Source analysis of scalp recorded data
shows a subset of twenty standard EEG channels
] illustrating the 4 Hz FMAER recorded from a single 7 year old neuro-typical research subject with normal language function. The upper image (Figure
A) utilizes the ears as reference point and the lower image (Figure
B) utilizes the common average reference
]. To the right, the corresponding topographic maps
] are shown taken at the peak of the 4 Hz sinusoidal response waveforms. Note the effects of changing the reference technique from ears to common average. The difference between data shown from the same subject in Figure
B reflects that ears (Figure
A) constitute poor reference sites when the adjoining temporal lobes are active. When the ear reference is employed, the maximal FMAER response is erroneously presented in the midline central-frontal region and appears absent in both temporal lobe sites (Figure
A). However, when the common average reference is employed, the maximal FMAER response is correctly observed in the left and right temporal regions independently (Figure
demonstrates the FMAER topography for the same 7 year old neuro-typical research subject with normal language function now illustrated with 24 electrodes and maps, derived from 128 channel data, using reference free mapping based upon the common average approach. Figure
illustrates details of the source analysis of the same 7 year old neuro-typical research subject with normal language function. PCA
] on the entire electrode set showed one primary, 4 Hz sine wave dominant component (top left column) which by source analysis decomposed into two major responses (top two center column) with origins in left and right posterior superior temporal gyri (right column) and with source orientation directed toward the central vertex region. The final two source components reflect primarily residual occipital and prefrontal alpha and blink activity along with small amounts of 4 Hz activity. Figure
shows these same data now mapped on a manufacturer (BESA) supplied age appropriate standard MRI. Note that bilateral temporal sources are in the planum temporale
and oriented towards the vertex region.
Figure 2 Normal FMAER - effect of reference electrode. The waveforms for 20 channels of a 4 Hz FMAER study are shown to the left as recorded from a neuro-typical 7 year old control subject. Electrode designations appear below each channel’s waveform which (more ...)
Figure 3 128 Channel mapping of normal FMAER, common average reference. The same data from the same 7 year old normal subject, shown in Figure
, are now depicted when utilizing 128 channels (24 selected waveforms as shown to the left) with utilization (more ...)
Figure 4 Source analysis of a normal subject’s FMAER. Source analysis is illustrated for the same 7 year old whose scalp data are shown in Figures
. The time base is approximately one second for all waveforms. The top of the (more ...)
Figure 5 FMAER source analysis in standard MRI atlas for age. The sources illustrated in the right pane of Figure
for the 7 year old normal subject are now shown within the standard 6–8 year old BESA software supplied standard MRI. Note that (more ...)
shows the results of source analyses of 15 right handed subjects including five 7–9 year old (left pane) and five 14–20 year old (center pane) neuro-typical controls. Note the tight clustering in the posterior temporal gyrus for the 7–9 year olds. The 14–20 year olds showed a similar pattern in the left temporal region with a slightly less restricted spatial distribution in the right temporal lobe. The right pane shows five 2–6 year old clinical patients with diagnoses of ADHD without clinical evidence of language dysfunction and with scalp FMAER patterns that appeared normal by visual inspection.
Figure 6 FMAER source locations for 15 subjects. The three panes each show three schematic head maps seen from the left, right, and posterior views. Each pane illustrates the locations of primary left and right temporal sources for the indicated groups. The colored (more ...)
Cortical FMAER from surgically placed grids and strips
shows schematic maps estimating grid and strip placement for six surgical patients for whom FMAER had been requested to facilitate localization of language-eloquent cortex. These studies were requested when language evaluation by direct cortical stimulation was felt to be potentially unreliable due to immaturity, behavioral difficulty, language disorder, and/or clinician-patient language barrier. This group spanned the 3–20 year old age range. Only grids involving the lateral temporal surface are shown. Grid electrode contacts showing responses following the 4 Hz FMAER stimulus are marked with a red X. Contacts that failed to respond show no X. Grid contacts in the frontal, parietal, inferior temporal or occipital regions never demonstrated FMAER responses. The boundary between contacts showing 4 Hz FMAER responses and those without response was typically quite abrupt.
Figure 7 Cortically recorded FMAER for six subjects. Five images represent a schematic representation of the left hemisphere (Cases 1–5) and one the right hemisphere (Case 6). Atop the hemisphere images are placed representations of one or more grids, (more ...)
Direct cortical stimulation demonstrated a small region of receptive language impairment in Case 1 within the mid left superior temporal gyrus. For Case 2 direct cortical stimulation induced receptive impairment in almost the same location. Testing by cortical stimulation was technically unsuccessful for cases 3 and 4 despite clear FMAER responses. For Case 5, no language interference was observed for cortical stimulation of any of the shown contacts. However, a delay was found in naming objects for contacts in the medial left anterior temporal base likely involving the parahippocampal gyrus and affecting memory. Case 6, where cortical recording was limited to the right hemisphere, showed as expected, no language interference anywhere within the right hemisphere. An FMAER was observed - with scalp electrodes - from the left posterior temporal region (not illustrated).
Thus, for cortical stimulation delineated language-eloquent contacts (Cases 1 and 2), co-resident corresponding FMAER responses were clearly obtained. Furthermore, for all six surgical cases, the contacts that showed FMAER responses roughly corresponded to the regions delineated in normal subjects by source analysis. However, it became clear that over the left as well as the right temporal cortex the FMAER responsive area extended beyond eloquent cortex as determined by cortical stimulation. It is unclear at this point whether this represents a response to the presence of cortical pathophysiology, such as seizure discharges, results from lack of detailed language assessment, or constitutes a normal phenomenon.
shows a single surgical patient for whom a grid with a very dense placement of electrode contacts was employed. The cortical anatomy and the grid placement as shown were reconstructed from the patient’s MRI and CT scans. The image (see legend) summarizes the results of the FMAER stimulation and the extensive cortical auditory language mapping by direct stimulation. Additional contacts on coarser grids and strips are grayed-out. None of these additional contacts demonstrated any response to FMAER or cortical stimulation. Of the eleven contacts (red) that showed impaired reading or word repetition upon direct cortical stimulation, ten showed well developed FMAER responses. Of the eight contacts (green) that resulted in the patient’s report of subjective voices or noise, five showed FMAER responses. Nine contacts showed FMAER responses yet failed to show concurrent language eloquence (yellow circles around blue contact) to cortical stimulation. The two contacts located in the upper right quadrant of the grid overlaid the angular gyrus. The detection of language eloquence there might have required more complex stimulation paradigms than were utilized. The six contacts located mainly in the upper left grid quadrant and just anterior to the indicated primary epileptic focus were found to overlay an underlying MRI detected lesion of undetermined type. When the regions of this lesion as well as the epileptic focus were surgically removed seizures ceased without obvious loss of language function.
Figure 8 Cortically recorded FMAER; high electrode density grid, one subject. The true lateral surface and grid contact locations are shown as reconstructed from MRI and CT studies. The superior surface (vertex) is shown above, inferior temporal surface below, (more ...)
Since preoperative scalp recorded FMAERs were not performed for any of the above patients, a direct comparison between scalp and cortical localization was not possible.
Clinical patients with mixed receptive and expressive speech disorders
show the scalp waveform appearance and source analysis results for two children with significant mixed receptive/expressive language disorder. Of note were the excellent non-dominant right temporal responses for both patients (Figures
A), and the essentially absent left temporal responses.
Figure 9 FMAER and source analysis, 5 year old with language delay. The top section (A) shows 20 channels of a scalp recorded FMAER with channel designation displayed below corresponding waveforms. Amplitude scale is to the right. The common average reference (more ...)
Figure 10 FMAER and source analysis, 7 year old with language delay. Display convention is as for Figure
. The clinical presentation was also quite similar. Again note the absent left temporal scalp response, top section (A). Again source analysis below (more ...)
For the 7 year old patient depicted in Figure
, the right temporal source showed normal morphology as well as location and orientation (Figure
B, red, center and right panes). While a left temporal response was clearly present, the waveform was of slightly lower amplitude (Figure
B, blue, middle pane) than noted on the right (Figure
B, red, middle pane). Although found within the left temporal lobe, the location and orientation of the left temporal source was quite aberrant (Figure
B, blue source dipole, right pane). Thus, this patient’s FMAER (Figure
A) appeared to be absent unilaterally in the scalp response display likely because of the aberrant left sided source location and aberrant source orientation.
For the 5 year old patient (Figure
B, lower three panes) the right sided primary source was placed normally in the right posterior superior temporal gyrus and was oriented normally (Figure
B, red source, lower middle and right panes). A weak and aberrant, very low amplitude left parietal poorly defined 4 Hz response was present. A left temporal 4 Hz response was not seen. (10B, blue source, middle and right panes).
the 5 year old patient’s FMAER data displayed in Figure
A are also shown when the ear reference method was used. Note the marked difference between the common average and ear reference conditions in the FMAER’s spatial distribution. The common average reference (Figure
A) demonstrated a highly localized response in the right temporal regions (T8, P8) whereas the use of the ear reference resulted in a broad, bilateral pattern which made visual detection of the missing left temporal response highly problematic.
Figure 11 Effect of EAR reference on FMAER with absent left sided response. The display convention is as for Figure
A. Note that redisplay of the Figure
A data utilizing ear reference causes the restricted right sided response (Figure
A patient with Landau-Kleffner syndrome before and after successful treatment
shows the FMAER scalp topographies for an initial study (top pane, 12 A) at the time of LKS diagnosis. Language, both receptive and expressive, had significantly declined. Although there were no clinical seizures, the waking EEG demonstrated bilateral anterior and independent left and right temporal seizure discharges (spike waves). Also there was a marked accentuation of discharges in sleep consistent with electrical status epilepticus of sleep (ESES). The FMAER was bilaterally absent (12 A). Approximately 13 months later, after treatment with nocturnal benzodiazepine, daytime lamotrigine, and daily prednisolone significant improvement in all aspects of language was observed. The EEG failed to demonstrate discharges in waking. In sleep there were only a few scattered discharges and ESES was absent. FMAER responses were clearly obtained in both temporal regions (bottom pane, 12 B).
Figure 12 FMAER, Landau-Kleffner syndrome before and after treatment. Display convention is as for the upper portions of Figures
. The top (A) shows absence of an FMAER response over either hemisphere before treatment. The bottom (more ...)
This case illustrates the FMAER’s utility for the identification of physiologic correlates of language improvement. The functional improvement in language was clearly accompanied by marked FMAER improvement.
A patient with Landau-Kleffner syndrome and evidence for rapidly declining function
shows the FMAER of an adolescent patient who presented with behavioral irritability and declining school performance. The patient showed no clear receptive or expressive dysphasia, however the patient had great difficulty remembering auditory information. The EEG demonstrated left central-parietal spikes with occasional spontaneous electrographic seizures (over ten seconds in length) with focal left central-parietal (CP5) spikes. The FMAER demonstrated a normal bilateral response (Figure
A). One month later the patient demonstrated further clinical deterioration with slowed speech production and receptive greater than expressive dysphasia. At that time the repeat FMAER demonstrated a clear left temporal deficit (Figure
Figure 13 FMAER, Landau-Kleffner syndrome, deterioration over one month. The FMAER is shown from a second subject with the Landau-Kleffner syndrome. Display convention is as for Figure
. The top display shows a normal FMAER response at the time the patient (more ...)
Source analysis of an average of 12 CP5 spikes from the time of the first study demonstrated the primary spike source (Figure
, red source, right pane) to be located in the left temporal base and possibly related to the memory difficulty. A secondary spike source was located in the left Wernicke’s region (Figure
, blue source, right pane), which may relate to the subsequent language deterioration. An additional tertiary source was seen in the right medial temporal base (Figure
, green source, right pane).
Figure 14 FMAER, Landau-Kleffner syndrome, CP5 spike source analysis. Source analysis for the patient described in Figure
is shown for the average of 12 CP5 (left parietal-temporal) spikes during a short electrographic seizure and at the time of the (more ...)
This case illustrates the FMAER’s ability to identify physiological deterioration accompanying progression of LKS. The functional deterioration was clearly associated with FMAER deterioration.
A summary of findings for 18 subjects with LKS and/or ESES
summarizes the findings for 18 right-handed patients carrying the clinical diagnosis of LKS, ESES, or most commonly both diagnoses. All patients had received both FMAER studies and overnight EEG monitoring by in-hospital or ambulatory recordings. Ages ranged from 5 to 15 years. All patients presented with declines in cognition, behavior, memory, and language. The type and degree of language abnormality was typically referred to as mixed receptive/expressive dysphasia. FMAER studies were performed prior to overnight monitoring and subsequent institution of pharmacological therapy. EEG epochs containing prominent artifact or discharges were eliminated from EEG segments used to form the FMAER.
Patients with LKS and/or ESES - earliest available study
The FMAER was considered abnormal when absent or distorted, either bilaterally or unilaterally. Of the 18 patients 13 showed abnormal FMAERs; 11 of the 13 showed bilateral and two showed exclusively left sided abnormalities. Unilateral right sided abnormalities were not observed.
Source analyses of the left and right temporal spike averages were performed in order to determine whether the primary source component involved the region of the corresponding side’s superior temporal gyrus and/or Wernicke’s gyrus. Table
additionally notes the presence or absence of generalized discharges, the location of focal discharges and the spike wave index for overnight recording.
Cases 4, 5, and 13 might be considered primary LKS without ESES since no generalized discharges were observed even in sleep. Cases 5 and 13 demonstrated focal EEG activation during sleep in contrast to generalized spike wave activation during sleep, observed for other cases. Cases 3, 4, 6, and 16 failed to demonstrate any sleep potentiation of discharges. In cases 4, 6, and 15 EEG during FMAER stimulation showed increased frequency of left temporal discharges. However, in these three cases the FMAER failed to initiate clinical or electrographic seizures.
Note that all of the cases with abnormal FMAERs (Cases 1–13) source analysis demonstrated left hemisphere EEG discharges with demonstrable primary sources in or close to the posterior superior left temporal region. Eight of the 13 cases also manifested epileptiform involvement of the homologous right side (Cases 1–4, 7–9, 12). Three (Cases 5, 6, 13) failed to show right sided discharges which obviated right sided source analysis. The two cases showing unilateral left sided FMAER abnormality (Cases 10, 11) did not show right posterior superior temporal sources.
Similarly, note that none of the studies with normal FMAERs (Cases 14–18) demonstrated primary sources in the left or right posterior temporal regions - two (Cases 15, 16) showed no right sided discharges for analysis. Case 15 (whose data are shown in Figures
) showed a prominent secondary source in the vulnerable left posterior temporal region during the first recorded study at a time when the FMAER remained normal. One month later, however, when the clinical symptoms had progressed, the left FMAER had become abnormal (Figure
B). A source analysis at the time of the second study was not possible since discharges were not recorded during the second study.
These cases demonstrate that the bilateral absence of the FMAER is primarily associated with the presence of focal discharges originating in or near the bilateral superior temporal gyri. Absence of just the left sided FMAER was associated with just left sided spike source involvement. Those with normal bilateral FMAERs did not show primary spike source involvement in either of the superior temporal gyri.
Two patients with autism spectrum disorder
shows the scalp FMAER study results from two patients diagnosed with autism spectrum disorder. Both patients had marked language impairment. One patient (Figure
A) demonstrated near normal bilateral FMAER scalp responses. Despite the patient’s severe mixed language impairment, he frequently and clearly mimicked parts of speech yet in a nonsensical, jargon-like manner. The other patient (Figure
B), who also demonstrated severe mixed language impairment, failed to produce word-like sounds of any kind; his vocal output exclusively involved grunts and screeches. This patient (Figure
B) demonstrated an excellent right sided response; his left sided response was absent. These two cases illustrate the FMAER’s potential utility in ASD without functional language. Partial speech component production was accompanied by an intact FMAER, while complete absence of all speech production was accompanied by an absent FMAER.
Figure 15 Normal and abnormal FMAERs in autism. The display convention is as for Figure
. In the current figure, the top pane (A) illustrates a normal FMAER in a patient with autism. The bottom pane (B) shows an abnormal FMAER that is absent in the left (more ...)