Larissa McKetton

Altered anterior visual system development following early monocular enucleation

Purpose Retinoblastoma is a rare eye cancer that generally occurs before 5 years of age and often results in enucleation (surgical removal) of the cancerous eye. In the present study, we sought to determine the consequences of early monocular enucleation on the morphological development of the anterior visual pathway including the optic chiasm and lateral geniculate nucleus. Methods A group of adults who had one eye enucleated early in life due to retinoblastoma was compared to binocularly intact controls. Although structural changes have previously been reported in late enucleation, we also collected data from one late enucleated participant to compare to our early enucleated participants. Measurements of the optic nerves, optic chiasm, optic tracts and lateral geniculate nuclei were evaluated from T1 weighted and proton density weighted images collected from each participant. Results The early monocular enucleation group exhibited overall degeneration of the anterior visual system compared to controls. Surprisingly, however, optic tract diameter and geniculate volume decreases were less severe contralateral to the remaining eye. Consistent with previous research, the late enucleated participant showed no asymmetry and significantly larger volume decreases in both geniculate nuclei compared to controls. Conclusions The novel finding of an asymmetry in morphology of the anterior visual system following long-term survival from early monocular enucleation indicates altered postnatal visual development. Possible mechanisms behind this altered development include recruitment of deafferented cells by crossing nasal fibres and/or geniculate cell retention via feedback from primary visual cortex. These data highlight the importance of balanced binocular input during postnatal maturation for typical anterior visual system morphology.

Abnormal Lateral Geniculate Nucleus and Optic Chiasm in Human Albinism

Our objective was to measure how the misrouting of retinal ganglion cell (RGC) fibers affects the organization of the optic chiasm and lateral geniculate nuclei (LGN) in human albinism. We compared the chiasmal structures and the LGN in both pigmented controls and patients with albinism by using high‐resolution structural magnetic resonance imaging (MRI). We studied 12 patients with oculocutaneous albinism and 12 age‐matched pigmented controls. Using a 3T MRI scanner, we acquired a T1‐weighted three‐dimensional magnetization‐prepared rapid gradient‐echo (MPRAGE) image of the whole brain, oriented so that the optic nerves, chiasm, and tracts were in the same plane. We acquired multiple proton density‐weighted images centered on the thalamus and midbrain, and averaged them to increase the signal, enabling precise manual tracing of the anatomical boundaries of the LGN. Albinism patients exhibited significantly smaller diameters of the optic nerves, chiasm and tracts, and optic chiasm and LGN volume compared with controls (P < 0.001 for all). The reductions in chiasmal diameters in the albinism compared with the control group can be attributed to the abnormal crossing of optic fibers and the reduction of RGCs in the central retina. The volume of the LGN devoted to the center of the visual field may be reduced in albinism due to fewer RGCs representing the area where the fovea would normally lie. Our data may be clinically useful in addressing how genetic deficits compromise proper structural and functional development in the brain. J. Comp. Neurol. 522:2680–2687, 2014.

Evidence of multisensory plasticity: Asymmetrical medial geniculate body in people with one eye.

The medial geniculate body (MGB) plays a central role in auditory processing with both efferent and afferent tracts to primary auditory cortex. People who have lost one eye early in life have enhanced sound localization, lack visual over auditory dominance and integrate auditory and visual information optimally, similar to controls, despite taking longer to localize unimodal visual stimuli. Compared to controls, people with one eye have decreased lateral geniculate nuclei (LGN) volume as expected given the 50% deafferentation of the visual system. However, LGN volume is larger than predicted contralateral to the remaining eye, indicating altered structural development likely through recruitment of deafferented LGN cells. Purpose: the current study investigated whether structural MGB changes are also present in this group given the changes they exhibit in auditory processing. Methods: MGB volumes were measured in adults who had undergone early unilateral eye enucleation and were compared to binocularly intact controls. Results: unlike controls, people with one eye had a significant asymmetry with a larger left compared to right MGB, independent of eye of enucleation. MGB volume correlated positively with LGN volume in people with one eye. Conclusions: volume asymmetry in the MGB in people with one eye may represent increased interactions between the left MGB and primary auditory cortex. This interaction could contribute to increased auditory and other left hemisphere-dominant processing, including language, as compensation for the loss of one half of visual inputs early in life. The positive correlation between MGB and LGN volume is not due to space constraints but rather indicates increased plasticity in both auditory and visual sensory systems following early eye enucleation.

Mapping intracerebral steal during a hypercapnic challenge

In patients with intracranial steno-occlusive disease, blood vessels distal to the stenosis are in a state of maximum compensatory vasodilation to maintain cerebral perfusion. With a global cerebral vasodilatory stimulus such as hypotension or hypercapnia, blood vessels in the nonaffected areas often vasodilate, causing intracerebral ‘‘steal’’ (ICS) of the blood flow away from the affected area, increasing the risk of cerebral ischemia (and subsequent stroke). Mapping of ICS could potentially be used as a tool to assess patients for the risk for stroke. Using blood oxygen level-dependent magnetic resonance (BOLD-MR) imaging as a surrogate of cerebral blood flow (CBF) and CO2 as a vasodilatory stimulus, we developed a non-invasive method to map ICS. Here, we present the cerebrovascular reactivity – D CBF/D end-tidal CO2 (PETCO2) – map of a 29-yr-old patient with 90% stenosis of the left proximal middle cerebral artery. The BOLD MR images were obtained while PETCO2 was controlled in a ramp sequence (see Figure) from 35 to 52 mmHg using a sequential breathing circuit and a computercontrolled gas blender (RespirAct, Thornhill Research, Inc., Toronto, ON, Canada). Using custom software, colour cerebrovascular reactivity maps are generated that indicate areas of normal (red) and paradoxical (i.e., steal) (blue) reactivity. The cerebrovascular reactivity values were measured as % BOLD-MR signal intensity per mmHg change in PETCO2. As the PETCO2 increases from 35 to 42 mmHg, steal (blue areas) develops on the left side of the brain, with normal reactivity on the right side (Figure, MR image A). With further increases in PETCO2 (from 42 to 52 mmHg) more steal appears on the left side (Figure, MR image B). Finally, a return to normocapnia results in a symmetrically opposite effect, with reverse steal on the healthy right side and increased blood flow to the compromised vascular bed on the left (Figure, MR image C). Understanding ICS may be important during perioperative care of patients with intracranial stenosis as both hypercapnia and hypotension could lead to hemodynamically mediated stroke.

No otoacoustic evidence for a peripheral basis underlying absolute pitch

Absolute pitch (AP) is the ability to identify or produce the perceived pitch of a sound (e.g., fundamental frequency of a piano note) without an external reference. This ability is relatively rare (~1/10,000 individuals possess it) and the mechanisms underlying AP are not well understood. This study examined whether there was evidence for a peripheral (i.e., cochlear) basis for AP based upon otoacoustic emissions (OAEs). The chief motivations were that both AP and spontaneous emissions (SOAEs) appear to have genetic components and anecdotal observations of prevalence in certain populations (e.g., relatively higher incidence of both in Asians). We examined SOAEs and stimulus-frequency emissions (SFOAEs) in both control (N = 21) and AP (N = 13) normal-hearing populations. We found no substantial differences in SOAE activity between groups (e.g., no evidence for one or more strong SOAEs that could act as a cue). SFOAE phase-gradient delays, measured using several probe levels (20–50 dB SPL), also showed no ...

Auditory processing in absolute pitch possessors

Absolute pitch (AP) is a rare ability in classifying a musical pitch without a reference standard. It has been of great interest to researchers studying auditory processing and music cognition since it is seldom expressed and sheds light on influences pertaining to neurodevelopmental biological predispositions and the onset of musical training. We investigated the smallest frequency that could be detected or just noticeable difference (JND) between two pitches. Here, we report significant differences in JND thresholds in AP musicians and non-AP musicians compared to non-musician control groups at both 1000 Hz and 987.76 Hz testing frequencies. Although the AP-musicians did better than non-AP musicians, the difference was not significant. In addition, we looked at neuro-anatomical correlates of musicianship and AP using structural MRI. We report increased cortical thickness of the left Heschl’s Gyrus (HG) and decreased cortical thickness of the inferior frontal opercular gyrus (IFO) and circular insular sulcus volume (CIS) in AP compared to non-AP musicians and controls. These structures may therefore be optimally enhanced and reduced to form the most efficient network for AP to emerge.Absolute pitch (AP) is a rare ability in classifying a musical pitch without a reference standard. It has been of great interest to researchers studying auditory processing and music cognition since it is seldom expressed and sheds light on influences pertaining to neurodevelopmental biological predispositions and the onset of musical training. We investigated the smallest frequency that could be detected or just noticeable difference (JND) between two pitches. Here, we report significant differences in JND thresholds in AP musicians and non-AP musicians compared to non-musician control groups at both 1000 Hz and 987.76 Hz testing frequencies. Although the AP-musicians did better than non-AP musicians, the difference was not significant. In addition, we looked at neuro-anatomical correlates of musicianship and AP using structural MRI. We report increased cortical thickness of the left Heschl’s Gyrus (HG) and decreased cortical thickness of the inferior frontal opercular gyrus (IFO) and circular insular su...

The aging brain and cerebrovascular reactivity

ABSTRACT Cerebrovascular reactivity (CVR) is a measure of vascular response to a vasoactive stimulus, and can be used to assess the health of the brain vasculature. In this current study we used different analyses of BOLD fMRI responses to CO2 to provide a number of metrics including ramp and step CVR, speed of response and transfer function analysis (TFA). 51 healthy control volunteers between the ages of 18–85 (26 males) were recruited and scanned at 3T field strength. Atlases reflecting voxel‐wise means and standard deviations were compiled to assess possible differences in these metrics between four age cohorts. Testing was carried out using an automated computer‐controlled gas blender to induce hypercapnia in a step and ramp paradigm, and monitoring end‐tidal partial pressures of CO2 (PETCO2) and O2 (PETO2). No significant differences were found for resting PETCO2 values between cohorts. Ramp CVR decreased significantly with age in white matter frontal regions comprising the ACA‐MCA watershed area, a finding that may be indicative of age related changes. Similarly, TFA showed that gain was reduced in the left white matter ACA‐MCA watershed area as well as the posterior and anterior cingulate cortex, and superior frontal gyrus in the oldest compared to youngest cohort. These findings, detailing changes in cerebrovascular regulation in the healthy aging brain should prove useful in mapping areas of dysregulated blood flow in individuals with vascular risk factors especially those at risk for developing vascular dementia. HIGHLIGHTSGray matter cerebrovascular reactivity metrics are largely stable across ages.White matter cerebrovascular reactivity metrics are largely stable across ages.The magnitude of the cingulum and frontal regions are affected in old age.No significant difference in resting end‐tidal pressure of carbon dioxide with aging.

Long-term changes in cerebrovascular reactivity following EC-IC bypass for intracranial steno-occlusive disease

The purpose of this retrospective observational study is to investigate the long-term changes in cerebrovascular reactivity (CVR) as a measure of cerebral hemodynamics in patients with intracranial steno-occlusive disease (IC-SOD) after they have undergone an Extracranial-intracranial (EC-IC) bypass. Twenty-six patients suffering from IC-SOD were selected from our CVR database. Nineteen patients underwent unilateral and 7 underwent bilateral revascularization. CVR measurements were done using BOLD-MRI and precisely controlled CO2 and expressed as ΔBOLD (%)/Δ PETCO2 (mmHg). Trends in CVR over time were compared in both vascularized and non-vascularized hemispheres. Repeated measures analysis of variance with Greenhouse-Geisser correction was used to determine CVR changes within the grey matter MCA for longitudinal assessments. Overall, re-vascularized hemisphere showed a significant increase in CVR at the first follow-up, followed by a slight decrease at the second follow-up that significantly increased compared to the pre-bypass. However, the changes in the postoperative CVR were quite variable across the patients. Similar variability was seen in subsequent follow-ups, with a slight overall decline in the long term CVR as compared with first post-operative CVR. Our study demonstrates that EC-IC bypass has a beneficial long-term effect on cerebral hemodynamics and this effect varies between patients probably due to the variability in the underlying vascular pattern receiving the bypass. Hence, in the postoperative follow-up of patients routine functional imaging to monitor cerebral hemodynamics may be useful as the risk of stroke and cognitive decline remain present with impaired CVR.

No otoacoustic evidence for a peripheral basis of absolute pitch

ABSTRACT Absolute pitch (AP) is the ability to identify the perceived pitch of a sound without an external reference. Relatively rare, with an incidence of approximately 1/10,000, the mechanisms underlying AP are not well understood. This study examined otoacoustic emissions (OAEs) to determine if there is evidence of a peripheral (i.e., cochlear) basis for AP. Two OAE types were examined: spontaneous emissions (SOAEs) and stimulus‐frequency emissions (SFOAEs). Our motivations to explore a peripheral foundation for AP were several‐fold. First is the observation that pitch judgment accuracy has been reported to decrease with age due to age‐dependent physiological changes cochlear biomechanics. Second is the notion that SOAEs, which are indirectly related to perception, could act as a fixed frequency reference. Third, SFOAE delays, which have been demonstrated to serve as a proxy measure for cochlear frequency selectivity, could indicate tuning differences between groups. These led us to the hypotheses that AP subjects would (relative to controls) exhibit a. greater SOAE activity and b. sharper cochlear tuning. To test these notions, measurements were made in normal‐hearing control (N = 33) and AP‐possessor (N = 20) populations. In short, no substantial difference in SOAE activity was found between groups, indicating no evidence for one or more strong SOAEs that could act as a fixed cue. SFOAE phase‐gradient delays, measured at several different probe levels (20‐50 dB SPL), also showed no significant differences between groups. This observation argues against sharper cochlear frequency selectivity in AP subjects. Taken together, these data support the prevailing view that AP mechanisms predominantly arise at a processing level in the central nervous system (CNS) at the brainstem or higher, not within the cochlea. HighlightsNo substantial difference in SOAE activity between absolute pitch subjects and controls.No difference in SFOAE phase‐gradient delays between absolute pitch subjects and controls.The data argue against sharper cochlear frequency selectivity in absolute pitch subjects.

Cerebrovascular Resistance: The Basis of Cerebrovascular Reactivity

The cerebral vascular network regulates blood flow distribution by adjusting vessel diameters, and consequently resistance to flow, in response to metabolic demands (neurovascular coupling) and changes in perfusion pressure (autoregulation). Deliberate changes in carbon dioxide (CO2) partial pressure may be used to challenge this regulation and assess its performance since CO2 also acts to change vessel diameter. Cerebrovascular reactivity (CVR), the ratio of cerebral blood flow (CBF) response to CO2 stimulus is currently used as a performance metric. However, the ability of CVR to reflect the responsiveness of a particular vascular region is confounded by that region’s inclusion in the cerebral vascular network, where all regions respond to the global CO2 stimulus. Consequently, local CBF responses reflect not only changes in the local vascular resistance but also the effect of changes in local perfusion pressure resulting from redistribution of flow within the network. As a result, the CBF responses to CO2 take on various non-linear patterns that are not well-described by straight lines. We propose a method using a simple model to convert these CBF response patterns to the pattern of resistance responses that underlie them. The model, which has been used previously to explain the steal phenomenon, consists of two vascular branches in parallel fed by a major artery with a fixed resistance unchanging with CO2. One branch has a reference resistance with a sigmoidal response to CO2, representative of a voxel with a robust response. The other branch has a CBF equal to the measured CBF response to CO2 of any voxel under examination. Using the model to calculate resistance response patterns of the examined branch showed sigmoidal patterns of resistance response, regardless of the measured CBF response patterns. The sigmoid parameters of the resistance response pattern of examined voxels may be mapped to their anatomical location. We show an example for a healthy subject and for a patient with steno-occlusive disease to illustrate. We suggest that these maps provide physiological insight into the regulation of CBF distribution.