VNS on regional cerebral activity in thalamic and insular regions. Seven subjects with epilepsy who had been receiving vagal nerve stimulation for at least 6 months underwent SPECT scanning with simultaneous scalp electroencephalographic (EEG) recording. Subjects were studied in two states; during VNS activity and during a comparison condition of VNS inactivity. A region of interest analysis demonstrated that rapid cycling stimulation (7 seconds on, 12 seconds off) was associated with relatively decreased activity in left and right medial thalamic regions. No systematic stimulation-related changes were observed on visual or spectral analysis of EEG data. The thalamus is involved in modulation of ongoing cortical EEG activity in animals. Our results support the hypothesis that VNS may exert an antiepileptic action by an effect on thalamic activity.

The amygdala theory of autism.

Brothers (Brothers L. Concepts in Neuroscience 1990;1:27-51) proposed a network of neural regions that comprise the "social brain", which includes the amygdala. Since the childhood psychiatric condition of autism involves deficits in "social intelligence", it is plausible that autism may be caused by an amygdala abnormality. In this paper we review the evidence for a social function of the amygdala. This includes reference to the Kluver-Bucy syndrome (which Hetzler and Griffin suggested may serve as an animal model of autism). We then review evidence for an amygdala deficit in people with autism, who are well known to have deficits in social behaviour. This includes a detailed summary of our recent functional magnetic resonance imaging (fMRI) study involving judging from the expressions of another person's eyes what that other person might be thinking or feeling. In this study, patients with autism or AS did not activate the amygdala when making mentalistic inferences from the eyes, whilst people without autism did show amygdala activity. The amygdala is therefore proposed to be one of several neural regions that are abnormal in autism. We conclude that the amygdala theory of autism contains promise and suggest some new lines of research.

Patterns of brain activity in patients with epilepsy and depression.

Depression is a recognized feature of epilepsy. This study tested the hypothesis that depression arising in patients with epilepsy would be associated with decreased activity in brain regions previously demonstrated to be hypoperfused both in primary depression and in depression secondary to movement disorders. Two groups of patients with temporal lobe epilepsy were studied, one of which also met DSM IV criteria for a major depressive episode. All underwent a SPECT scan using the blood flow marker,(99m)Tc-HMPAO. An automated voxel-based analysis demonstrated no regions of relatively decreased activity in the depressed compared with the non-depressed patients. Sites of relative hyperactivity in the depressed group were concentrated in the left hemisphere, particularly in dorsolateral prefrontal cortex, striatum, thalamus and temporo-parietal regions. Comparison of these data with normal population data revealed that in the depressed epilepsy group regional activities were within the normal range whilst corresponding results from the non-depressed group were below it. Depressed patients with epilepsy have cerebral regions with greater perfusion than non-depressed people with epilepsy, although they are not hyperperfused compared with normals. Our results suggest that depression in people with epilepsy may arise from a mechanism which differs from that underlying the development of depression in patients with movement disorders.

Cerebral correlates of preserved cognitive skills in autism: a functional MRI study of embedded figures task performance.

When considering the cognitive abilities of people with autism, the majority of studies have explored domains in which there are deficits. However, on tests of local processing and visual search, exemplified by the Embedded Figures Task (EFT), people with autism have been reported to demonstrate superiority over normal controls. This study employed functional MRI of subjects during the performance of the EFT to test the hypothesis that normal subjects and a group with autism would activate different brain regions and that differences in the patterns of these regional activations would support distinct models of cerebral processing underlying EFT performance in the two groups. It was found that several cerebral regions were similarly activated in the two groups. However, normal controls, as well as demonstrating generally more extensive task-related activations, additionally activated prefrontal cortical areas that were not recruited in the group with autism. Conversely, subjects with autism demonstrated greater activation of ventral occipitotemporal regions. These differences in functional anatomy suggest that the cognitive strategies adopted by the two groups are different: the normal strategy invokes a greater contribution from working memory systems while the autistic group strategy depends to an abnormally large extent on visual systems for object feature analysis. This interpretation is discussed in relation to a model of autism which proposes a predisposition towards local rather than global modes of information processing.

Social intelligence in the normal and autistic brain: an fMRI study.

There is increasing support for the existence of 'social intelligence' [Humphrey (1984) Consciousness Regained], independent of general intelligence. Brothers et al. 1990) J. Cog. Neurosci., 4, 107-118] proposed a network of neural regions that comprise the 'social brain': the orbito-frontal cortex (OFC), superior temporal gyrus (STG) and amygdala. We tested Brothers' theory by examining both normal subjects as well as patients with high-functioning autism or Asperger syndrome (AS), who are well known to have deficits in social intelligence, and perhaps deficits in amygdala function [Bauman & Kemper (1988) J. Neuropath. Exp. Neurol., 47, 369]. We used a test of judging from the expressions of another person's eyes what that other person might be thinking or feeling. Using functional magnetic resonance imaging (fMRI) we confirmed Brothers' prediction that the STG and amygdala show increased activation when using social intelligence. Some areas of the prefrontal cortex also showed activation. In contrast, patients with autism or AS activated the fronto-temporal regions but not the amygdala when making mentalistic inferences from the eyes. These results provide support for the social brain theory of normal function, and the amygdala theory of autism.

Possible roles for mismatch negativity in neuropsychiatry.

OBJECTIVE: This article reviews research on the main characteristics of mismatch negativity (MMN) and its applications in neuropsychiatry. BACKGROUND: Event-related potentials (ERPs) have been used to study many aspects of information processing. Mismatch negativity is an early auditory ERP that has been identified as an index of an automatic (preconscious) alerting mechanism stimulating an individual to attend to unexpected environmental events. Disturbances of MMN may relate to abnormalities of auditory information processing contributing to the pathophysiology of neuropsychiatric conditions. METHOD: The authors review (1) studies that have evaluated the electrophysiological aspects of MMN and (2) studies that have investigated the different applications of MMN in neuropsychiatry. RESULTS: The first part of this article describes the characteristics of MMN, its cerebral origins, and electrophysiological parameters. We then discuss the role of "echoic memory" as well as that of attention and vigilance. In the second part of the article, disturbances in MMN associated with schizophrenia, depressive illness, dementing processes, and other neuropsychiatric states are discussed. CONCLUSIONS: MMN is a preconscious cognitive ERP, the main generators and functions of which are well defined. Observations relating to the origins of MMN and its role in early auditory information processing together with its possible behavioral significance, combined with observations of MMN aberrations in psychiatric conditions, may provide novel insights into the pathophysiology of neuropsychiatric states.

Vulnerability to emotionally negative stimuli in Parkinson's disease: an investigation using the Emotional Stroop task.

OBJECTIVE: The objective of this study was to determine whether the pathophysiological changes associated with Parkinson's disease (PD) lead to an increased vulnerability to react to negative emotional stimuli and hence to depression. It is hypothesized that nondepressed PD patients will demonstrate, associated with particular PD and/or cognitive variables, vulnerability to the interfering effects of negative words on the Emotional (sad) Stroop task (EST). BACKGROUND: Depression has been reported to occur frequently in PD, but there is controversy regarding its pathophysiology: psychosocial factors versus neurobiologic ones. METHOD: Thirty nondepressed/ nondemented patients with idiopathic PD attending a specialist movement disorders clinic were assessed from their emotional state (Beck's Depression Inventory [BDI], and Hospital Anxiety and Depression Scale) and from their cognitive state (Mini-Mental State Examination, Stroop tasks [including the EST], Modified Card Sorting Test, Word Fluency tasks, Digit Span, and Trail Making tests). In addition, information was gathered on PD-related variables such as severity (Hoehn and Yahr scale), duration of the disease, and type of motor response to dopaminergic drugs. The sample was split into two groups according to the median BDI score to allow for comparisons. One-way ANOVA techniques were used to look for significant differences between variables in the two groups. Bivariate correlations were used to look for significant relationships between variables in each group. RESULTS: The two groups only differed in parameters measuring emotional state. Only the subjects with higher BDI scores showed significant correlations between EST performance and cognitive and PD-related variables. CONCLUSIONS: Those PD patients with more severe forms of illness and a greater level of prefrontal cognitive dysfunction are more vulnerable to the distracting effects of external negative stimuli. According to the cognitive model of depression, this may ultimately lead to the development of clinical depression.

A prospective study of the early postsurgical psychiatric associations of epilepsy surgery.

OBJECTIVES: To examine prospectively the frequency and nature of psychiatric symptoms seen in patients during the first three months after temporal lobe surgery for chronic intractable epilepsy and in addition to study the relation between presurgical mental state, laterality of surgery, and postsurgical seizure and psychiatric course. METHOD: A consecutive series of 60 patients being assessed for temporal lobe surgery for intractable epilepsy were studied. They were interviewed before surgery and at six weeks and again at three months after operation. RESULTS: At six weeks after surgery half of those with no psychopathology preoperatively had developed symptoms of anxiety or depression and 45% of all patients were noted to have increased emotional lability. By three months after surgery emotional lability and anxiety symptoms had diminished whereas depressive states tended to persist. Patients with a left hemispheric focus were more likely to experience persisting anxiety. CONCLUSION: The early months after surgery for epilepsy are characterised by the relatively common presence of psychiatric symptoms. It is proposed that presurgical and early postsurgical neuropsychiatric involvement in programmes of surgery for epilepsy will help to improve the quality of the treatment package offered to patients.

Psychiatric profiles and patterns of cerebral blood flow in focal epilepsy: interactions between depression, obsessionality, and perfusion related to the laterality of the epilepsy.

OBJECTIVES: In a study of patients with focal epilepsy the hypothesis was explored that different measurements of psychopathology are related to specific distributions of cerebral perfusion. METHODS: Forty patients had SPECT performed with (99m)Tc-HMPAO. In addition, patients received a psychiatric evaluation with the following psychiatric questionnaires: the Beck depression inventory, the Leyton obsessionality inventory, the Bear-Fedio questionnaire, and the social stress and support interview. Patients were analysed in two groups according to the laterality of the epilepsy. Nine patients were excluded based on poor quality scans (n = 1), unlateralised epilepsy (n = 4), and left or ambidextrous handedness (n = 4). RESULTS: There were no overall differences between the left and right epilepsy groups on measures of psychopathology. Associations were found between scores on some of the rating scales and regional cerebral blood flow. Specifically, for patients with left sided epilepsy, higher scores on the Beck depression inventory were associated with lower contralateral temporal and bilateral frontal perfusion, and higher occipital perfusion. For patients with right sided epilepsy higher scores on the Leyton obsessionality inventory were associated with increased perfusion in ipsilateral temporal, thalamic, and basal ganglia regions and bilateral frontal regions. CONCLUSION: The results do not support the notion that lateralised epileptogenic lesions are associated with different levels of depression, obsessionality, or personality traits. They support the view that certain psychopathological symptom patterns are related to specific regional dysfunctions depending on the laterality of a hemispheric lesion.

Blunted left cingulate activation in mood disorder subjects during a response interference task (the Stroop).

Functional neuroimaging studies have found abnormal anterior cingulate activity in depressed subjects, and other studies have shown that the cingulate gyrus becomes active in healthy subjects during interference tasks. The authors hypothesized that subjects with mood disorder might show blunted cingulate activation during the standard Stroop interference task or during a modified version involving sadness-laden words. In contrast to 11 age- and sex-matched healthy control subjects who activated the left cingulate during the standard Stroop, 11 mood-disordered subjects activated the right anterior cingulate gyrus only slightly and instead showed increased activity in the left dorsolateral prefrontal and visual cortex. This study supports theories of blunted limbic and paralimbic activation and abnormal cingulate activity in depression and adds to the growing knowledge of the functional neuroanatomy of depression.

Depression in Parkinson's disease. A positron emission study.

BACKGROUND: This study investigated biological correlates of depression in patients with idiopathic Parkinson's disease (PD). We tested the hypothesis that in patients with PD and depression, there was regional dysfunction involving brain areas previously implicated in functional imaging studies of patients with primary depression. METHOD: Using positron emission tomographic measurements of regional cerebral blood flow (rCBF), patterns of resting rCBF were measured in ten patients with PD and major depression, and ten patients with PD alone. The results were compared with findings from ten patients with primary depression and ten normal controls, scanned using identical methods as part of an earlier study. Groups were matched for age, sex and symptom severity. RESULTS: Bilateral decreases in rCBF were observed in anteromedial regions of the medial frontal cortex and the cingulate cortex (Brodmann's areas (BA) 9 and 32) in the depressed PD group, compared with those with PD alone and compared with normal controls. This regional disturbance overlapped that observed in patients with primary depression. CONCLUSIONS: The findings indicate that the medial prefrontal cortex is a common area of neural dysfunction in the manifestation of both primary depression and depression in PD.

Striatal dopamine receptor binding in epileptic psychoses.

In order to study the nature of dopaminergic activity in epileptic psychoses we investigated striatal dopamine receptor binding in 14 patients with epilepsy. Seven of the patients were acutely psychotic when studied, having recently developed a periictal schizophreniform psychosis. The remaining patients were not psychotic. All patients were scanned using single photon emission tomography (SPET) with 123I-IBZM, a specific dopamine D2 receptor ligand. A region of interest analysis was performed. Comparison of mean basal ganglia to occipital cortex activity ratios in the two groups demonstrated significantly reduced specific binding of 123I-IBZM to striatal D2 receptors in the psychotic patients compared to those without psychosis.

An idiot savant calendrical calculator with Gilles de la Tourette syndrome: implications for an understanding of the savant syndrome.

We describe the existence of the savant syndrome in association with Gilles de la Tourette's Syndrome (GTS). The presentation of savant abilities is typical of that previously described. Similarities between autism, the disorder most characteristically associated with savants, and GTS in terms of obsessionality are noted. Previously reported psychological studies of autistic savants are briefly reviewed and, together with evidence from neuroimaging in GTS, obsessive compulsive disorder (OCD), and autism, used to support a model of the underpinnings of savant skills.

Vigabatrin and depression.

Ten patients who developed a major depressive episode in association with vigabatrin treatment for intractable epilepsy are reported. The depression usually occurred early in the course of treatment, but when delayed followed a recent increase in dose. Depressive symptoms occurred at doses varying between 1.5 g and 4 g a day, often but not always when patients were experiencing a decrease in their seizure frequency. Most patients had a history of affective disturbance, sometimes in association with other GABAergic drugs. The observations support a possible role for GABAergic mechanisms in the biology of mood disorders.