Using fMRI to investigate speech-stream segregation and auditory attention in healthy adults and patients with memory complaints

Poor memory for recent conversations is the commonest presenting symptom in patients attending a cognitive neurology clinic. They also frequently have greater difficulty following and remembering conversations in the presence of background noise and/or unattended speech. While the ability to participate in and recall conversations depends on several cognitive functions (language-processing, attention, episodic and working memory), without the ability to perform auditory scene analysis, and more specifically speech-stream segregation, recall of verbal information will be impaired as a consequence of poor initial registration, over and above impaired encoding and subsequent retrieval. This thesis investigated auditory attention and speech-stream segregation in healthy participants (‘controls’) and patients presenting with ‘poor memory’, particularly a complaint of difficulty remembering recent verbal information. Although this resulted in the recruitment of many patients with possible or probable Alzheimer’s disease, it also included patients with mild cognitive impairment (MCI) of uncertain aetiology and a few with depression. Functional MRI data revealed brain activity involved in attention, working memory and speech-stream segregation as participants attended to a speaker in the absence and presence of background speech. The study on controls demonstrated that the right anterior insula, adjacent frontal operculum, left planum temporale and precuneus were more active when the attended speaker was partially masked by unattended speech. Analyses also revealed a central role for a right hemisphere system for successful attentive listening, a system that was not modulated by administration of a central cholinesterase inhibitor. Therefore, this study identified non-auditory higher-order regions in speech-stream segregation, and the demands on a right hemisphere system during attentive listening. Administration of a central cholinesterase inhibitor did not identify any benefit in the present patient group. However, my research has identified systems that might be therapeutic targets when attempting to modulate auditory attention and speech-stream segregation in patients with neurodegenerative disease.Open Acces

An open-label observational study and meta-analysis of non-invasive vagus nerve stimulation in medically refractory chronic cluster headache

BACKGROUND: Many patients with cluster headache (CH) are inadequately controlled by current treatment options. Non-invasive vagus nerve stimulation (nVNS) is reported to be effective in the management of CH though some studies suggest that it is ineffective. OBJECTIVE: To assess the safety and efficacy of nVNS in chronic cluster headache (CCH) patients. METHOD: We prospectively analysed data from 40 patients with refractory CCH in this open-label, observational study. Patients were seen in tertiary headache clinics at the National Hospital for Neurology and Neurosurgery and trained to use nVNS as preventative therapy. Patients were reivewed at one month and then three-monthly from onset. The primary endpoint was number of patients achieving ≥50% reduction in attack frequency at 3  months. A meta-analysis of all published studies evaluating the efficacy of nVNS in CCH was also conducted. We searched MEDLINE and EMBASE for all studies investigating the use of nVNS as a preventive or adjunctive treatment for CCH with five or more participants. Combined mean difference and responder proportions with 95% confidence intervals (CI) were calculated from the included studies. RESULTS: 17/40 patients (43%) achieved ≥50% reduction in attack frequency at 3  months. There was a significant reduction in monthly attack frequency from a baseline of 124 (±67) attacks to 79 (±63) attacks in month 3 (mean difference 44.7; 95% CI 25.1 to 64.3; p < 0.001). In month 3, there was also a 1.2-point reduction in average severity from a baseline Verbal Rating Scale of 8/10 (95% CI 0.5 to 1.9; p = 0.001). Four studies, along with the present study, were deemed eligible for meta-analysis, which showed a responder proportion of 0.35 (95% CI 0.07 to 0.69, n = 137) and a mean reduction in headache frequency of 35.3 attacks per month (95% CI 11.0 to 59.6, n = 108), from a baseline of 105 (±22.7) attacks per month. CONCLUSION: This study highlights the potential benefit of nVNS in CCH, with significant reductions in headache frequency and severity. To better characterise the effect, randomised sham-controlled trials are needed to confirm the beneficial response of VNS reported in some, but not all, open-label studies

Speech Registration in Symptomatic Memory Impairment

Background: An inability to recall recent conversations often indicates impaired episodic memory retrieval. It may also reflect a failure of attentive registration of spoken sentences which leads to unsuccessful memory encoding. The hypothesis was that patients complaining of impaired memory would demonstrate impaired function of “multiple demand” (MD) brain regions, whose activation profile generalizes across cognitive domains, during speech registration in naturalistic listening conditions.Methods: Using functional MRI, brain activity was measured in 22 normal participants and 31 patients complaining of memory impairment, 21 of whom had possible or probable Alzheimer’s disease (AD). Participants heard a target speaker, either speaking alone or in the presence of distracting background speech, followed by a question to determine if the target speech had been registered.Results: Patients performed poorly at registering verbal information, which correlated with their scores on a screening test of cognitive impairment. Speech registration was associated with widely distributed activity in both auditory cortex and in MD cortex. Additional regions were most active when the target speech had to be separated from background speech. Activity in midline and lateral frontal MD cortex was reduced in the patients. A central cholinesterase inhibitor to increase brain acetylcholine levels in half the patients was not observed to alter brain activity or improve task performance at a second fMRI scan performed 6–11 weeks later. However, individual performances spontaneously fluctuated between the two scanning sessions, and these performance differences correlated with activity within a right hemisphere fronto-temporal system previously associated with sustained auditory attention.Conclusions: Midline and lateralized frontal regions that are engaged in task-dependent attention to, and registration of, verbal information are potential targets for transcranial brain stimulation to improve speech registration in neurodegenerative conditions

An open-label observational study and meta-analysis of non-invasive vagus nerve stimulation in medically refractory chronic cluster headache

BackgroundMany patients with cluster headache (CH) are inadequately controlled by current treatment options. Non-invasive vagus nerve stimulation (nVNS) is reported to be effective in the management of CH though some studies suggest that it is ineffective.ObjectiveTo assess the safety and efficacy of nVNS in chronic cluster headache (CCH) patients.MethodWe prospectively analysed data from 40 patients with refractory CCH in this open-label, observational study. Patients were seen in tertiary headache clinics at the National Hospital for Neurology and Neurosurgery and trained to use nVNS as preventative therapy. Patients were reivewed at one month and then three-monthly from onset. The primary endpoint was number of patients achieving ≥50% reduction in attack frequency at 3  months. A meta-analysis of all published studies evaluating the efficacy of nVNS in CCH was also conducted. We searched MEDLINE and EMBASE for all studies investigating the use of nVNS as a preventive or adjunctive treatment for CCH with five or more participants. Combined mean difference and responder proportions with 95% confidence intervals (CI) were calculated from the included studies.Results17/40 patients (43%) achieved ≥50% reduction in attack frequency at 3  months. There was a significant reduction in monthly attack frequency from a baseline of 124 (±67) attacks to 79 (±63) attacks in month 3 (mean difference 44.7; 95% CI 25.1 to 64.3; p &lt; 0.001). In month 3, there was also a 1.2-point reduction in average severity from a baseline Verbal Rating Scale of 8/10 (95% CI 0.5 to 1.9; p = 0.001). Four studies, along with the present study, were deemed eligible for meta-analysis, which showed a responder proportion of 0.35 (95% CI 0.07 to 0.69, n = 137) and a mean reduction in headache frequency of 35.3 attacks per month (95% CI 11.0 to 59.6, n = 108), from a baseline of 105 (±22.7) attacks per month.ConclusionThis study highlights the potential benefit of nVNS in CCH, with significant reductions in headache frequency and severity. To better characterise the effect, randomised sham-controlled trials are needed to confirm the beneficial response of VNS reported in some, but not all, open-label studies

Association of Clinical and Neuroanatomical Factors With Response to Ventral Tegmental Area DBS in Chronic Cluster Headache

Background: Deep brain stimulation (DBS) of the ventral tegmental area (VTA) is a surgical treatment option for selected patients with refractory chronic cluster headache (CCH). We aimed to identify clinical and structural neuroimaging factors associated with response to VTA DBS in CCH. // Methods: This prospective observational cohort study examines consecutive patients with refractory CCH treated with VTA DBS by a multidisciplinary team in a single tertiary neuroscience centre as part of usual care. Headache diaries and validated questionnaires were completed at baseline and regular follow up intervals. All patients underwent T1-weighted structural MRI prior to surgery. We compared clinical features using multivariable logistic regression, and neuroanatomical differences using voxel-based morphometry (VBM) between responders and non-responders. // Results: Over a ten-year period, 43 patients (mean age 53 years, SD 11.9), including 29 males, with a mean duration of CCH 12 years (SD 7.4), were treated and followed up for at least one year (mean follow-up duration 5.6 years). Overall, there was a statistically significant improvement in median attack frequency from 140 to 56 per month (Z = -4.95, p <0.001), attack severity from 10/10 to 8/10 (Z = -4.83, p <0.001) and duration from 110 to 60 minutes (Z = -3.48, p <0.001). Twenty-nine (67.4%) patients experienced ≥50% improvement in attack frequency and were therefore classed as responders. There were no serious adverse events. The most common side effects were discomfort or pain around the battery site (seven patients) and transient diplopia and/or oscillopsia (six patients). There were no differences in demographics, headache characteristics, or comorbidities between responders and non-responders. VBM identified increased neural density in non-responders in several brain regions, including the orbitofrontal cortex, anterior cingulate cortex, anterior insula, and amygdala which were statistically significant (p <0.001). // Discussion: VTA DBS showed no serious adverse events, and, although there was no placebo control, was effective in approximately two-thirds of patients at long-term follow up. This study did not reveal any reliable clinical predictors of response. However, non-responders had increased neural density in brain regions linked to processing of pain and autonomic function, both of which are prominent in the pathophysiology of CCH