Magnetic Resonance Spectroscopy (MRS) and Positron Emission Tomography (PET) Imaging in Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is characterised by structural and functional deficits in the cortico-striato-thalamic-cortical (CSTC) circuitry and abnormal neurochemical changes are thought to modulate these deficits. The hypothesis that an imbalanced concentration of the brain neurotransmitters, in particular glutamate (Glu) and gamma-amino-butyric acid (GABA), could impair the normal functioning of the CSTC, thus leading to OCD symptoms, has been tested in humans using magnetic resonance spectroscopy (MRS) and positron emission tomography (PET). This chapter summarises these neurochemical findings and represents an attempt to condense such scattered literature. We also discuss potential challenges in the field that may explain the inconsistent findings and suggest ways to overcome them. There is some convergent research from MRS pointing towards abnormalities in the brain concentration of neurometabolite markers of neuronal integrity, such as N-acetylaspartate (NAA) and choline (Cho). Lower NAA levels have been found in dorsal and rostral ACC of OCD patients (as compared to healthy volunteers), which increase after CBT and SSRI treatment, and higher Cho concentration has been reported in the thalamus of the OCD brain. However, findings for other neurometabolites are very inconsistent. Studies have reported abnormalities in the concentrations of creatine (Cr), GABA, glutamate (Glu), glutamine (Gln), Ins (myo-inositol), and serotonin (5-HT), but most of the results were not replicated. The question remains whether the NAA and Cho findings are genuinely the only neurochemical abnormalities in OCD or whether the lack of consistent findings for the other neurometabolites is caused by the lower magnetic field (1-3 Tesla (T)) used by the studies conducted so far, their small sample sizes or a lack of proper control for medication effects. To answer these questions and to further inform the biological underpinning of the symptoms and the cognitive problems at the basis of OCD we need better controlled studies using clear medicated vs unmedicated groups, larger sample sizes, stronger magnetic fields (e.g. at 7 T), and more consistency in the definition of the regions of interest.

Abnormal Auditory Processing and Underlying Structural Changes in 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2 DS), one of the highest genetic risk for the development of schizophrenia, offers a unique opportunity to understand neurobiological and functional changes preceding the onset of the psychotic illness. Reduced auditory mismatch negativity response (MMN) has been proposed as a promising index of abnormal sensory processing and brain pathology in schizophrenia. However, the link between the MMN response and its underlying cerebral mechanisms in 22q11.2 DS remains unexamined. We measured auditory-evoked potentials to frequency deviant stimuli with high-density electroencephalogram and volumetric estimates of cortical and thalamic auditory areas with structural T1-weighted magnetic resonance imaging in a sample of 130 individuals, 70 with 22q11.2 DS and 60 age-matched typically developing (TD) individuals. Compared to TD group, the 22q11.2 deletion carriers reveal reduced MMN response and significant changes in topographical maps and decreased gray matter volumes of cortical and subcortical auditory areas, however, without any correlations between MMN alteration and structural changes. Furthermore, exploratory research on the presence of hallucinations (H+\H-) reveals no change in MMN response in 22q11.2DS (H+ and H-) as compared to TD individuals. Nonetheless, we observe bilateral volume reduction of the superior temporal gyrus and left medial geniculate in 22q11.2DSH+ as compared to 22q11.2DSH- and TD participants. These results suggest that the mismatch response might be a promising neurophysiological marker of functional changes within the auditory pathways that might underlie elevated risk for the development of psychotic symptoms.

Abnormal development of early auditory processing in 22q11.2 Deletion Syndrome.

The 22q11.2 Deletion Syndrome (22q11.2 DS) is one of the highest genetic risk factors for the development of schizophrenia spectrum disorders. In schizophrenia, reduced amplitude of the frequency mismatch negativity (fMMN) has been proposed as a promising neurophysiological marker for progressive brain pathology. In this longitudinal study in 22q11.2 DS, we investigate the progression of fMMN between childhood and adolescence, a vulnerable period for brain maturation. We measured evoked potentials to auditory oddball stimuli in the same sample of 16 patients with 22q11.2 DS and 14 age-matched controls in childhood and adolescence. In addition, we cross-sectionally compared an increased sample of 51 participants with 22q11.2 DS and 50 controls divided into two groups (8-14 and 14-20 years). The reported results are obtained using the fMMN difference waveforms. In the longitudinal design, the 22q11.2 deletion carriers exhibit a significant reduction in amplitude and a change in topographic patterns of the mismatch negativity response from childhood to adolescence. The same effect, reduced mismatch amplitude in adolescence, while preserved during childhood, is observed in the cross-sectional study. These results point towards functional changes within the brain network responsible for the fMMN. In addition, the adolescents with 22q11.2 DS displayed a significant increase in amplitude over central electrodes during the auditory N1 component. No such differences, reduced mismatch response nor increased N1, were observed in the typically developing group. These findings suggest different developmental trajectories of early auditory sensory processing in 22q11.2 DS and functional changes that emerge during the critical period of increased risk for schizophrenia spectrum disorders.

Subcortical electrophysiological activity is detectable with high-density EEG source imaging.

Subcortical neuronal activity is highly relevant for mediating communication in large-scale brain networks. While electroencephalographic (EEG) recordings provide appropriate temporal resolution and coverage to study whole brain dynamics, the feasibility to detect subcortical signals is a matter of debate. Here, we investigate if scalp EEG can detect and correctly localize signals recorded with intracranial electrodes placed in the centromedial thalamus, and in the nucleus accumbens. Externalization of deep brain stimulation (DBS) electrodes, placed in these regions, provides the unique opportunity to record subcortical activity simultaneously with high-density (256 channel) scalp EEG. In three patients during rest with eyes closed, we found significant correlation between alpha envelopes derived from intracranial and EEG source reconstructed signals. Highest correlation was found for source signals in close proximity to the actual recording sites, given by the DBS electrode locations. Therefore, we present direct evidence that scalp EEG indeed can sense subcortical signals.