Andrea Wijtenburg

Cerebellar-Stimulation Evoked Prefrontal Electrical Synchrony Is Modulated by GABA

Cerebellar-prefrontal connectivity has been recognized as important for behaviors ranging from motor coordination to cognition. Many of these behaviors are known to involve excitatory or inhibitory modulations from the prefrontal cortex. We used cerebellar transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) to probe cerebellar-evoked electrical activity in prefrontal cortical areas and used magnetic resonance spectroscopy (MRS) measures of prefrontal GABA and glutamate levels to determine if they are correlated with those potentials. Cerebellar-evoked bilateral prefrontal synchrony in the theta to gamma frequency range showed patterns that reflect strong GABAergic inhibitory function (r = − 0.66, p = 0.002). Stimulation of prefrontal areas evoked bilateral prefrontal synchrony in the theta to low beta frequency range that reflected, conversely, glutamatergic excitatory function (r = 0.66, p = 0.002) and GABAergic inhibitory function (r = − 0.65, p = 0.002). Cerebellar-evoked prefrontal synchronization had opposite associations with cognition and motor coordination: it was positively associated with working memory performance (r = 0.57, p = 0.008) but negatively associated with coordinated motor function as measured by rapid finger tapping (r = − 0.59, p = 0.006). The results suggest a relationship between regional GABA levels and interregional effects on synchrony. Stronger cerebellar-evoked prefrontal synchrony was associated with better working memory but surprisingly worse motor coordination, which suggests competing effects for motor activity and cognition. The data supports the use of a TMS-EEG-MRS approach to study the neurochemical basis of large-scale oscillations modulated by the cerebellar-prefrontal connectivity.

12.4 BRAIN LACTATE IS RELATED TO COGNITION IN SCHIZOPHRENIA

Abstract Laura Rowland, University of Maryland School of Med: Bioenergetic function may be altered in schizophrenia as supported by post-mortem, preclinical, cerebrospinal fluid, and 31P-magnetic resonance spectroscopy (MRS) research. Impairments in bioenergetic function may lead to cognitive and functional dysfunction, characteristics of the illness. First, a 7T MRS study that tested the hypothesis that frontal lactate concentrations are elevated in schizophrenia and related to cognitive impairments will be presented. Second, recent advances in brain lactate measurements with 3T MRS will be presented. Methods Twenty-nine controls and 27 participants with schizophrenia completed the study. MRS scanning was conducted on a Philips ‘Achieva’ 7T scanner, and spectra were acquired from a frontal voxel using STEAM (TE/TM/TR=14/33/3000 ms, 128 NEX, 16 NEX water). Participants completed the MATRICS Consensus Cognitive Battery (MCCB) for cognitive function and UCSD Performance-Based Skills Assessment (UPSA) for functional capacity. The relationships between lactate, MCCB, and UPSA were examined. 3T MRS test-retest measures of lactate were conducted on a Siemens Prisma scanner using spectra editing (TE/TR=140/3, editing pulse at 4.1ppm with 30Hz bandwidth, 360 NEX, 16 NEX water). Results Patients had significantly higher lactate compared to controls (p = 0.045). Higher lactate was associated with poorer general cognitive function (r=-0.36, p=0.01) Visual learning, processing speed, and reasoning/problem solving cognitive domains showed the strongest relationships with lactate. Poorer functional capacity (r=-0.43, p=0.001) was also related to higher lactate. 3T spectral editing studies showed excellent reproducibility with a mean coefficient of variation of 4%. Discussion Higher frontal lactate levels in schizophrenia support the hypothesis that brain bioenergetics are altered and related to cognitive and functional impairments in schizophrenia. Higher lactate could be due to inefficient aerobic metabolism causing a shift towards anaerobic metabolism or poor utilization of lactate. Lactate measurements are doable at 3T field strength and may be a useful biomarker of cognition in schizophrenia. Interventions to promote efficient mitochondrial energy metabolism may prove useful for enhancing cognition and alleviating functional impairments in schizophrenia.

T180. LOWER GLUTAMATE LEVEL IN TEMPORO-PARIETAL AREA MAY PREDICT A BETTER RESPONSE TO TDCS IN SCHIZOPHRENIA: A PILOT STUDY

Abstract Background Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique which uses a weak electric current from electrodes across the scalp to modulate targeted brain areas. It has been suggested that tDCS may be useful in reducing psychotic symptoms such as auditory hallucination. The aim of this study was to find alteration of key neurotransmitters in schizophrenia in temporo-parietal area (TPA) after tDCS intervention, using magnetic resonance spectroscopy (MRS) technique. Methods Ten schizophrenia patients with auditory hallucination were recruited from the outpatient clinic of Seoul National University Hospital (SNUH). The anode was placed over the left dorsolateral prefrontal cortex (DLPFC), and the cathode was placed over the left TPA. Patients underwent MRS scan with the very short echo time phase rotation STEAM sequence before and after the tDCS sessions, respectively. Results Seven of the participants completed MRS scans before and after the tDCS sessions. Positive and Negative Symptom Scale (PANSS) total and general psychophathology scale showed a significant improvement after tDCS. There was no significant difference between glutamate/creatinine (Cr) level before and after tDCS sessions. However, a significant positive correlation between the pre-tDCS glutamate/Cr value in left TPA and the improvement in auditory hallucination measured by Auditory Hallucination Rating Scale (AHRS) after tDCS was found. Discussion The results of this investigation show that the schizophrenia patients whose auditory hallucination benefits the most from tDCS treatment had lower glutamate/Cr level in left TPA. Previous studies regarding the relationship between glutamatergic system and treatment response mostly have only focused on the frontal area and striatum. However, this study suggests a potential role of glutamatergic system in TPA in predicting treatment response of auditory hallucination.

TMS evoked N100 reflects local GABA and glutamate balance

BACKGROUND Animal studies suggest that synchronized electrical activities in the brain are regulated by the primary inhibitory and excitatory neurotransmitters gamma-aminobutyric acid (GABA) and glutamate, respectively. Identifying direct evidence that this same basic chemical-electrical neuroscience principle operates in the human brains is critical for translation of neuroscience to pathological research. OBJECTIVE/HYPOTHESIS We hypothesize that the background neurochemical concentrations may affect the cortical excitability probed by transcranial magnetic stimulation (TMS). METHODS We used TMS with simultaneous evoked potential recording to probe the cortical excitability and determined how background frontal cortical GABA and glutamate levels measured using magnetic resonance spectroscopy (MRS) modulate frontal electrical activities. RESULTS We found that TMS-evoked N100 reflects a balance between GABA-inhibitory and glutamate-excitatory levels. About 46% of individual variances in frontal N100 can be explained by their glutamate/GABA ratio (r = -0.68, p = 0.001). Both glutamate (r = -0.51, p = 0.019) and GABA (r = 0.55, p = 0.01) significantly contributed to this relationship but in opposite directions. CONCLUSION The current finding encourages additional mechanistic studies to develop TMS evoked N100 as a potential electrophysiological biomarker for translating the known inhibitory GABAergic vs. excitatory glutamatergic chemical-electrical principle from animal brain studies to human brain studies.