Effects of Hippocampal Lesions

#### **Chapter 8**

## Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection for Medically Intractable Temporal Lobe Epilepsy

*Tomokatsu Hori, Hideki Shiramizu and Hajime Miyata*

#### **Abstract**

Transsylvian selective amygdalohippocampectomy resulted in postoperative verbal memory decline in patients with mesial temporal lobe epilepsy of the languagedominant side. Mapping whole-brain connectivity changes have been studied recently of different surgical resection approaches for temporal lobe epilepsy. The subtemporal resection is the least disruptive to long-range connectivity, which may explain its better cognitive outcome. Finally, the authors introduced subtemporal multiple hippocampal transections technique in a case of hippocampal sclerosis negative left mesial temporal lobe epilepsy, and postoperative neuropsychological examinations revealed improvement of cognitive function immediately after the operation contrasting transsylvian multiple hippocampal transections in which verbal memory remains dropped. The authors introduced another new operation to left mesial temporal lobe epilepsy patient with hippocampal sclerosis by multiple hippocampal transections plus disconnection between CA1 and subiculum at the hippocampal head. Operative result is satisfactory in terms of neuropsychological and operative outcome.

**Keywords:** amygdalohippocampectomy, transsylvian, subtemporal, multiple hippocampal transection (MHT), disconnection CA1 and subiculum, neuropsychological outcome, hippocampal sclerosis (HS)

#### **1. Introduction**

The limbic lobe is located at the most medial portion of the cerebral hemisphere, like as a band surrounding the orifice into the lateral ventricle. The limbic lobe is mainly consisted of the hippocampal formation, the amygdaloid complex, and the cingulate cortices. These areas are concerned with the basic brain higher functions, such as emotion, memory, attention, cognition, and so on. Each area has the specific structural organization and the fiber connections executing the specific function. The circuit of memory, so-called Papez circuit, is consisted of the

hippocampal formation, mammillary body, anterior and midline thalamic nuclei, posterior cingulate cortex, and the retrohippocampal cortices. On the other hand, the circuit of the emotion, so-called Yakovlev circuit, is consisted of the amygdala, the mediodorsal thalamic nucleus, anterior cingulate cortex, and the orbitofrontal cortex. Although memory and emotion are processed on the independent circuit, there are also several structures where the fibers from the two circuits meet together, such as the nucleus accumbens, the entorhinal cortex, and the hypothalamic area. Memory information is stored efficiently only when the brain is in appropriate state for memory acquisition. This state, the motivating state for memory, is determined by the levels of awareness, cognition, attention, emotion, and other influences. The motivating state might change signal processing in the hippocampus. Classical anatomical observations with Golgi staining of hippocampal neurons are the basis for the simple trisynaptic circuit (dentate granule cells (DG)-Cornu Ammonis 3 (CA3), CA3 to CA1 concept of hippocampal function (**Figure 1**).

Recent anatomical work has revealed much richer synaptic connections between hippocampal neuron subfields (DG, CA3, CA2, and CA1) and wide distribution of axons along the longitudinal axis of the hippocampus [1].

Temporal lobe epilepsy (TLE) is involving the limbic system, especially amygdala and hippocampus which influences emotion, memory, attention, and cognition.

Despite various medical drugs have been tried to control intractable TLE, surgical treatment gives better seizure control comparing to prolonged medical

#### **Figure 1.**

*Schema illustrating disconnection between CA1 and subiculum (red line). Yellow arrow is mossy fiber, blue arrow is Schaffer collateral, green arrow is alveus hippocampi, and red line is disconnection between CA1 and subiculum just until hippocampal sulcus. This histology is sectioned from normal hippocampus taken from cadaver without central nervous lesion.*

*Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

treatment [2]. But in this randomized control study, substantial number (around 5%) of surgical patients complained of postoperative memory difficulty, but the authors acknowledge that although this complication is important, but the benefit is worth the risk. Concerning such memory problems, in surgical population, MR negative language-dominant-side mesial TLE group, so-called paradoxical temporal lobe epilepsy (PTLE) [3], is at great risk of postoperative memory deficits. Until now, neurosurgeons have made great efforts to stop such a postoperative memory decline by adopting various operative approaches, such as reducing size of temporal lobectomy, selective amygdalohippocampectomy, and recent radiosurgical interventions [4].

In this chapter of this book, our further efforts to escape from such a postoperative memory decline such as subtemporal multiple hippocampal transection (MHT) with or without disconnection between cornu ammonis (CA1) and subiculum will be presented in detail (**Figure 1**). These techniques and results are never reported in the world literature.

#### **2. Neuropsychological results of various surgical treatments for TLE**

Temporal lobe epilepsy (TLE) is one of the most intractable epilepsy involving the limbic system, especially amygdala and hippocampus which influences emotion, memory, attention, and cognition.

Despite various medical drugs have been tried to control intractable TLE, surgical treatment gives better seizure control comparing to prolonged medical treatment [2]. Concerning memory problems, in surgical population, MR negative language-dominant-side mesial TLE group, so-called paradoxical temporal lobe epilepsy (PTLE) [3], is at great risk of postoperative memory deficits. Until now, neurosurgeons have made great efforts to stop such a postoperative memory decline by adopting various operative approaches, such as reducing size of temporal lobectomy, selective amygdalohippocampectomy, and recent radiosurgical interventions [4].

Morino et al. reported comparison of neuropsychological results after selective amygdalohippocampectomy versus anterior temporal lobectomy (ATL) [5]. Transsylvian selective amygdalohippocampectomy (TSSAH) is an operative technique planned to spare unaffected brain region during surgical treatment for mesial temporal lobe epilepsy (MTLE). In contrast to standard anterior temporal lobectomy (ATL), the advantages of TSSAH with respect to postoperative cognitive outcome are equivocal without randomized control study. Morino et al. compared cognitive function before and after surgery in 49 patients with unilateral mesial temporal lobe seizures who underwent either ATL (*n* = 17) or TSSAH (*n* = 32). All patients received neuropsychological testing before and 1 year after surgery. The intelligence quotient (IQ) increased postoperatively in both surgical groups. Memory evaluation in the ATL group revealed a postoperative decline in nonverbal memory after right-sided resection and a postoperative decline in verbal memory after left-sided resection. In the TSSAH group, there was a slight postoperative decline only in verbal memory after left-sided resection, but other memory function was preserved. There was significant postoperative improvement in verbal memory after right-sided resection. Overall, memory function was better preserved in the TSSAH group than in the ATL group.

There is another change of operative procedure invented by Shimizu et al. [6], that is, transsylvian multiple hippocampal transection (TSMHT).

**Table 1** is a summary of memory scores by transsylvian multiple hippocampal transection (TSMHT) for PTLE [6, 7]. Preoperative verbal memory score dropped 1 month after surgery, but 1 year after surgery improved up to preoperative level.

How about the neuropsychological results after subtemporal **amygdalohippocampectomy (sSAH**) for **TLE** [8, 9]. **Figure 2** shows combined neuropsychological results of sSAH by Takaya (left panel) [8] and Hori (right panel) [9]. Both WMS-R and WAIS-R scores show significant improvements postoperatively comparing to preoperative levels. This is the difference between TSSAH and sSAH.

Usami et al. reported their operative results by transsylvian approach with multiple hippocampal transection and multiple subpial transection (MST) with lesionectomy (TSMHT +MST/L) technique [10] for TLE. As it is clearly shown, follow-up results show some deterioration of scores, especially VIQ. **Figures 2** and **3** show the difference of postoperative cognitive function between TSSAH MHT + MST/L and sSAH [8–10].

There were **chang**es in neuropsychological function after surgery on the verbally dominant side (n = 12). There were no significant differences between the preoperative indices and those at the last v**isi**t. The values were as follows (mean SD preoperatively, at the last v**isi**t; p-value): verbal memory (85 13, 78 18; 0.14), visual memory (94 24, 102 16; 0.08), general memory (85 16, 82 19; 0.29), delayed recall (79 18, 87 19; 0.09), attention and concentration (89 21, 88 22; 0.10). Regarding IQ, there was a significant difference in VIQ (87 19, 80 19; 0.045\*), but not in PIQ (89 28, 88 23; 0.42) or FIQ (86 25, 82 21; 0.16) [10].

#### **3. Subtemporal amygdalohippocampectomy**

There are many surgical techniques to cure medically intractable TLE such as conventional temporal lobectomy. But, concerning the language-dominant-side TLE without hippocampal sclerosis (PTLE) surgical removal of mesial temporal structures may result in neuropsychological problems, especially decline of verbal memory. Usually, temporal lobectomy 4–4.5 cm away from the temporal tip is used for language-dominant-side TLE [2]. Postoperative verbal memory decline is a major concern especially for language-dominant-side TLE without HS so-called PTLE [3, 7]. For mesial TLE of which amygdala and hippocampal head are epileptic foci, selective amygdalohippocampectomy is used by various routes including transsylvian, through superior temporal gyrus or sulcus (T1), middle temporal gyrus or sulcus (T2), and inferior temporal gyrus or sulcus (T3) depending on the preference of neurosurgeons (**Figure 4**). In 1993, subtemporal amygdalohippocampectomy (sSAH) technique has been introduced for mesial temporal lobe epilepsy to abolish postoperative neuropsychological deterioration observed in usual anterior temporal lobectomy [11]. The conventional subtemporal approach has been modified to diminish temporal lobe compression pressure and the risk of damage to the temporal stem. In this technique, the approach has been changed from usual anterolateral approach to posterolateral, thereby avoiding the voluminous and deeply embedded anterior temporal lobe in the middle fossa. By this approach, the retraction pressure is decreased and the temporal stem which is important bottleneck of temporal information were spared. To



*Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

#### **Figure 2.**

*Left panel adopted from Takaya et al. [8], and right panel from Hori et al. [9]. Left panel: cognitive improvement might result from a combined effect of good seizure control and minimize the regions of the brain with postoperative functional impairment. Improved cerebral function in terms of WMS-R scores in mesial temporal lobe epilepsy after sSAH was demonstrated [8]. Right panel: bar graphs showing changes in IQs in patients in whom the language-dominant and nondominant hemisphere was resected by sSAH [9].*

**Figure 3.** *Adopted from Usami et al. [10].*

*Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

#### **Figure 4.**

*A,B,C Microscopic procedure of subtemporal amygdalohippocampectomy. A: Temporal base is retracted, and fusiform gyrus is identified (double arrows). A small bridging vein was just riding on the collateral sulcus, and the vein is preserved. B: Fusiform gyrus, collateral sulcus is identified, and temporal horn is opened, then amygdala and hippocampal head are identified. At the choroid plexus (arrow head), the anterior choroid artery (arrow) is identified at the tips of the forceps. The suction tube touches the surface of the hippocampus. After the hippocampus (about 2.5 3.0 cm usually in length) anterior to the choroidal point is removed, the amygdala, the parahippocampal gyrus, and the uncus were removed, so that in every patient the amygdala can be removed* en bloc*, and neuropathologically is examined. It is different point between TSSAH and sSAH. C: After sSAH, PCA (black star), basal vein (small black star), optic nerve (short arrow), and anterior choroidal artery (long arrow) are well exposed.*

date, the authors using this approach have operated on more than 50 patients with medically intractable temporal lobe epilepsy whose epileptic foci were in the mesial temporal lobe structure; the inferior temporal gyrus, the temporal tip, the vein of Labbe, and the ventral bridging veins were preserved using with dissecting technique without adverse events. It can be used to remove as much of the posterior hippocampus as necessary, and it can be extended to conventional lobectomy if necessary. If there is some drawback in this approach, a part of basal temporal language area is sacrificed in order to reach temporal horn (**Figure 5A-C**). One patient among 50 patients with HS negative language-dominant-side TLE (PTLE) has shown postoperative severe memory deficits. Although the patient has shown gradual improvement of her memory in these 20 years during her postoperative period, she is still complaining of memory problem and it is compromising her daily job, even if operated upon by sSAH.

#### **4. Minimally invasive subtemporal approach**

Recently, Busby et al. [12] reported whole-brain tract changes after mapping and analyzed the potential impact of different surgical resection approaches for TLE. The main aim of this study was to perform systematic "pseudo-neurosurgery" based on existing resection methods on healthy neuroimaging data and measuring the effect on long-tract connectivity. They use anatomical connectivity mapping (ACM) to determine long-range disconnection, which is complementary to existing measures of local integrity such as fractional anisotropy or mean diffusivity. ACMs were generated for each diffusion scan in order to compare whole-brain connectivity with an "ideal resection," nine anterior temporal lobectomy and three selective approaches. For *en bloc* resections, as distance from the temporal pole increased, reduction in connectivity was evident within the arcuate fasciculus, inferior longitudinal fasciculus, inferior front-occipital fasciculus, and the uncinate fasciculus.

Increasing the height of resections dorsally reduced connectivity within the uncinate fasciculus. sSAH was associated with connectivity modes most similar to the "ideal" baseline resection, compared to TSSAH and middle-temporal approaches. In conclusion, Busby N, et al. showed the utility of ACM in assessing long-range disconnections/disruptions during temporal lobe resections, where they identified the sSAH as the least disruptive to long-range connectivity which may explain its better cognitive outcome. Of course, magnetic resonance (MR)-guided focused ultrasound treatment of mesial TLE is an ideal treatment if properly sonicated at the key structures of intractable TLE.

In 2021, Whiting AC and Smith KA, et al. [13] reported seizure and neuropsychological outcomes in a large series of selective amygdalohippocampectomies with a minimally invasive sSAH which is almost similar to our approach.

All patients in this study had at least 1 year of follow-up (mean [SD] 4.52 [2.57] years), of whom 57.9% (88/152) had Engel Class I seizure outcomes.

Engel's classification is as follows:

Class I: Seizure free or no more than a few early, nondisabling seizures; or seizures upon drug withdrawal only.

Class II: Disabling seizures occur rarely during a period of at least 2 years; disabling seizures may have been more frequent soon after surgery; nocturnal seizure.

Class III: Worthwhile improvement; seizure reduction for prolonged periods but less than 2 years.

*Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

*Types and Frequency of HS in our operative specimen in terms of ILAE Classification. HS type 1 (25 of 41 cases, 61%) is equivalent to 'classical' Ammon's horn sclerosis in which neuronal loss and gliosis is most severe in CA1, followed by CA3, CA4, with relative sparing of CA2 and often associated with loss of dentate granule cells and/or dispersion. HS type 2 represents neuronal loss and gliosis almost confined to CA1 (CA1 sclerosis), and only 1 case (2%) was identified in our study. HS type 3 (7 cases, 17%) is characterized by a reverse distribution of the sclerotic lesion to HS type 1, in which neuronal loss and gliosis is the most severe in CA4 followed by CA3, with relative sparing of CA2 and CA1, that is equivalent to endofolium sclerosis (EFS). In addition to these three HS types, we also identified 8 cases (19%) without apparent neuronal loss and gliosis (no HS).*

Class IV: No worthwhile improvement; some reduction, no reduction, or worsening are possible.

The patients with at least 2 years of follow-up (mean [SD] 5.2 [2.36] years), 56.5% (70/124) had Engel Class I seizure outcomes. Of the 152 patients with at least 1 year of clinical follow-up, only 38 (25%) completed both preoperative and postoperative neuropsychological testing by a neuropsychologist. The mean difference in scores was statistically significant in the dominant hemisphere group for the RAVLT–short delay test (p = 0.02) and the BNT (Boston Naming Test) (p = 0.04). The mean difference in scores was statistically significant in the nondominant group only with the BNT (p = 0.04). Many patients were unable to complete both preoperative and postoperative neuropsychological examinations for a variety of reasons. Concerning this decline, it might be influenced by some bias, that is, only 25% of all patients are examined, and a small number of neuropsychologically declined group of patients are prone to be examined.

Adverse events were low, with a 1.3% (2/152) permanent morbidity rate and 0.0% mortality rate.

This study reports a large series of patients who have undergone sSAH, with a minimally invasive technique. The sSAH approach described in this study appears to be a safe, effective, minimally invasive technique for the treatment of MTLE among the surgical methods ever reported in the literature.

#### **5. Neuropsychological results after subtemporal amygdalohippocampectomy**

In 2007, the authors [9] evaluated operative, neuropathological, and neuropsychological results after selective subtemporal amygdalohippocampectomy (sSAH) for refractory temporal lobe epilepsy in patients who were observed for at least 2 years after surgery. More than 26 consecutive patients underwent sSAH for non-lesional, medically refractory TLE. Neuropsychological evaluation using the Wechsler Adult Intelligence Scale (WAIS) was done before surgery in all patients, 2 months after surgery in 24 patients, and at 2-year follow-up in 19 patients. The data were compared between the 13 patients in whom the language-dominant hemisphere was surgically treated and the six patients in whom the languagenondominant hemisphere was treated. After surgery, 84% of the patients showed either Engel Class I or II seizure outcome. There were no permanent subjective complications except postoperative memory impairment in one patient with normal intelligence without HS. Neuropathological examination revealed HS in 19 patients. No significant differences in IQ and verbal memory test scores were observed between the patients in whom the language-dominant hemisphere was treated and those in whom the language-nondominant hemisphere was treated. One patient without HS whose language-dominant hemisphere was treated by sSAH, postoperative memory loss is only her complication. In this patient, although her memory has slightly improved, her job is compromised by memory loss. Considering this situation, neurosurgeons should explore better operative technique to escape from such postoperative memory loss, especially for language-dominant-side TLE without HS (PTLE).

Significant postoperative improvements in verbal IQ, performance IQ (PIQ), and full-scale IQ (FIQ) were observed over time. No significant differences were found between pre- and postoperative verbal memory test scores, and no subjective visual field loss was marked in any patient. Thus, sSAH provides good surgical and neuropsychological results and does not cause significant postoperative decline of verbal memory even if performed on the language-dominant side. In **Figure 2**, graphs depicting changes in IQs in patients in whom the language-dominant hemisphere was resected and patients in whom the language-nondominant hemisphere was resected, changes were time-dependent (VIQ, P = 0.0107; PIQ, p = 0.0002; FIQ, p = 0.0003), with no significant differences between the dominant and nondominant hemisphere groups (VIQ, p = 0.9102, PIQ, p = 0.7454; FIQ, p = 0.8361), and significant increases in VIQ, PIQ, and FIQ were observed over time.

Takaya et al. [8] evaluated the effects of sSAH on cerebral glucose metabolism and memory function in 15 patients with medically intractable MTLE with HS using [18F] fluorodeoxyglucose PET (FDG-PET) and the Wechsler Memory Scale-Revised (WMS-R). The patients were evaluated before and 1–5 years (mean 2.6 years) after surgery. In patients with MTLE of the language-dominant hemisphere, the basal temporal language area was preserved by this surgical approach. Postoperative glucose metabolism increased in extratemporal areas ipsilateral to the affected side, such as the dorsolateral prefrontal cortex, and the dorsomedial and ventromedial frontal cortices. Glucose metabolism also increased in the bilateral inferior parietal lobules and in the remaining temporal lobe regions remote from the resected mesial temporal region, such as the superior temporal gyrus and the temporal pole. By contrast, postoperative glucose metabolism decreased only in the mesial temporal area near the *Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

resected region. Postoperative verbal memory, delayed recall, and attention/concentration scores were significantly better than preoperative scores regardless of the resected side (**Figure 2** Left). This study suggests that the selective removal of the epileptogenic region in MTLE using subtemporal approach improved cerebral glucose metabolism in the areas receiving projections from the affected mesial temporal lobe. Cognitive improvement might result from a combination of good seizure control and minimize the area of the brain with postoperative functional impairment. Improved cerebral function in terms of WMS-R scores in mesial temporal lobe epilepsy after sSAH was demonstrated in **Figure 2** Left [8].

Judging from these figures, the difference between our neuropsychological results and Takaya's results is not clear, indicating that sparing incision of basal language area in Takaya's series may not influence the results.

#### **6. Histological classification of hippocampal sclerosis**

As demonstrated in **Figure 5**, HS type 1 (25 of 41 cases, 61%) is equivalent to "classical" Ammon's horn sclerosis in which neuronal loss and gliosis are most severe in CA1, followed by CA3, and CA4, with relative sparing of CA2 and often associated with loss of dentate granule cells and/or dispersion [14, 15]. HS type 2 represents neuronal loss and gliosis almost confined to CA1 (CA1 sclerosis), and only one case (2%) was identified in our study. HS type 3 (7 cases, 17%) is characterized by a reverse distribution of the sclerotic lesion to HS type 1, in which neuronal loss and gliosis are the most severe in CA4 followed by CA3, with relative sparing of CA2 and CA1, that is equivalent to endofolium sclerosis (EFS). In addition to these three HS types, we also identified eight cases (19%) without apparent neuronal loss and gliosis (no HS). Subiculum was relatively well preserved in all cases. Granule cell dispersion is one of the abnormal structural changes that has been shown in patients with temporal lobe epilepsy. In a normal situation, the granule cells in dentate gyrus should be tightly packed. But in granule cell dispersion, the compact formation was lost, and the axons need to extend longer to reach the neighboring granule cells. It might be a consequence of a migration disorder, and the first hypothesis considers an initial injury that releases toxin(s) that affect the normal migration of granule cells. The second hypothesis concerns the role of reelin. Reelin is required for normal neuronal lamination in humans, and the lack of this expression can lead to migration defect associated with temporal lobe epilepsy.

Types of HS did not correlate with age at operation and duration of illness, suggesting that these types represent distinct pathology of MTLE, the mean age of onset in patients with type 1 sclerosis tends to be younger than those at least with no HS but this is not statistically significant (Kruskal-Wallis test), the history of initial precipitating injury is not correlated with histological subtypes or postoperative seizure control, and type 1 sclerosis seems to correlate with better postsurgical seizure outcome than other types [14, 15].

The choice of the operative procedure is important factor affecting the seizure outcome, and that lateral temporal structure is also involved in the epileptogenicity in a subset of patients with MTLE (**Tables 2** and **3**).

In 2019, Seki et al. [16] reported an analysis of proliferating neuronal progenitors and immature neurons in the human hippocampus surgically removed from control and epileptic patients. Adult neurogenesis in the mammalian hippocampus is a wellknown phenomenon (**Figure 6**).



*Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*


#### **Table 3.**

*HS types and clinical features.*

#### **Figure 6.**

*Amygdala sclerosis. Amygdala sclerosis is detected in only one patient with HS type 1 (Table 2). Amygdala basolateral nucleus, Left: Nissl' stain, Right: glial fibrillary acidic protein (GFAP) stain.*

It remains controversial as to what extent adult neurogenesis actually occurs in hippocampus, and how brain diseases, such as epilepsy, affect human adult neurogenesis. We analyzed polysialylated neural cell adhesion molecule (PSA-NCAM) cells and proliferating neuronal progenitor (Ki67+/mammalian Hu protein B (HuB)+/ doublecortin (DCX) + cells in the surgically removed hippocampus of epileptic patients. In control patients, a substantial number of PSA-NCAM+ cells were distributed densely below the granule cell layer (GCL). In epileptic patients with granule cell dispersion, the number of PSA-NCAM+ cells were reduced, and aberrant PSA-NCAM+ cells were found. However, the numbers of Ki67+/HuB+/DCX+ cells were very low in both control and epileptic patients. The large number of PSA-NCAM+ cells and few DCX+/HuB+/Ki-67+ cells observed in the controls suggest that immature-type neurons are not recently generated neurons, and that the level of hippocampal neuronal production in adult humans is low. These results also suggest that PSA-NCAM is a useful marker for analyzing the pathology of epilepsy, but it is not evident that these bizarre PSA-NCAM neurons are the results or cause of intractable epilepsy (**Figure 7**). Different interpretations of the immunohistochemical results between humans and rodents should be examined in future.

#### **Figure 7.**

*In control patients, a substantial number of PSA-NCAM+ cells were distributed densely below the granule cell layer (GCL). In epileptic patients with granule cell dispersion, the number of PSA-NCAM+ cells were reduced, and aberrant PSA-NCAM+ cells were found.*

#### **7. Technique of the multiple hippocampal transection (MHT)**

The consequences of resection of the hippocampus, where its function is still preserved, can be a decrease in verbal memory or visual–spatial memory, intelligence, emotional and speech performance, as well as cognitive disorders. To solve this problem, Shimizu et al. [6] in 2006 reported the technique of the multiple hippocampal transection (MHT). The concept of MHT originated on the basis of multiple subpial transection in eloquent areas of the neocortex. Uda et al. [17] reported differences based on the surgical side: MHT on the nondominant side resulted in significant improvements in verbal but not visual memory, whereas MHT on the dominant side did not lead to significant increase in verbal or visual memory.

The principle of surgical treatment of mesial temporal lobe epilepsy by multiple transverse transection of the hippocampus is the mechanical disruption of the longitudinal pathways of the hippocampus.

Recent anatomical evidence suggests a functionally significant back-projection pathway from the subiculum to the CA1. A critical role for CA1-projecting subicular neurons in object-location learning and memory show that this projection modulates place-specific activity of CA1 neurons and their responses to displaced objects. Together, these experiments reveal a novel pathway by which cortical inputs, particularly those from the visual cortex, reach the hippocampal output region CA1. It is established that the hippocampus has two types of pathways: (1) trisynaptic pathways, which are located in parallel loops oriented orthogonally to the longitudinal axis of the hippocampus; (1) from entorhinal cortex to granule cell layer (perforant fiber), (2) from GCL to CA3 (mossy fiber), and (3) from CA3 to CA1 (Schaffer collateral fiber). These fiber systems are so-called trisynaptic circuit of the hippocampus (**Figure 1**).

There are two longitudinal pathways that run along the long axis of the hippocampus [7]. Loops of trisynaptic pathways going into the entorhinal cortex are important for processing and stabilizing memory. The longitudinal path of the hippocampus does not play an important physiological role; on the contrary, it facilitates the

*Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

**Figure 8.** *Multiple subtemporal hippocampal transection every 5 mm apart.*

synchronization of pathological epileptic discharges and their propagation along the hippocampus and, further, to extrahippocampal structures, thus contributing to the development of a seizure. For the pathological electrical activity in the hippocampal neurons to develop into an epileptic seizure, synchronization of the critical number of neurons – exceeding 5 mm thickness – located in the hippocampal segment is necessary. Therefore, if longitudinal horizontal interneuronal fibers along the axis of the hippocampus are separated with an interval of 5 mm, then the pathological connection is interrupted and, an epileptic seizure stop (**Figure 8**).

#### **8. The results of long-term changes in cognitive function after MHT on the verbally dominant side**

Usami et al. [10] reported the results of long-term changes in cognitive function after surgery on the verbally dominant side (n = 12). This clinical research is most recent and reliable because of containing fair number of verbally dominant side. There were no significant differences (**Figure 3**) between the preoperative indices and those at the last visit. Regarding intelligence, there was a significant difference in VIQ (8719,8019; 0.045\*), but not in PIQ or FIQ. They concluded that, in all neuropsychological batteries, the average indices declined temporarily at 1 month, recovered to the preoperative level at 6 months, and were maintained for a long time after MHT + multiple subpial transection/lesionectomy (MST/L). There were no statistically significant differences between the preoperative and last-visit values in all batteries. In three patients, verbal memory indices dropped >20 points from preoperative figures after >5 years. Although VIQ (verbal intelligence quotient) and FIQ (full-scale intelligence quotient) declined temporarily at 1 month, they recovered to preoperative levels at 6 months. PIQ (performance intelligence quotient) and FIQ were preserved at the last visit, whereas VIQ had declined at the last visit in comparison with that on the preoperative test (p = 0.045). Judging from these results, transsylvian approach

influenced this decline of VIQ comparing to our gain of VIQ for language-dominant side by sSAH operation (**Figure 2** Right Panel).

The important finding was that there was a significant discrepancy between memory indices and morphologic changes of the mesial temporal lobe and associated structures.

Memory preservation: postoperative cognitive impairment has been an important and controversial issue in the surgical treatment of mTLE. Patients with PTLE have a significant risk of postoperative memory decline. Long-term observation after medial temporal resection revealed that the memory impaired by surgery did not recover over time.

Although the Wada test (sodium amytal is injected into the internal carotid artery to induce a temporary state of hemianesthesia during which language and memory function of the unaffected hemisphere are tested) is not a reliable predictor of postoperative memory decline, Usami et al. recently demonstrated that parahippocampal high-gamma activity could provide predictive information about whether the mesial temporal lobe can be resected without causing memory decline.

The postoperative decline in verbal memory impairs cognitive performance in patients with MTLE. Verbal memory function after anterior temporal lobectomy or transsylvian SAH deteriorates at the group level in patients with dominant-side MTLE, whereas it tends to improve in patients with nondominant-side MTLE (Morino et al. [5]).

In our study, an improvement in verbal memory was observed regardless of the resected side. Previous studies have reported that sSAH might escape from verbal memory decline in patients with dominant-side MTLE [7, 18, 19]. Preservation of the basal temporal language area resulted in improved verbal memory 1 year after the operation, even when the anti-epileptic drug (AED) dosage remained unchanged. Mikuni et al. also shows a longlasting improvement in verbal memory following sSAH. The basal temporal language area is located between 10 mm and 75 mm posterior to the temporal tip and is important in processing verbal information. Verbal IQ is the ability to understand and reason using concepts framed in words, and it improved after 2 years. Performance IQ (PIQ) is designed to provide a measure of an individual's overall visuospatial intellectual abilities score and full-scale IQ (FIQ) which is an overall score as well as scores for component abilities. Both PIQ and FIQ improved after both 2 months and 2 years postoperatively.

#### **9. Subtemporal multiple hippocampal transection (New technique to preserve memory)**

In 2021, a 51-year-old man showing left amygdala enlargement with medically intractable epilepsy patient without hippocampal sclerosis (HS) was introduced to our clinic. FDG-PET analysis (**Figure 9**) showed left mesial temporal lobe epilepsy with normal intelligence; in this patient, the authors adopted subtemporal selective amygdalotomy with multiple hippocampal transections (**Figures 8** and **10**). He has shown improved neuropsychological examination scores 3 months after surgery, and intractable seizure stopped after surgery (Engel's Class I) and returned to his previous job immediately after the operation (**Figure 11**, **Table 4**).

#### **10. Pathophysiological characteristics associated with epileptogenesis in human HS**

In 2017, Kitaura et al. [20] reported pathophysiological characteristics associated with epileptogenesis in human HS. Majority of seizures originate primarily from the *Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

#### **Figure 9.**

*MR showing left amygdala enlargement, hyperintensity (FLAIR lower left and lower middle), and FDG-PET demonstrated hyper FDG activity at the amygdala (upper & lower right).*

hippocampus. They investigated epileptiform activities ex vivo using living hippocampal tissue taken from patients with MTLE. Flavoprotein fluorescence imaging and local field potential recordings revealed that epileptiform activities developed from the subiculum. Moreover, physiological and morphological experiments revealed possible impairment of K+ clearance in the subiculum affected by HS. K+ clearance is mainly regulated by astrocytes Kir 4.1 so that these findings indicate the role of astrocytes in epileptogenesis in HS. Stimulation of mossy fibers induced recurrent trans-synaptic activity in the granule cell layer of the dentate gyrus, suggesting that mossy fiber sprouting in HS also contributes to the epileptogenic mechanism presumably in addition to bizarre PSA-NCAM positive immature neurons observed in our specimen. These

#### **Figure 10.** *After amygdalotomy multiple hippocampal transections (blue line) were performed to hippocampal head.*

**Figure 11.**

*Postoperative MRI demonstrated removal of basolateral nucleus of amygdala and preservation of hippocampus by MHT.*


#### **Table 4.**

*Pre- and postoperative neuropsychological examinations showing improvement in this patient.*

*Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

#### **Figure 12.**

*Schematic representation of the results. (A) Control hippocampus showing anatomical orientation: from entorhinal cortex to granule cell layer (perforant fiber), from GCL to CA3 (mossy fiber), and from CA3 to CA1 (Schaffer collateral fiber). These fiber systems are called trisynaptic circuit of the hippocampus. Please refer to Figure 1. (B) No-HS. Enhanced activities are initiated in the subiculum and extend backward to the CA1. Please refer to Figure 8. (C) HS. Epileptogenesis in the subiculum and MFS in GCL are evident. Adopted and modified from Kitaura et al. [20].*

results indicate that pathophysiological alterations involving the subiculum and dentate gyrus could be responsible for epileptogenesis in patients with MTLE (**Figure 12**).

In the No-HS group also, the activities in the subiculum and CA1 were temporarily correlated with each other. The activity in the subiculum is always being followed by that in CA1, suggesting that activity generated primarily in the subiculum was able to propagate into CA1 via feedback projection from the subiculum to CA1.

The activity generated primarily in the subiculum was able to propagate into CA1 via feedback projection from the subiculum to CA1. Kitaura et al. proposed that minimally invasive surgical approach involving disconnection of the circuit between the subiculum and the CA1 might be effective to control seizure.

#### **11. New technique proposal for the language-dominant left TLE with HS (Type 1)**

A 31-year-old woman is introduced to our clinic for the management of intractable left TLE. Her MR demonstrated typical HS. In consideration of her intractability, the amygdalotomy and multiple hippocampal transection by subtemporal approach with disconnection of subiculum and CA1 are considered to

#### **Figure 13.**

*Operative pictures showing amygdalotomy and hippocampal transection by subtemporal approach with disconnection of subiculum and CA1. Upper left: collateral sulcus (aspirator and forceps) and temporal horn opened showing hippocampus and amygdala. Upper right: After amygdalotomy (removal of basolateral nucleus), internal carotid artery and anterior choroidal artery were seen beyond arachnoid membrane. Lower left: After multiple hippocampal transection (blue line), continuous disconnection (yellow line) between CA1 and subiculum from alveus to hippocampal sulcus (lower right schema, red arrow) was done.*

improve her seizure. Operative pictures show amygdalotomy and hippocampal transection by subtemporal approach with disconnection of subiculum and CA1 (**Figure 13**).

Postoperative neuropsychological examinations have improved already 1 day after the operation (Frontal Assessment Battery (FAB) and Hasegawa Dementia Scale (HDS)-Revised in **Table 5**), and seizure stopped. **Figure 14** demonstrated preoperative coronal T2W image and postoperative coronal T2W images,


#### **Table 5.**

*Results of preoperative and postoperative neuropsychological examinations in this patient.*

*Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

#### **Figure 14.**

*Preoperative coronal T2W images showing amygdala (upper left) and HS (upper right), and postoperative coronal T2W images showing amygdalotomy (lower left) and MHT and disconnection between CA1 and subiculum.*

showing amygdalotomy (lower left) and MHT and disconnection between CA1 and subiculum. Two months after surgery, neuropsychological examinations showed slight improvement comparing to preoperative levels (**Table 5** except FAB, HDS-R). Seizure control is satisfactory, and only two auras were seen during 1 year after the operation.

For disconnection between CA1 and subiculum for HS type 1, it is relatively easy to disconnect, because in HS type 1, CA1 is extremely atrophic and longitudinal limit of CA1 and subiculum is easy to identify.

#### **12. Conclusion**

1.Temporal lobe epilepsy, one of the most common forms of epilepsy involving limbic system and intractable for medical treatment, is the most challenging target for neurosurgeons, and various technical improvements are reported. Among these procedures, subtemporal selective amygdalohippocampctomy is seemingly least invasive in terms of neuropsychological function.


### **Abbreviations**


*Subtemporal Multiple Hippocampal Transection with/without CA1-Subiculum Disconnection… DOI: http://dx.doi.org/10.5772/intechopen.109549*

### **Author details**

Tomokatsu Hori1,2\*, Hideki Shiramizu2 and Hajime Miyata<sup>3</sup>

1 Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan

2 Department of Neurosurgery, Moriyama Neurological Center Hospital, Tokyo, Japan

3 Department of Neuropathology, Research Institute for Brain and Blood Vessels-Akita, Akita, Japan

\*Address all correspondence to: thori@moriyamaikai.or.jp

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[2] Wiebe S, Blume WT, Girvin JP, Eliasziw M. Effectiveness and efficiency of surgery for temporal lobe epilepsy study group: A randomized, controlled trial of surgery for temporal-lobe epilepsy. The New England Journal of Medicine. 2001;**345**:311-318

[3] Cohen-Gadol AA, Bradley CC, Williamson A, Kim JH, Westerveld M, et al. Normal magnetic resonance imaging and medial temporal lobe epilepsy: the clinical syndrome of paradoxical temporal lobe epilepsy. Journal of Neurosurgery. 2005;**102**: 902-909

[4] Marathe K, Alim-Marvasti A, Dahele K, Xiao F, Buck S, O'Keeffe AG, et al. Resective, ablative and radiosurgical interventions for drug resistant mesial temporal lobe epilepsy: A systematic review and meta-analysis of outcomes. Frontiers in Neurology. 9 Dec 2021;**12**. Article 777845. www. frontiersin.org. DOI: 10.3389/fneur. 2021.777845

[5] Morino M, Uda T, Naito K, Yoshimura M, Ishibashi K, Goto K, et al. Comparison of neuropsychological outcomes after selective amygdalohippocampectomy versus anterior temporal Lobectomy. Epilepsy & Behavior. 2006;**4**:95-100

[6] Shimizu H, Kawai K, Sunaga S, et al. Hippocampal transection for treatment of left temporal lobe epilepsy with preservation of verbal memory. Journal of Clinical Neuroscience. 2006;**13**:322-328

[7] Morino M. Surgical technique and neuropsychological outcome of transsylvian hippocampal transection in 26 patients with paradoxical temporal lobe epilepsy. Brain and Nerve (Japanese). 2011;**63**(4):347-354

[8] Takaya S, Mikuni N, Mitsueda T, Satow T, Taki J, Kinoshita M, et al. Improved cerebral function in mesial temporal lobe epilepsy after subtemporal amygdalohippocampectomy. Brain. 2009;**132**:185-194

[9] Hori T, Yamane F, Ochiai T, Kondo S, Shimizu S, Ishii K, et al. Selective subtemporal amygdalohippocampectomy for refractory temporal lobe epilepsy: operative and neuropsychologcal outcomes. Journal of Neurosurgery. 2007; **106**:134-141

[10] Usami K, Kubota M, Kawai K, Kunii N, Matsuo T, Ibayashi K, et al. Long-term outcome and neuroradiologic changes after multiple hippocampal transection combined with multiple subpial transection or lesionectomy for temporal lobe epilepsy. Epilepsia. 2016; **57**:931-940

[11] Hori T, Tabuchi S, Kurosaki M, Kondo S, Takenobu A, Watanabe T. Subtemporal amygdalohippocampectomy for treating medically intractable temporal lobe epilepsy. Neurosurgery. 1993;**33**:50-56

[12] Busby N, Halai AD, Parker GJM, Coope DJ, Ralph LMA. Mapping whole brain connectivity changes: The potential impact of different surgical resection approaches for temporal lobe epilepsy. Cortex. 2019;**113**:1-14

[13] Whiting AC, Chen T, Swanson KI, Walker CT, Godzik J, Catapano JS, et al. Seizure and neuropsychological

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outcomes in a large series of selective amygdalohippocampectomies with a minimally invasive subtemporal approach. Journal of Neurosurgery. 2021;**134**:1685-1693

[14] Hori T, Miyata H, Seki T. Surgical results of temporal lobe epilepsy based on ILAE hippocampal sclerosis classification and abnormal immature granule cells are specific to hippocampal sclerosis Type 1. Annal Epilepsy Seizures. 2018;**1**:1-6

[15] Miyata H, Hori T, Vinters HV. Surgical pathology of epilepsy-associated non-neoplastic cerebral lesions: A brief introduction with special reference to hippocampal sclerosis and focal cortical dysplasia. Neuropathology. 2013;**33**: 442-458

[16] Seki T, Hori T, Miyata H, Maehara M, Namba T. Analysis of proliferating neuronal progenitors and immature neurons in the human hippocampus surgically removed from control and epileptic patients. Scientific Reports. 2019;**9**:18194

[17] Uda T, Morino M, Ito H, et al. Transsylvian hippocampal transection for mesial temporal lobe epilepsy: Surgical indications, procedure, and postoperative seizure and memory outcomes. Journal of Neurosurgery. 2013;**119**:1098-1104

[18] Mikuni N, Miyamoto S, Ikeda S, Satow T, Taki Jn Takahashi J, et al. Subtemporal hippocampectomy preserving the basal temporal language area for intractable mesial temporal lobe epilepsy: Preliminary results. Epilepsia. 2006;**47**:1347-1353

[19] Miyamoto S, Kataoka H, Ikeda A, Takahashi J, Usui K, Takayama M, et al. A combined subtemporal and transventricular/transchoroidal fissure

approach to medial temporal lesions. Neurosurgery. June 2004;**54**(5): 1162-1167; discussion 1167-1169. DOI: 10.1227/01.NEU.0000119234.61432.E8

[20] Kitaura H, Shirozu H, Masuda H, Fukuda M, Fujii Y, Kakita A. Pathoohsiological characteristics associated with epileptogenesis in hippocampal sclerosis. eBioMedicine. 2018;**29**:38-46

#### **Chapter 9**

## Beyond Memory in H.M., The World's Most Famous "Hippocampal Amnesic"

*Donald G. MacKay*

#### **Abstract**

Patient H.M. (Henry Moliason) suffered a wide range of cognitive deficits attributable to the damage to his hippocampal formation but not to his well-established deficits in the ability to recall newly encountered facts, events, names, and objects, which formed the basis for his early diagnosis as a "hippocampal amnesic." Among Henry's "non-memory" or cognitive deficits that this chapter reviews are his impaired ability to create new and grammatical sentence plans, to identify who-did-what-towhom in novel sentences and to understand and read aloud novel sentences containing familiar words that he understood without difficulty in isolation, but not in novel sentence contexts such as metaphors. Also reviewed are his deficits in detecting novel forms concealed within complex visual arrays, in identifying anomalous objects in novel visual scenes, in detecting and describing what makes captioned cartoons funny, and in combining familiar concepts into new and useful ideas. The chapter concludes by relating Henry's non-memory deficits to fundamental questions of this book, for example, What is the role of the hippocampal formation in human memory and cognition? And how does the hippocampal formation work?

**Keywords:** patient H.M., the hippocampal formation, language deficits, visual cognition deficits, memory deficits

#### **1. Introduction**

William Scoville discovered the link between memory and the hippocampal formation by chance in 1953 after he met Henry Moliason (age 27) in his office at the Hartford Hospital in Connecticut. Asked to eliminate or at least reduce the intensity and frequency of Henry's life-threatening epileptic seizures, Scoville surmised that Henry's convulsions probably originated in his hippocampus (in the middle of the brain, roughly between the ears: See **Figure 1**). With consent from Henry and his parents, Scoville drilled small holes in Henry's skull above his eyes, and using X-ray imagery, inserted thin metal tubes into the hippocampal region, and suctioned out about half of Henry's hippocampal formation bilaterally while leaving his neocortex virtually intact.

#### **Figure 1.**

*The human hippocampus shown through a "window" into the medial temporal lobe. (Artist's rendition of an original illustration by Henry Vandyke Carter that appeared in Henry Gray's 1918 Anatomy of the Human Body.) Neither Henry's surgical damage nor the connections linking the hippocampus to surrounding structures in the hippocampal formation are shown.*

This experimental operation essentially cured Henry's epilepsy and perhaps saved his life. However, it immediately became clear that something was terribly wrong. Henry could no longer remember things he had done hours, minutes, or even seconds earlier. He could not even find his way back from the bathroom to his bed in the hospital [1].

Henry's memory problems became a source of intense scientific scrutiny that soon made him famous around the world as "patient H.M." However, Scoville informed other neurosurgeons that he had inadvertently removed the engine for forming new memories in Henry's brain and warned against applying his surgical procedure in future cases.

Over the next fifty years, Henry participated in hundreds of psychological experiments at the Massachusetts Institute of Technology (MIT), and after he died at age eighty-two, neuroscientists conducted sophisticated analyses of his brain (which he bequeathed to MIT) and wrote several books about how research with Henry helped advance the behavioral and brain sciences [1, 2]. I dedicated my own recent book to Henry, "an ordinary man who became famous by generously devoting his life to helping scientists understand his memory, mind, and brain, trusting in the promise that what they learned about him would "help others." [3]. Researchers reading the present review of Henry's contributions to understanding the role of the hippocampal formation in human memory, visual cognition, language comprehension, and language production clearly represent the type of "others" that Henry wanted to help.

However, three limits to the scope of this review deserve comment. It only reviews studies that report deficits attributable to Henry's damaged hippocampal formation (rather than to damage elsewhere in his brain, e.g., the cerebellum), studies that experimentally study Henry's cognitive deficits independently of his memory deficits (by presenting, e.g., continuously displayed text, instructions, and pictorial stimuli that participants need not commit to memory), and studies that

*Beyond Memory in H.M., The World's Most Famous "Hippocampal Amnesic" DOI: http://dx.doi.org/10.5772/intechopen.111609*

statistically compare performance for Henry versus control groups that resemble him in age, background, IQ, and education but lack damage in the hippocampal region. Also beyond the purview of this review are experiments with Henry not directly related to the memory versus non-memory issue (e.g., [4–11]), as well as the many experiments that established his famous deficits in recalling newly encountered names, facts, and events.

My UCLA lab conducted approximately twenty-five experiments with Henry at MIT and statistically compared his results in each study with those of 8–12 comparable control participants tested under similar conditions at UCLA.

#### **2. Henry's non-memory deficits**

This section reviews Henry's visual cognition, language comprehension, and sentence production deficits in studies that did not require the learning or recall of newly encountered names, facts, events, and objects (the classical definition of memory).

#### **2.1 Henry's visual cognition deficits**

Henry's performance on three tasks (hidden figure, what's-wrong-here, and visual cartoon comprehension) illustrate the general nature of his visual cognition deficits.

#### *2.1.1 Henry's hidden figure deficit*

Canadian neuropsychologist Brenda Milner accidentally discovered Henry's hidden figure deficit when trying to confirm her personal impression that Henry functioned without difficulty in his everyday visual world and only experienced problems when forced to remember where he had been or where he was going. To validate this impression, she had Henry complete the standard hidden figures test, a classic paperand-pencil measure of the ability to detect target figures camouflaged in complex visual scenes. On a typical hidden figures trial, instructions asked Henry to inspect a shape (shown to the left on a page) and trace that target shape hidden within a complex concealing array shown to the right. In a real-life analog of this task, soldiers try to detect an enemy combatant (the target) camouflaged in a forest (the concealing array). Unlike a soldier, however, Henry had to detect abstract target shapes that were unmoving, unfamiliar to him, and visible throughout each trial (rendering recall unnecessary).

Henry correctly traced significantly fewer camouflaged targets than the memorynormal controls, a deficit indicating serious impairment to his ability to consciously recognize forms in complex visual scenes. However, Millner and many other neuropsychologists ignored Henry's hidden figures deficit and continued to consider him a "pure memory" case, with memory problems but no cognitive deficits [12].

Undeterred by this lack of interest, my UCLA lab replicated and refined Henry's hidden figures deficit by adding a condition where participants traced *familiar* hidden targets, which were forms that Henry experienced frequently in daily life before and after his lesion, e.g., squares, circles, right-angle triangles [13]. In this *familiar* target condition, Henry and the controls correctly traced the same number of targets, a seemingly minor fine-tuning of Henry's hidden figure deficit that paved the way for theoretical ideas discussed in Section 5 about why Henry experienced the selective deficits in cognition and memory that he did.

However, for the standard *unfamiliar* target condition, control participants in our study [14] traced reliably more targets in the concealing arrays than did Henry, a replication of Milner's hidden figure deficit that addresses a hypothesis in Bussey et al. that perceptual deficits due to parahippocampal damage reflect a memory problem [15]. Henry's hidden figure deficit in our study clearly reflected a perceptual problem [16].

#### *2.1.2 Henry's what's-wrong-here deficits*

Having confirmed and honed Henry's hidden figures deficit, my UCLA lab re-examined Henry's perceptual world in other ways. One involved a children's game found in books such as *What's Wrong Here: Hundreds of Zany Things to Find*. These books display complex everyday scenes, for example, a school classroom containing over a hundred busy people and objects, some of which are erroneous or anomalous, say, a bird flying upside down in a fish bowl filled with water, or an impossible-toopen door with hinges on the same side as its doorknob. Children enjoy discovering what's-wrong-here in pictures.

In our laboratory version of the game, Henry and suitable control participants inspected a series of what's-wrong-here pictures, circled as many erroneous objects as possible within each picture, and explained why each circled object was anomalous within a generous time limit [17].

Henry correctly circled significantly fewer erroneous objects than the controls, and he misidentified many of his circled objects without correcting himself, something the controls never did. For example, Henry called a clearly drawn rabbit "a dog" and called an ordinary wastebasket on the floor beside a teacher's desk "a window." Because Henry always correctly identified the identical objects *when depicted in isolation in a subsequent test*, Henry's object identification errors were clearly specific to the what's-wrong-here scenes, consistent with a problem in disentangling unfamiliar forms from their unfamiliar surroundings in complex visual displays, as in the original hidden figure test [18].

#### *2.1.3 Henry's cartoon comprehension deficits*

New higher-level deficits in Henry's visual cognition and sentence comprehension emerged in an experimental test of his ability to understand captioned cartoons [19]. Participants in this UCLA study saw a sequence of cartoons with instructions to explain what made them funny and to read aloud their captions (which only contained words Henry knew before his surgery). One example is Gary Larson's cartoon, "Raising the dead," which depicts two women in armchairs chatting —a normal scene except that both are *ghosts*. A ghost woman named Edith is listening to the other complain about problems raising her ghost children, Billy and Sally. Illustrating her difficulties, the cartoon shows Sally floating head first down a stairway, while Billy flits aimlessly around the room. The caption reads: "Oh, I don't know. Billy's been having trouble in school and Sally's always having some sort of crisis. I tell you, Edith, it's not easy raising the dead."

Control participants in this study consistently detected humor in the cartoons and never misread their captions in ways that would preclude comprehension of why they were funny. Not Henry. For example, Henry misread the Larson caption as, "I tell Edith it's not [long pause] easy, the raising the dead," messing up the sentence prosody and omitting the critical word *you* in *I tell you, Edith, it's not easy raising the* 

*Beyond Memory in H.M., The World's Most Famous "Hippocampal Amnesic" DOI: http://dx.doi.org/10.5772/intechopen.111609*

*dead,* all without self-correction. Henry apparently thought the speaker was talking to someone not depicted in the cartoon, rather than to Edith, the ghost mother seated beside her.

Henry's uncorrected caption-reading errors did not just render full understanding of cartoons impossible. They also suggested an inability to grasp *who-said-what-towhom* in the cartoons*,* reflecting a serious comprehension deficit that my UCLA lab established in a subsequent study (described shortly).

Nor was confusion about who spoke to whom Henry's only problem. He did not grasp what the cartoons were about, another basic prerequisite to getting the jokes. For example, Henry did not see that the Larsen cartoon depicted ghosts. Noting that he could see through Larson's ghost-speaker to the armchair on which she sat, Henry suggested that the cartoonist had drawn her wrong and complained that "she" (the cartoonist) just "bl. .. the. .. blackens the whole way, and everything.. ." using some kind of "blackening rule." Unlike Henry, the control participants never misidentified visual forms in the cartoons nor mistakenly ascribed an outline to artistic error.

#### **3. Henry's language comprehension deficits**

Consistent with Henry's caption-reading errors, four sources of evidence indicated deficits in Henry's ability to comprehend and read aloud various types of sentences, a skill he mastered in grade school and high school, many years before his age 27 surgery.

#### **3.1 Deficits in identifying who-did-what-to-whom in sentences**

Henry's failure to comprehend who-did-what-to-whom in Larson's cartoon echoed an important finding in a 1966 experiment that I conducted at MIT [20]. In that study, Henry saw various types of ambiguous sentences on cards with instructions to describe the two meanings of each sentence as quickly as possible. Henry readily detected both meanings in some types of ambiguous sentences, but relative to controls, he displayed a major deficit in detecting the dual meanings of sentences resembling *John is the one to help today,* where *John should help us* is one meaning and *we should help John* is the other*.* Henry clearly had a problem working out who-didwhat-to-whom in ambiguous sentences.

But could Henry understand who-did-what-to-whom in *unambiguous* sentences? To find out, my UCLA lab ran an experiment in which Henry and memory-normal controls read unambiguous sentences on a computer screen, one at a time, and then answered a multiple-choice comprehension question displayed on the same screen [21]. For example, after reading *The water that the mother spilled surprised the young child*, participants answered the comprehension question *who spilled the water: the mother, the young child, or nobody*? Control participants correctly answered significantly more comprehension questions than Henry, firmly establishing a deficit in his ability to understand the most important information that sentences can convey: who-does-what-to-whom [22].

#### **3.2 Deficits in reading sentences aloud**

Can Henry comprehend and accurately read aloud the individual words in unambiguous sentences? To find out, my UCLA lab first had participants read lists of familiar words presented one at a time on cards, for example, *GOT, ATE, STOMACH, HOT, WHO, DOGS, ACHES, BOYS, and THE*. Henry made no more mistakes than the controls when reading those isolated words.

Days later, however, Henry experienced major deficits when asked to read the same words re-organized into sentences, for example, *the boys who ate hot dogs got stomach aches,* instead of GOT*, ATE, STOMACH, HOT, WHO, DOGS, ACHES, BOYS, and THE.*

Unlike the controls, Henry now made dozens of uncorrected reading errors that rendered his utterances ungrammatical. He also paused abnormally at critical points within the sentences, for example, misreading *The boys who ate hot dogs got stomach aches* as *The boys* [unusually long pause] *ate hot dogs got stomach aches* (Note Henry's ungrammatical omission of the word *who*) [23].

#### **3.3 Deficits in comprehending metaphors**

Metaphors, such as *Life is a Journey,* are powerful linguistic tools. They shape everyday thinking and help people comprehend and learn ideas that are otherwise difficult to acquire [24]. Can Henry comprehend metaphors? To answer this question, my UCLA lab asked Henry and suitable controls to indicate what metaphoric sentences mean. On each trial, participants saw a short metaphoric sentence on a computer screen with instructions to choose the best of three possible ways to interpret it. By way of illustration, these were the three choices for the metaphor *Maybe we should stew over his suggestion*:


The memory-normal controls chose the correct metaphoric interpretation reliably more often than Henry, indicating a deficit in his ability to comprehend metaphors. Indeed, Henry performed worse than chance (random guessing) because he usually chose the incorrect interpretation with the same critical word as the target sentence; here the word *STEW* capitalized in the original metaphor *Maybe we should STEW over his suggestion* and the incorrect literal interpretation: *Let us make sure to cook the STEW long enough* [23]. Henry clearly understood the *individual words* but not the overall meaning of the metaphoric sentences.

#### **3.4 Deficits in detecting what's right versus wrong in sentences**

Another UCLA study tested whether Henry could distinguish between grammatical versus ungrammatical sentences. He could not. Asked to respond "Yes," to grammatical sentences such as *She hurt herself,* and "No," to ungrammatical sentences such as *He hurt herself*, Henry answered correctly significantly less often than suitable control participants, with performance close to chance (50%). Henry clearly had a deficit in comprehending whether sentences are grammatical versus ungrammatical [25].

*Beyond Memory in H.M., The World's Most Famous "Hippocampal Amnesic" DOI: http://dx.doi.org/10.5772/intechopen.111609*

Did he fail to understand the instructions? Did he not care? To find out, my UCLA team reran the previous study, adding foil sentences and a test for guessing. The foil sentences thoroughly shuffled the words in grammatical sentences such as *She has decided to buy a house*, yielding ungrammatical strings such as *Decided has house she a buy to*. Like the control participants, Henry invariably called these foils ungrammatical, indicating clear comprehension of the instructions.

To assess guessing, the experimenter immediately asked participants who responded, "No, ungrammatical," to identify the wrong or misplaced word and then correct that word to make the sentence grammatical. This was easy for the control participants. For example, after identifying *be* as the misplaced word in *Will be Harry blamed for the accident*, they quickly produced a corrected version such as *Will Harry be blamed for the accident.*

Not Henry, however. He called correct words incorrect and failed to correct words he deemed wrong. For example, Henry identified *blamed* as the incorrect word in *Will be Harry blamed for the accident*, but insisted that further information about the blame was needed to correct this error. Henry was indeed guessing when he called sentences ungrammatical.

#### **4. Henry's language production deficits**

Many sources of evidence indicate that Henry suffered language production deficits. Length constraints limit us to just one source here: His performance on the standardized test of language competence (TLC) [26]. In a typical TLC trial, participants see two words above a picture, together with continuously displayed instructions to use both words in a single grammatical sentence that accurately describes the picture.

Control participants found this task easy. For example, asked to use the words *ALTHOUGH* and *WRONG* in a single grammatical sentence that describes a woman in a sports store discussing a tracksuit with a salesman, one control participant quickly responded *The woman decided to buy the suit ALTHOUGH it looked WRONG.* A panel of judges blind to speaker identity later rated this transcribed response 100% correct on the three evaluative dimensions shown in **Table 1**.

**Table 1** also shows Henry's response to the same sportswear picture: "*Because it's wrong for her to be he's dressed just as this that he's dressed and the same way*," a response that the panel of judges rated as inaccurate, ungrammatical and incoherent, and a rambling series of non sequiturs (see **Table 1**). Across all trials, Henry included significantly fewer must use words than the controls, and the panel of judges rated his utterances ungrammatical, inaccurate, or incoherent significantly more often than those of the controls.

Why did Henry include significantly fewer must use words in his utterances than the controls? The coherence rating for Henry's utterance in **Table 1** suggests one reason. Henry was freely generating familiar phrases (e.g., *the same way*) without relating the picture to the must use words, a free association strategy that may also explain why the judges more often considered Henry's TLC descriptions incoherent, ungrammatical, and inaccurate.

Did the damage to Henry's hippocampal formation shape his free association strategy? Almost certainly. Henry could easily retrieve phrase memories formed before his age 27 surgery, for example, the common phrase *the same way*. However,


#### **Table 1.**

*An illustrative TLC trial, with scene description, must use words, the completely correct response of a control participant, and Henry's response, rated on three evaluative dimensions and scored for inclusion of the must use words.*

the damage to his hippocampal formation prevented him from forming new and situation-appropriate phrases and sentences. How do we know? Because my UCLA lab analyzed hundreds of unintended and uncorrected errors that rendered Henry's TLC utterances ungrammatical, inaccurate, and incoherent errors that speak volumes about how the hippocampal formation goes about creating new memories in the cortex.

Henry's TLC errors fell into two categories: *Omissions* (where participants omit units that are essential in a grammatical sentence) and C*ombination errors* (where participants conjoin two or more units into a sequence that is impermissible or ungrammatical). **Table 2** illustrates both types of error in an utterance Henry produced on a single TLC trial. The TLC picture shows three people: a woman server at a cafeteria counter, a man ordering food from her, and a woman ahead of him in line who already has the food she ordered on a tray. *PIE* and *EITHER* are the must use words.

To describe this scene, a typical control participant produced both must use words in a single grammatical sentence, for example, "*I want* either *some* pie *or some cake"* (see **Table 2**)*.* Not Henry, however. Instead of his intended utterance, *I want some of what she had*, Henry said "I want some her [long pause] what she had" (see **Table 2**).

How did this study determine what participants intended, planned or wanted to say? Determining what *normal participants* intended to say after they made an error was easy. Our experimenters simply asked them what they meant or noted how they spontaneously corrected their errors. For example, a normal speaker who says *Put it on the chair, I mean table*, clearly intended to say, *Put it on the table*. These scoring procedures indicated that control participants occasionally produced omission errors on the TLC but made no category-combination errors whatsoever.

For the hundreds of errors that Henry produced on the TLC, however, determining intent was more challenging because Henry never spontaneously corrected his omission and category-combination errors and never clarified what he meant to say when asked [27]. My UCLA lab therefore developed and adopted a more general set of


#### **Table 2.**

*Omission and combination errors illustrated in a single TLC trial, with scene description, must use words, and Henry's errors analyzed by comparing his actual versus intended utterance and the correct response of a typical control participant.*

scoring procedures that allowed us to specify participants' intent (independent of the speaker) as the "best possible correction" of an anomalous utterance (see [28]).

Henry's missing word *of* is clearly an omission error that renders his utterance ungrammatical (see **Table 2**). However, why is his phrase "*SOME HER*" ungrammatical? The reason is that only common nouns (e.g., *fun* and *games*) can follow an indefinite determiner such as *some* in grammatical English sentences (e.g., *We played some games and had* s*ome fun)*. When the pronoun *her* follows *some* in a phrase, an utterance becomes ungrammatical.

Another important observation about Henry's *SOME HER* is that the word *HER* intrudes some aspect of the upcoming word *SHE* in Henry's intended utterance*, I want some of what SHE had*. What aspect of *SHE* intruded? It was not its syntax because unlike *SHE*, *HER* is a possessive pronoun. It was not its speech sounds because *SHE* and *HER* share no speech sounds whatsoever.

Rather Henry's *HER* almost certainly reflects intrusion of the *CONCEPT* "female," which underlies three aspects of what he was trying to say: the forthcoming word *SHE* in his intended utterance, the lady server in the TLC picture, and the woman leaving with food on her tray, an analysis suggesting that Henry's TLC errors may reflect a breakdown in the uniquely human ability to combine conceptual units when creating situation-appropriate sentences such as *I want some of what she had*.

The next section expands on this idea, arguing that Henry's errors lay bare the sophisticated and elegant functions of the neural machinery that allow the human hippocampal formation to conjoin smaller concepts into larger internal representations in the cortex including internal representations for comprehending, perceiving, remembering and describing experiences, and events and the visual world.

#### **5. The hippocampal formation in cognition and memory: Lessons from H.M**

What possible lessons can the Brain and Cognitive Sciences take from the research with Henry reviewed here? This section outlines five categories of lessons: 1).

Different brain mechanisms create new memories versus retrieve old or preformed ones, 2). Distinguishing between pre-formed versus newly formed memories in the brain can be tricky, 3). The hippocampal formation performs the same basic function in visual cognition, language comprehension, and language production, 4). And performs the same basic function in memory for facts, names, events, and common objects, and 5). Lessons from future tests of hypotheses derived from research with Henry reviewed here.

#### **5.1 Distinct mechanisms create new memories vs. retrieve old ones**

Why did Henry misread the sentence, The boys who ate hot dogs got stomach aches, as the boys ate hot dogs [abnormally long pause] got stomach aches (omitting the critical word WHO), whereas he easily and correctly read the same words presented one at a time in isolation, for example, GOT, ATE, STOMACH, HOT, WHO, DOGS, ACHES, BOYS and THE?

This type of finding (repeated across every domain of cognition that we have examined with H.M.) indicates that mechanisms in the hippocampal formation create new internal representations, whereas a separate mechanism located elsewhere retrieves old or pre-formed neural representations. For example, current evidence indicates that memories for familiar words reside in the language areas of the neocortex whereas mechanisms for retrieving those words reside in the frontal lobes. Because Henry's frontal lobes and cortical language areas were intact, he could, therefore, retrieve and read without difficulty isolated words learned before his surgery.

However, word retrieval is insufficient to make novel sentences sound like sentences when reading aloud. Engaging the hippocampal formation to create new internal representations of the relations between words and phrases in novel sentences is necessary to do this. For example, to correctly read the sentence *The boys who ate hot dogs got stomach aches,* the hippocampal formation must create three new neocortical phrase units to represent *the boys, ate hot dogs*, and *got stomach aches*, and to signal the relations between them by adding the word *who* and inserting pauses of varying lengths, as in *The boys* [short pause] *who ate hot dogs* [major pause] *got stomach aches*. The damage to Henry's hippocampal formation, therefore, prevented him from doing this.

Nevertheless, Henry deserves thanks for *trying* to read the sentences as sentences. He might have adopted a word-by-word reading strategy throughout our reading studies, pausing after each word in the sentences as if reading a list. This strategy would have precluded the mysterious pauses and word omissions that my lab was at pains to explain. Because Henry did not adopt this strategy, science now has a clear understanding of how the hippocampal formation contributes to normal sentence reading.

#### **5.2 New versus old memories in the brain: Lessons from H.M.**

The distinction between new versus old or preformed memories in the brain was a source of confusion in early research with Henry. For example, Dr. Brenda Milner, the famous Canadian neuropsychologist, defined any never previously encountered stimulus as *new*, an assumption that led her to falsely conclude that the hippocampus plays no role in processing new perceptual information. To refine Milner's new versus old definition and demonstrate the critical role of the hippocampal formation in novel perceptual processing required decades of research.

#### *Beyond Memory in H.M., The World's Most Famous "Hippocampal Amnesic" DOI: http://dx.doi.org/10.5772/intechopen.111609*

To see why, consider in detail the Gollin fragmented-figures test of perceptual abilities that Milner administered to Henry and memory-normal controls in the 1960s. On the first trial of this test, participants see a picture of a familiar object, say, an elephant, that is so fragmented that nobody can correctly guess what it is. In subsequent trials (2–5), participants see the same picture with progressively less fragmentation until everyone can correctly identify version 5. The participant's goal is to correctly name all of the fragmented objects in as few trials as possible.

The results indicated that Henry could initially identify a fragmented image as readily as controls, even though that exact fragment pattern had not been viewed before. Her conclusion: Henry's hippocampal lesion did not prevent him from processing new perceptual information.

But were the fragmented pictures *as overall stimulus patterns* really the basis for participants' responses? It seems more likely that they correctly guessed, for example, "elephant*,"* as soon as a fragment in the progressively less fragmented picture of an elephant revealed a unique elephant feature, say, its distinctive tusk, trunk, or tail. If so, Henry's non-deficit merely indicates what the present research has shown: that retrieving and recognizing visual features that Henry acquired long before his lesion does not require hippocampal engagement. Based on his childhood experiences with elephants and elephant pictures, Henry could respond "elephant" with no need to create a new internal representation for the complete fragmented elephant picture *per se*.

We can, therefore, return to the original question: Does hippocampal engagement play a role in processing new perceptual information? Results from two other conditions in Milner's fragmented-figure study suggest that maybe it did. One involved a simple rerun of the test one hour later. When Milner's participants again saw the same progressively less fragmented pictures repeated, performance improved significantly more for the memory-normal controls than for Henry. Why? Milner suggested that the normal controls achieved this benefit by learning the verbal labels of the Gollin figures during the first test, allowing them (but not Henry because of his verbal memory deficits) to quickly sample from the correct population of names on the retest. However, another retest 20 weeks later contradicted this name recall hypothesis. Although interference should have obliterated Henry's memory for the names by then, Henry performed better on the hidden figure test after the 20-week delay than after the one-hour delay.

Finally, Milner's results do not contradict a plausible alternate hypothesis that the intact hippocampal system of the normal participants created new internal representations of the evolving perceptual information on the fragmented-figures test so that they (but not Henry) could remember how, say, fragments of the elephant's trunk evolved from unrecognizable to recognizable as the elephant picture became progressively less fragmented, thereby enabling faster correct recognition of the objects *per se* (and not just their names).

In summary, the distinction between new versus old in cognition and the brain is subtle, multidimensional, and dependent on the *functional* stimuli in a task. The functional stimuli can be new when normal participants initially experience a sequence of hidden figures but not when they experience the same sequence a second time. Similarly for reading isolated words versus sentences. To read isolated words, listlike prosody (fixed pause durations between the words) suffices, but instructions to correctly read a novel sentence creates a functionally different stimulus that requires speakers to compute the relations between words in the sentence and adjust their prosodic intonation and pause lengths accordingly.

Another important dimension to the new versus old distinction is the state of a participant's memories. To count as old rather than new, a stimulus must have an internal representation in the participant's brain that is *pre-formed and functional for the task at hand.* In a lexical decision task, for example, where participants must respond YES to words and NO to nonwords, a once familiar but now forgotten word can represent a new rather than old stimulus if aging and infrequent use has degraded the participant's internal representation for that word (see e.g., [29]).

#### **5.3 The hippocampal formation functions similarly across different cognitive domains**

Despite obvious differences in how language comprehension, sentence planning, and visual cognition are tested, Henry's deficits indicate that the hippocampus serves to create new internal representations in all three domains. For example, Henry's deficit in the standard hidden figures test indicated that lacking a hippocampus, he could not form the new internal representations required to detect unfamiliar targets in concealing arrays. However, he readily detected familiar targets, for example, squares, circles, and right-angle triangles, because he acquired pre-formed internal representations of those target forms long before the lesion to his hippocampal formation.

Henry's deficits in detecting anomalous objects in what's-wrong-here scenes, for example, an impossible-to-open door with hinges on the same side as its doorknob, demands a similar account. For Henry, an impossible-to-open door looks normal because, lacking an intact hippocampal formation, he could not form a new internal representation of the novel relations between hinges and doorknob that distinguish normal from impossible doors.

Henry's language comprehension deficits require a similar account. For example, grammatical sentences such as *She hurt herself* and ungrammatical sentences such as *He hurt herself* were equivalent for Henry because, without a functional hippocampal system, he could not form new internal representations of the relations between the words in either type of sentence. Similarly for metaphors, Henry's damaged hippocampal system prevented him from creating the new internal representations required to comprehend one kind of event, for example, *taking the time to talk and think about something*—in terms of another— *cooking slowly, as with a stew* in the metaphoric sentence *Maybe we should stew over his suggestion*.

Similarly in language production. Why did Henry produce hundreds of ungrammatical utterances on the TLC, saying, for example, "I want some her [long pause] what she had," when asked to use two continuously displayed words in a single grammatical sentence describing a picture of a man, a cafeteria counter, and a woman with food on a tray? The answer is that without an intact hippocampal formation, Henry could not relate the TLC picture to the must use words in order to create a new internal representation for producing grammatical sentences such as *I want either some cake or some pie.*

#### **5.4 The hippocampal formation functions similarly in cognition and the classical domains of memory**

To compare how the hippocampal formation functions in cognition (previous section) versus the four classical domains of memory, this section examines the role of the intact hippocampal system in creating memories for newly encountered facts, names, events, and objects.

*Beyond Memory in H.M., The World's Most Famous "Hippocampal Amnesic" DOI: http://dx.doi.org/10.5772/intechopen.111609*

**Memory for facts.** How would a young child form a memory for 2x2 = 4 as a newly encountered fact? Via hippocampal engagement that creates a new internal representation resembling a sentence that means *Two multiplied by two is four*.

**Memory for names.** How would normal speakers of English create an internal representation of the newly encountered name of my son: *Ken MacKay*? Via hippocampal engagement that simultaneously and powerfully activates two preformed units in the cortex, one representing his familiar given name, *KEN*, and the other representing his family name, MACKAY (familiar to anyone reading this chapter)*.* The powerful co-activation of these preformed units will quickly create strong new synapses that link *KEN* and *MACKAY* to a new or "uncommitted" neural unit that will represent his combined first and last names.

However, weak new connections can also be formed *without hippocampal engagement* when preformed units are repeatedly activated over prolonged periods of time. This explains why, for example, Henry slowly came to recognize and occasionally use the name *Suzanne Corkin* after encountering her name virtually daily over decades, one of many observations suggesting that normal hippocampal engagement simply speeds up the fundamental process of massive repetition that underlies all new connection formation.

**Memory for events**. How would a normal adult form memories of recently experienced events such as a *visit to the dental clinic*? Via hippocampal engagement that creates an internal representation that conjoins neural units in event categories such as [actor] + [action] + [where] + [when], much like the hippocampal engagement process that creates sentences such as *I stupidly scheduled my dentist for that day* or *He happily clobbered the ball out of the stadium:* by conjoining neural units in the linguistic categories [pronoun] + [adverb] + [verb] + [noun phrase] + [prepositional phrase].

**Memory for common objects.** How do children create memories for frequently encountered objects such as a classic American penny? By engaging their hippocampus to form an internal representation that is good enough to distinguish pennies from other coins and objects. This good enough internal representation consists of a surprisingly small number of perceptual features, for example, *small, round, coppercolored,* and *engraved with the profile of Abraham Lincoln* that children then use to guide their subsequent interactions with pennies [30, 31].

As a consequence, naturally acquired penny memories are quite unlike an eidetic image in the brain that one might inspect and report as an adult. Such an eidetic image would include at least 37 penny features resembling those in **Table 3** below (all of which are easy to see in the photographs of a penny shown in **Figure 2**).

So children's ability to recall only three or four features of a penny represents an accuracy level of about 10%, and *adult* participants in memory experiments, e.g., [32], achieve a *similar accuracy level*, reflecting virtually no improvement relative to children. Why do decades of everyday interactions with pennies yield so little learning? The reason is that adults only rarely, if at all engage their hippocampal formation to add new penny features to their "good enough" internal representation of a penny that they formed as children and have continued to use in everyday financial transactions since then.

#### **5.5 Possible lessons from future tests of hypotheses derived from research with Henry**

New lessons for the field may come from future tests of hypotheses derived from the research with Henry reviewed here. To illustrate just one of many such testable hypotheses, consider the claim in Section 5.1 (on Memory for names) that engagement


#### **Table 3.**

*Thirty-seven Features of a Classic American Penny, with major features in caps and subordinate and minor features in lower case. To verify the features, see the photographs in Figure 2.*

**Figure 2.** *Photographs that verify the 36 penny features analyzed in Table 3.*

#### *Beyond Memory in H.M., The World's Most Famous "Hippocampal Amnesic" DOI: http://dx.doi.org/10.5772/intechopen.111609*

of activating mechanisms in the hippocampal formation serves to simultaneously and powerfully activate two preformed units in the cortex, thereby quickly creating strong new synapses that link both preformed units to a new or "uncommitted" neural unit that constitutes the internal representation for a newly encountered name such as *Ken MacKay*. A future study employing advanced technology will be able to test whether two preformed units in the cortex become simultaneously and powerfully activated when participants learn a newly encountered combination of familiar proper names. That same study will also be able to determine whether the strong co-activation of those preformed cortical units originated somewhere within the hippocampal formation. And the study that reports both of these hypothetical results will feature H.M. in its reference section. So will a possible follow-on study that precisely localizes where in the hippocampal formation the mechanisms for co-activating proper names are located.

#### **6. Conclusions**

In addition to his well-known deficits in memory for newly encountered names, events, facts, and objects, H.M. experienced a wide range of non-memory deficits reviewed here. Four conclusions emerged: 1). The hippocampal formation creates new internal representations in the cortex for comprehending novel linguistic information, perceiving novel visual forms, and creating novel sentences, 2). The hippocampal formation likewise creates new internal representations for freshly encountered facts, names, events, and objects, the classical domains of memory, 3). The hippocampal formation does not store preformed memories, nor is it essential for their retrieval. Mechanisms for retrieving preformed internal representations from the cortex reside elsewhere in the brain, for example, the frontal cortex, 4). Finally, Henry's contributions to the Brain and Cognitive Sciences seem unlikely to end soon as future studies continue to test hypotheses derived from research with Henry, especially recent hypotheses about how the hippocampal formation works in memory, visual cognition, language comprehension, and sentence production.

#### **Author details**

Donald G. MacKay Psychology Department, University of California Los Angeles, CA, USA

\*Address all correspondence to: mackay@ucla.edu

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### *Edited by Douglas D. Burman*

Ever since side effects from bilateral hippocampectomy were identified in Henry Molaison (patient "HM") during the 1950s, a critical role of the hippocampus has been recognized in the formation of declarative episodic memories. Other cognitive functions have since been proposed, such as a role in navigation, but memory has often been suggested to explain hippocampal involvement. Proving a distinct functional role in cognition is difficult, as memory can be implicated in most cognitive activities. Even when a behavior relies on memory, however, the functionality of the hippocampus extends far beyond, especially evident during activities requiring interactions between cognitive systems. Relational memory is supported by hippocampal connections with widespread regions of the cortex; these interconnections also play a fundamental role in children's writing abilities and expertise in musical performance. Besides enhancing individual lives, such activities can play a vital role in sustaining cultural values across generations. Interactions with the environment that do not directly depend on mnemonic activity can affect plasticity in hippocampal connections, modified through natural chemicals, pharmacological drugs, and non-pharmacological behaviors. Navigational properties of the hippocampal system are not limited to memory, containing the same navigational elements as our Global Positional System (GPS). Even cognitive deficits arising from hippocampal lesions in "HM" were not limited to memory, as they included deficits in understanding cognitive relationships available in visual scenes, novel sentence contexts, and humorous situations. This book shows an expansive role of the hippocampus in cognition that goes beyond its recognized role in generating new episodic memories.

Published in London, UK © 2023 IntechOpen © Jezperklauzen / iStock

Hippocampus - More than Just Memory

Hippocampus

More than Just Memory

*Edited by Douglas D. Burman*