Johan N. van der Meer

Reduced parietal P300 amplitude is associated with an increased risk for a first psychotic episode.

BACKGROUND P300 abnormalities indicate changes in information processing and are one of the most reliable biological markers of schizophrenia. We sought to investigate whether abnormalities in P300 (P3) or other event-related potentials are also present in subjects at ultra high risk (UHR) for developing psychosis and whether they are helpful in predicting transition to psychosis. METHODS The N1, N2, N2b, P2, and P3 amplitudes were assessed in 61 UHR subjects, of whom 18 subjects (30%) made a transition to psychosis over a 3-year follow-up period (UHR + T: age 20.4 years) and 43 (70%) did not (UHR + NT: age 19.3 years), and 28 age- and intelligence-matched healthy control subjects (age 20.0 years). Psychopathology was also assessed. RESULTS The UHR + T subjects showed smaller parietal P3 amplitudes, compared with control subjects and UHR + NT subjects. Moreover, the N2b was higher in control subjects compared with both UHR groups. We found no differences in N1 or P2 components between the groups, and our UHR subjects did not exhibit bilateral P3 asymmetry. Reduced P3 amplitudes were the best predictor for subsequent psychosis in the UHR group. The P3 reduction was related to increased social anhedonia and withdrawal and a lower global assessment of social functioning and social personal adjustment. CONCLUSIONS The UHR + T subjects showed reduced parietal P3 amplitudes. In addition, a reduced P3 amplitude was the best predictor for subsequent psychosis. If replicated, these findings might contribute to a more accurate prediction of a first psychotic episode. Furthermore, reduced social functioning might be related to information processing deficits in UHR subjects.

White matter abnormalities in adults with 22q11 deletion syndrome with and without schizophrenia

Dysfunction of cerebral white matter (WM) is a potential factor underlying the neurobiology of schizophrenia. People with 22q11 deletion syndrome have altered brain morphology and increased risk for schizophrenia, therefore decreased WM integrity may be related to schizophrenia in 22q11DS. We measured fractional anisotropy (FA) and WM volume in 27 adults with 22q11DS with schizophrenia (n=12, 22q11DS SCZ+) and without schizophrenia (n=15, 22q11DS SCZ-), 12 individuals with idiopathic schizophrenia and 31 age-matched healthy controls. We found widespread decreased WM volume in posterior and temporal brain areas and decreased FA in areas of the frontal cortex in the whole 22q11DS group compared to healthy controls. In 22q11DS SCZ+ compromised WM integrity included inferior frontal areas of parietal and occipital lobe. Idiopathic schizophrenia patients showed decreased FA in inferior frontal and insular regions compared to healthy controls. We found no WM alterations in 22q11DS SCZ+ vs. 22q11DS SCZ-. However, there was a negative correlation between FA and PANSS scores (Positive and Negative Symptom Scale) in the whole 22q11DS group in the inferior frontal, cingulate, insular and temporal areas. This is the first study to investigate WM integrity in adults with 22q11DS. Our results suggest that pervasive WM dysfunction is intrinsic to 22q11DS and that psychotic development in adults with 22q11DS involves similar brain areas as seen in schizophrenia in the general population.

Auditory ERP components before and after transition to a first psychotic episode

We investigated the course of Event Related Potentials (ERP) from prior to until shortly after a first psychotic episode in subjects at Ultra High Risk (UHR) for psychosis. N1, N2, N2b, P2 and P3 amplitudes were assessed using an auditory active oddball paradigm in 15 UHR subjects who made a transition to psychosis (UHR+T) at follow up, 23 subjects without a transition (UHR+NT) and 17 matched healthy controls at inclusion and again after approximately 18 months. Repeated-measures analyses revealed no significant time effects for any of the ERP components. However, an interaction effect was found for N1 amplitudes. Post-hoc analyses showed that N1 amplitudes were smaller at follow up compared to baseline only in UHR+T subjects. P3 amplitudes showed no further reduction after psychotic onset. These findings suggest that discernable ERP components behave differently during progression from the prodromal phase to the first psychotic episode. These findings may give insight in pathophysiological mechanisms underlying the genesis of psychosis.

Disorganized Sensorimotor Integration in Mutation-Positive Myoclonus-Dystonia: A Functional Magnetic Resonance Imaging Study

BACKGROUND Myoclonus-dystonia is an autosomal dominantly inherited movement disorder clinically characterized by myoclonic jerks and dystonic postures or movements of the upper body. Functional imaging studies in other, mainly heterogeneous groups of dystonia do agree on dysfunction of the striato-pallido-thalamo-cortical circuit. OBJECTIVE To study cerebral activation patterns with functional magnetic resonance imaging in a genetically defined homogeneous group of patients with dystonia. DESIGN, SETTING, AND PATIENTS Thirteen clinically affected SGCE mutation carriers and 11 control subjects were studied in a case-control study. Intervention A finger-tapping motor task was performed in a block design using 3.0-T magnetic resonance imaging. MAIN OUTCOME MEASURES Blood oxygenation level-dependent signals were compared between groups. RESULTS In SGCE mutation carriers, we observed significant hyperresponsiveness in contralateral inferior parietal cortical areas, ipsilateral premotor and primary somatosensory cortex, and ipsilateral cerebellum during the motor task compared with healthy control subjects. CONCLUSIONS The cortical activation patterns in SGCE mutation carriers during this motor task point to a disorganized sensorimotor integration in this uniform group of patients with dystonia and are consistent with functional neuroimaging studies in other types of (hereditary) dystonia.

Interactions between Affective and Cognitive Processing Systems in Problematic Gamblers: A Functional Connectivity Study

Background Motivational and cognitive abnormalities are frequently reported in pathological gambling. However, studies simultaneously investigating motivational and cognitive processing in problematic gamblers are lacking, limiting our understanding of the interplay between these systems in problematic gambling. Studies in non-clinical samples indicate that interactions between dorsal “executive” and ventral “affective” processing systems are necessary for adequate responses in various emotive situations. Methods We conducted a generalized Psycho-Physiological Interaction (gPPI) analysis to assess the influence of affective stimuli on changes in functional connectivity associated with response inhibition in 16 treatment seeking problematic gamblers (PRGs) and 15 healthy controls (HCs) using an affective Go-NoGo fMRI paradigm including neutral, gambling-related, positive and negative pictures as neutral and affective conditions. Results Across groups, task performance accuracy during neutral inhibition trials was positively correlated with functional connectivity between the left caudate and the right middle frontal cortex. During inhibition in the gambling condition, only in PRGs accuracy of task performance was positively correlated with functional connectivity within sub-regions of the dorsal executive system. Group interactions showed that during neutral inhibition, HCs exhibited greater functional connectivity between the left caudate and occipital cortex than PRGs. In contrast, during inhibition in the positive condition, PRGs compared to HCs showed greater functional connectivity between the left caudate and occipital cortex. During inhibition trials in the negative condition, a stronger functional connectivity between the left caudate and the right anterior cingulate cortex in PRGs compared to HCs was present. There were no group interactions during inhibition in the gambling condition. Conclusions During gamble inhibition PRGs seem to benefit more from functional connectivity within the dorsal executive system than HCs, because task accuracy in this condition in PRGs is positively correlated with functional connectivity, although the groups show similar connectivity patterns during gamble inhibition. Greater functional connectivity between the ventral affective system and the dorsal executive system in PRGs in the affective conditions compared to HCs, suggests facilitation of the dorsal executive system when affective stimuli are present specifically in PRGs.

Dopaminergic modulation of the human reward system: a placebo-controlled dopamine depletion fMRI study

Reward related behaviour is linked to dopaminergic neurotransmission. Our aim was to gain insight into dopaminergic involvement in the human reward system. Combining functional magnetic resonance imaging with dopaminergic depletion by α-methylparatyrosine we measured dopamine-related brain activity in 10 healthy volunteers. In addition to blood-oxygen-level-dependent (BOLD) contrast we assessed the effect of dopaminergic depletion on prolactin response, peripheral markers for dopamine and norepinephrine. In the placebo condition we found increased activation in the left caudate and left cingulate gyrus during anticipation of reward. In the α-methylparatyrosine condition there was no significant brain activation during anticipation of reward or loss. In α-methylparatyrosine, anticipation of reward vs. loss increased activation in the right insula, left frontal, right parietal cortices and right cingulate gyrus. Comparing placebo versus α-methylparatyrosine showed increased activation in the left cingulate gyrus during anticipation of reward and the left medial frontal gyrus during anticipation of loss. α-methylparatyrosine reduced levels of dopamine in urine and homovanillic acid in plasma and increased prolactin. No significant effect of α-methylparatyrosine was found on norepinephrine markers. Our findings implicate distinct patterns of BOLD underlying reward processing following dopamine depletion, suggesting a role of dopaminergic neurotransmission for anticipation of monetary reward.

Is There a Role for Combined EMG-fMRI in Exploring the Pathophysiology of Essential Tremor and Improving Functional Neurosurgery?

Background Functional MRI combined with electromyography (EMG-fMRI) is a new technique to investigate the functional association of movement to brain activations. Thalamic stereotactic surgery is effective in reducing tremor. However, while some patients have satisfying benefit, others have only partial or temporary relief. This could be due to suboptimal targeting in some cases. By identifying tremor-related areas, EMG-fMRI could provide more insight into the pathophysiology of tremor and be potentially useful in refining surgical targeting. Objective Aim of the study was to evaluate whether EMG-fMRI could detect blood oxygen level dependent brain activations associated with tremor in patients with Essential Tremor. Second, we explored whether EMG-fMRI could improve the delineation of targets for stereotactic surgery. Methods Simultaneous EMG-fMRI was performed in six Essential Tremor patients with unilateral thalamotomy. EMG was recorded from the trembling arm (non-operated side) and from the contralateral arm (operated side). Protocols were designed to study brain activations related to voluntary muscle contractions and postural tremor. Results Analysis with the EMG regressor was able to show the association of voluntary movements with activity in the contralateral motor cortex and supplementary motor area, and ipsilateral cerebellum. The EMG tremor frequency regressor showed an association between tremor and activity in the ipsilateral cerebellum and contralateral thalamus. The activation spot in the thalamus varied across patients and did not correspond to the thalamic nucleus ventralis intermedius. Conclusion EMG-fMRI is potentially useful in detecting brain activations associated with tremor in patients with Essential Tremor. The technique must be further developed before being useful in supporting targeting for stereotactic surgery.

Sensory gating in subjects at ultra high risk for developing a psychosis before and after a first psychotic episode

Abstract Objectives. To explore sensory gating deficits in subjects at Ultra High Risk (UHR) for psychosis before and after transition to a first psychotic episode. Methods. Sensory gating was assessed with the paired click paradigm in 61 UHR subjects, of whom 18 (30%) made a transition to psychosis (UHR + T) over a 3-year follow-up period and 28 matched healthy controls. Subjects were assessed at inclusion and again after approximately 18 months. P50, N100 (N1) and P200 (P2) sensory gating was established using the amplitude on the first (S1) and second (S2) click, the ratio- (S2/S1) and the difference score (S1-S2). Psychopathology was also assessed. Results. At baseline, UHR + T subjects presented smaller N1 difference scores compared to UHR + NT subjects and controls. The N1 difference score contributed modestly to the prediction of a first psychotic episode. Repeated measure analyses revealed smaller N1 and P2 S1 amplitudes, smaller P2 difference scores and larger P2 ratios at follow-up compared to baseline in UHR + T subjects. Conclusion. The N1 difference score may be helpful in predicting a first psychosis. N1 and P2 sensory gating measures also showed alterations between the prodromal phase and the first psychosis, suggesting that these changes may relate to the onset of a frank psychotic episode.

Clinical and neurophysiological characterization of myoclonus in complex regional pain syndrome

The origin of myoclonus in patients with complex regional pain syndrome (CRPS) is unknown. Eight patients with CRPS related myoclonus were clinically evaluated and studied with intermuscular and corticomuscular coherence analysis. Jerks were present at rest, aggravated during action and were frequently associated with tremulousness or dystonia. Electromyography demonstrated a burst duration ranging from 25 to 240 ms with burst frequencies varying from <1 jerk/s during rest to 20 Hz during action. Coherence studies showed increased intermuscular coherence in 4 patients in the 6 to 12 Hz band, as reported in patients with enhanced physiological tremor. In 2 patients side‐to‐side coherence was observed, pointing to a central oscillatory drive. Significant coherence entrainment was detected in 5 patients. We conclude that the characteristics of myoclonus in CRPS are different from other forms of myoclonus.

Dopaminergic modulation of the reward system in schizophrenia: A placebo-controlled dopamine depletion fMRI study

BACKGROUND The brain reward circuitry innervated by dopamine is critically disturbed in schizophrenia. This study aims to investigate the role of dopamine-related brain activity during prediction of monetary reward and loss in first episode schizophrenia patients. METHODS We measured blood-oxygen-level dependent (BOLD) activity in 10 patients with schizophrenia (SCH) and 12 healthy controls during dopamine depletion with α-methylparatyrosine (AMPT) and during a placebo condition (PLA). RESULTS AMPT reduced the activation of striatal and cortical brain regions in SCH. In SCH vs. controls reduced activation was found in the AMPT condition in several regions during anticipation of reward and loss, including areas of the striatum and frontal cortex. In SCH vs. controls reduced activation of the superior temporal gyrus and posterior cingulate was observed in PLA during anticipation of rewarding stimuli. PLA patients had reduced activation in the ventral striatum, frontal and cingulate cortex in anticipation of loss. The findings of reduced dopamine-related brain activity during AMPT were verified by reduced levels of dopamine in urine, homovanillic-acid in plasma and increased prolactin levels. CONCLUSIONS Our results indicate that dopamine depletion affects functioning of the cortico-striatal reward circuitry in SCH. The findings also suggest that neuronal functions associated with dopamine neurotransmission and attribution of salience to reward predicting stimuli are altered in schizophrenia.