Directional DBS of the Fornix in Alzheimer's Disease Achieves Long-Term Benefits: A Case Report.

Background: Current treatments for Alzheimer's disease (AD) modulate global neurotransmission but are neither specific nor anatomically directed. Tailored stimulation of target nuclei will increase treatment efficacy while reducing side effects. We report the results of the first directional deep brain stimulation (dDBS) surgery and treatment of a patient with AD in an attempt to slow the progression of the disease in a woman with multi-domain, amnestic cognitive status. Methods: We aimed to assess the safety of dDBS in patients with AD using the fornix as stimulation target (primary objective) and the clinical impact of the stimulation (secondary objective). In a registered clinical trial, a female patient aged 81 years with a 2-year history of cognitive decline and diagnoses of AD underwent a bilateral dDBS surgery targeting the fornix. Stimulation parameters were set between 3.9 and 7.5 mA, 90 µs, 130 Hz for 24 months, controlling stimulation effects by 18F-fluoro-2-deoxy-D-glucose (18F-FDG) scans (baseline, 12 and 24 months), magnetoencephalography (MEG) and clinical/neuropsychological assessment (baseline, 6, 12, 18, and 24 months). Results: There were no important complications related to the procedure. In general terms, the patient showed cognitive fluctuations over the period, related to attention and executive function patterns, with no meaningful changes in any other cognitive functions, as is shown in the clinical dementia rating scale (CDR = 1) scores over the 24 months. Such stability in neuropsychological scores corresponds to the stability of the brain metabolic function, seen in PET scans. The MEG studies described low functional connectivity at baseline and a subsequent increase in the number of significant connections, mainly in the theta band, at 12 months. Conclusion: The dDBS stimulation in the fornix seems to be a safe treatment for patients in the first stage of AD. Effects on cognition seem to be mild to moderate during the first months of stimulation and return to baseline levels after 24 months, except for verbal fluency. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT03290274], identifier [NCT03290274].

Temporal dynamics of amygdala response to emotion- and action-relevance.

It has been proposed that the human amygdala may not only encode the emotional value of sensory events, but more generally mediate the appraisal of their relevance for the individual's goals, including relevance for action or task-based needs. However, emotional and non-emotional/action-relevance might drive amygdala activity through distinct neural signals, and the relative timing of both kinds of responses remains undetermined. Here, we recorded intracranial event-related potentials from nine amygdalae of patients undergoing epilepsy surgery, while they performed variants of a Go/NoGo task with faces and abstract shapes, where emotion- and action-relevance were orthogonally manipulated. Our results revealed early amygdala responses to emotion facial expressions starting ~ 130 ms after stimulus-onset. Importantly, the amygdala responded to action-relevance not only with face stimuli but also with abstract shapes (squares), and these relevance effects consistently occurred in later time-windows (starting ~ 220 ms) for both faces and squares. A similar dissociation was observed in gamma activity. Furthermore, whereas emotional responses habituated over time, the action-relevance effect increased during the course of the experiment, suggesting progressive learning based on the task needs. Our results support the hypothesis that the human amygdala mediates a broader relevance appraisal function, with the processing of emotion-relevance preceding temporally that of action-relevance.

Human amygdala response to unisensory and multisensory emotion input: No evidence for superadditivity from intracranial recordings.

The amygdala is crucially implicated in processing emotional information from various sensory modalities. However, there is dearth of knowledge concerning the integration and relative time-course of its responses across different channels, i.e., for auditory, visual, and audiovisual input. Functional neuroimaging data in humans point to a possible role of this region in the multimodal integration of emotional signals, but direct evidence for anatomical and temporal overlap of unisensory and multisensory-evoked responses in amygdala is still lacking. We recorded event-related potentials (ERPs) and oscillatory activity from 9 amygdalae using intracranial electroencephalography (iEEG) in patients prior to epilepsy surgery, and compared electrophysiological responses to fearful, happy, or neutral stimuli presented either in voices alone, faces alone, or voices and faces simultaneously delivered. Results showed differential amygdala responses to fearful stimuli, in comparison to neutral, reaching significance 100-200 ms post-onset for auditory, visual and audiovisual stimuli. At later latencies, ∼400 ms post-onset, amygdala response to audiovisual information was also amplified in comparison to auditory or visual stimuli alone. Importantly, however, we found no evidence for either super- or subadditivity effects in any of the bimodal responses. These results suggest, first, that emotion processing in amygdala occurs at globally similar early stages of perceptual processing for auditory, visual, and audiovisual inputs; second, that overall larger responses to multisensory information occur at later stages only; and third, that the underlying mechanisms of this multisensory gain may reflect a purely additive response to concomitant visual and auditory inputs. Our findings provide novel insights on emotion processing across the sensory pathways, and their convergence within the limbic system.

Emotional arousal modulation of right temporoparietal cortex in depression depends on parental depression status in women: first evidence.

BACKGROUND: Structural and Electroencephalography (EEG) abnormalities in right temporoparietal cortex have been associated with family history of depression (FH). Here we investigate if functional abnormalities in this area, indexed by attenuated responses to emotionally arousing stimuli, are also family-history-dependent. METHODS: Neuromagnetic activity for emotional and neutral complex scenes was recorded by Magnetoencephalography (MEG) in 20 depressed patients without, 8 depressed patients with FH, and 15 healthy controls. Emotion-sensitive neuronal steady state responses were cortical source localized and tested for group-by-emotion interactions. RESULTS: The group-by-emotion interaction (F(4, 80)=4.4, p=0.004) was explained by a significant modulation of right temporoparietal cortex activity by emotional arousal in controls and patients without FH. This effect was reduced in FH positive patients. The difference between patient groups remained when clinical variables such as symptom severity were accounted for. LIMITATIONS: All patients were medicated, but differences between patient groups remained after accounting for medication dosage. Further, the sample size was limited, but data-driven resampling statistics showed the robustness of our effects. Finally, the sample consists of female patients only and we cannot generalize our results to male samples. CONCLUSIONS: Patients with FH show impaired recruitment of attention-relevant cortical circuitry by emotional stimuli. The neuroanatomical locus of this effect accords with previous reports on structural abnormalities and electrophysiological deficits at rest in individuals with FH. Our results speak to the relevance of right temporoparietal dysfunction in emotional information processing as a potential endophenotype for depression with FH.

Memory fMRI in left hippocampal sclerosis: optimizing the approach to predicting postsurgical memory.

BACKGROUND: An optimal technique for clinical memory fMRI is not established. Previous studies suggest activity in right parahippocampal gyrus and right hippocampus shows the strongest difference between left hippocampal sclerosis (HS) patients and normal control subjects and that the difference in activity between left and right hippocampus predicts postoperative memory change. METHODS: The authors studied 30 patients with mesial temporal lobe epilepsy (mTLE) and left HS, 12 of whom subsequently underwent surgery, and 13 normal control subjects. The patients who had surgery underwent neuropsychometric evaluation pre- and postoperatively. All subjects underwent a verbal memory encoding event-related fMRI study. Activation maps were assessed visually. Subsequently, the brain regions involved in the memory task were revealed by group averaging; these regions were used to determine regions of interest (ROIs) for subsequent analysis. By use of stepwise discriminant function and stepwise multiple regression, the ROIs that optimally discriminated between patients and normal control subjects and that optimally predicted postoperative verbal memory outcome were determined. RESULTS: Visual inspection of individual patient activation statistic maps revealed noisy data that did not afford visual interpretation. Stepwise discriminant function revealed the difference between left and right hippocampal activity best discriminated between patients and normal control subjects. Stepwise multiple regression revealed left hippocampal activity was the strongest predictor of postoperative verbal memory outcome; greater left hippocampal activity predicted a greater postoperative decline in memory. CONCLUSIONS: Patients with left hippocampal sclerosis (HS) differ from normal control subjects in the distribution of memory-encoding activity between left and right hippocampus. Functional adequacy of left hippocampus best predicts postoperative memory outcome in left HS.

Pre-operative verbal memory fMRI predicts post-operative memory decline after left temporal lobe resection.

Functional MRI (fMRI) of cognitive tasks depends on technology widely available in the clinical sphere, but has yet to show a role in the investigation of patients. We report here the first demonstration of a clinically valuable role for cognitive fMRI. Temporal lobe epilepsy (TLE) is commonly caused by hippocampal sclerosis and is frequently resistant to drug treatment. Surgical resection of the left hippocampus in this setting can cure seizures, but may produce significant verbal memory decline, which is hard to predict. We report 10 right-handed TLE patients with left hippocampal sclerosis who underwent left hippocampal resection. We compared currently used data for the prediction of post-operative verbal memory decline in such patients with a novel fMRI assessment of verbal memory encoding. Multiple regression analyses showed that fMRI provided the strongest independent predictor of memory outcome after surgery. At the individual subject level, the fMRI data had high positive predictive value for memory decline.